JP7748616B2 - Liquid-filled combination container, container set, and method of manufacturing liquid-filled container - Google Patents

Description

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

Containers for storing liquids are known (see, for example, Patent Document 1). Depending on the type of liquid, oxygen can cause the liquid to decompose inside the container. To address this issue, it is possible to use containers with oxygen barrier properties.

JP 2011-212366 A

However, oxygen can dissolve in the liquid during production. Containers with oxygen barrier properties cannot address liquid deterioration caused by dissolved oxygen. In other words, conventional technology cannot adequately suppress oxygen-induced deterioration of liquids stored in containers. The present disclosure aims to suppress oxygen-induced deterioration of liquids.

A first liquid-containing combination container according to the present disclosure comprises:
a first container containing a liquid of volume γ (mL) and at least a portion of which is oxygen permeable;
a second container that houses the first container and has oxygen barrier properties;
The sum of 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 is at least (2.56 x 10 ^-4 x (β x T/α)) times the volume γ (mL), where T is the ambient temperature (K), β is the saturated solubility (mg/L) of oxygen in the liquid in an air atmosphere under atmospheric pressure at temperature T (K), and α is the oxygen concentration (%) in the second container.

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

In the combination container containing the first and second liquids according to the present disclosure, the oxygen concentration α may be less than 1%.

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

In the first and second liquid-containing combination containers according to the present disclosure, the first container and the second container may contain a volume of gas that is greater than the sum of the volume γ (mL) multiplied by (2.56×10 ⁻⁴ × β×T) and the maximum volume (mL) of the first container minus the volume γ (mL) multiplied by 21.0.

In a combination container containing first and second liquids according to the present disclosure, the volume γ (mL) may be greater than half the maximum volume (mL) of the first container.

In the combination container containing the first and second liquids according to the present disclosure, the volume γ may be 0.5 mL or more.

In a combination container containing first and second liquids 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 combination container containing the first and second liquids according to the present disclosure, the volume γ may be 20 mL or less.

In a combination container containing first and second liquids according to the present disclosure, the first container may be capable of containing a gas while maintaining a negative pressure.

In a combination container containing first and second liquids according to the present disclosure, the second container may be under negative pressure.

In a combination container containing first and second liquids according to the present disclosure, the first container may be under negative pressure.

In a combination container containing first and second liquids according to the present disclosure,
the first container has a container body having an opening and a plug that closes the opening,
The oxygen may be permeable through the plug.

In the combination container containing the first and second liquids according to the present disclosure, the container body may have oxygen barrier properties.

In a combination container containing first and second liquids according to the present disclosure,
the first container has a container body having an opening and a plug that closes the opening,
The material constituting the stopper may have an oxygen permeability coefficient greater than that of the material constituting the container body.

In a combination container containing first and second liquids according to the present disclosure,
the first container has a container body having an opening and a plug that closes the opening,
The plug may be constructed at least in part from silicone.

In the combination container containing the first and second liquids according to the present disclosure, the container body may be made of glass.

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

In the combination container containing the first and second liquids according to the present disclosure, the cylinder may have oxygen barrier properties.

In a combination container containing first and second liquids according to the present disclosure,
The first container includes a syringe having a cylinder and a piston having a gasket disposed in the cylinder to define a space for containing the liquid,
The oxygen permeability coefficient of the material constituting the gasket may be greater than the oxygen permeability coefficient of the material constituting the cylinder.

In a combination container containing first and second liquids according to the present disclosure,
The first container includes a syringe having a cylinder and a piston having a gasket disposed in the cylinder to define a space for containing the liquid,
The gasket may be constructed at least in part from silicone.

In the combination container containing the first and second liquids according to the present disclosure, the cylinder may be made of glass.

A first container set according to the present disclosure comprises:
a first container containing a liquid of volume γ (mL) and at least a portion of which is oxygen permeable;
a second container capable of accommodating the first container and having oxygen barrier properties;
The sum of the maximum volume (mL) of the first container minus the volume γ (mL) and the maximum volume (mL) of the second container minus the volume (mL) occupied by the first container 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 of volume γ (mL) and at least a portion of which is oxygen permeable;
a second container capable of accommodating the first container and having oxygen barrier properties;
The sum of the maximum volume (mL) of the first container minus the volume γ (mL) and the maximum volume (mL) of the second container minus the volume (mL) occupied by the first container 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 of volume γ (mL) and at least a portion of which is oxygen permeable;
a second container capable of accommodating the first container and having oxygen barrier properties;
In a state in which the first container is contained and the second container is closed, the first container and the second container can contain a total volume of gas that is greater than 0.663 times the volume γ (mL).

A fourth container set according to the present disclosure includes:
a first container containing a liquid of volume γ (mL) and at least a portion of which is oxygen permeable;
a second container capable of accommodating the first container and having oxygen barrier properties;
In a state in which the first container is contained and the second container is closed, the first container and the second container can contain a total volume of gas that is greater than 0.921 times the volume γ (mL).

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

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

In the first to fourth container sets according to the present disclosure, when the first container is housed and the second container is closed, the first and second containers may be capable of accommodating a volume of gas that is greater than the sum of 0.663 times the volume γ (mL) and 21.0 times the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container.

In the first to fourth container sets according to the present disclosure, when the first container is housed and the second container is closed, the first and second containers may be capable of accommodating a total volume of gas greater than the sum of 0.921 times the volume γ (mL) and 21.0 times the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container.

In the first to fourth container sets according to the present disclosure, the volume γ (mL) may be greater 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 in the first container may be 1.5% or less.

A first method for manufacturing a liquid-filled container 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 liquid of volume γ (mL) and is at least partially oxygen permeable;
the second container has oxygen barrier properties,
When the first container is contained and the second container is closed, the first container and the second container contain a total volume of gas that is greater than (2.56 × 10 ⁻⁴ × β × T) times the volume γ (mL), where T is the temperature of the environment (K) and β is the saturated solubility (mg/L) of oxygen in the liquid in an air atmosphere under atmospheric pressure at temperature T (K).

A second method for manufacturing a liquid-filled container 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 liquid of volume γ (mL) and is at least partially oxygen permeable;
the second container has oxygen barrier properties,
The sum of 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 is at least (2.56 x 10 ^-4 x (β x T/α)) times the volume γ (mL), where T is the ambient temperature (K), β is the saturated solubility (mg/L) of oxygen in the liquid in an air atmosphere under atmospheric pressure at temperature T (K), and α is the oxygen concentration (%) in the second container.

In the method for manufacturing 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 for manufacturing first and second liquid-filled containers according to the present disclosure, when the first container is housed and the second container is closed, the first container and the second container may contain a volume of gas that is greater than the sum of the volume γ (mL) multiplied by (2.56×10 ⁻⁴ ×β×T) and the maximum volume (mL) of the first container minus the volume γ (mL) multiplied by 21.0.

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

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

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

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

In the manufacturing method for 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.

This invention can prevent liquid from deteriorating due to oxygen.

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

One embodiment of the present invention will now be described with reference to the drawings. Note that in the drawings accompanying this specification, the scale and aspect ratios have been appropriately altered and exaggerated from those of the actual product for the sake of clarity and ease of understanding.

Figures 1 to 9 are diagrams illustrating one embodiment of the present disclosure. The container set 20 includes a first liquid-containing container 30L and a second container 40. The first liquid-containing container 30L includes a first container 30 and a 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 is capable of containing the first liquid-containing container 30L. The liquid-containing combination container 10L includes the first liquid-containing container 30L and the second container 40, and the first liquid-containing container 30L is contained in the second container 40. With this liquid-containing combination container 10L, by adjusting the oxygen concentration in the second container 40, it is possible to adjust not only the oxygen concentration in the first container 30 but also the amount of oxygen dissolved in the liquid L.

The components of the liquid-containing combination container 10L will be described in further detail below with reference to the illustrated example. First, the liquid-containing first container 30L will be described.

As described above, the liquid-containing first container 30L includes a first container 30 and a liquid L contained within the first container 30. At least a portion of the first container 30 is permeable to oxygen. On the other hand, the first container 30 is capable of sealing the liquid L. In other words, the first container 30 is permeable to oxygen but impermeable to the liquid L.

The liquid L contained in the first container 30 is not particularly limited. The liquid may be a solution containing 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, broth, stock, or a concentrated liquid obtained by concentrating one or more of these. The liquid as medicine may be an oral medication, an external medication, or an injection. In addition to food and medicine, the liquid L may also be blood or a bodily fluid.

The interior of the first container 30 may be sterile. That is, the liquid L may be a liquid that must be maintained in a sterile state. Examples of liquid L that must be maintained in a sterile state include food and pharmaceuticals. Liquid L as food or pharmaceuticals is highly sensitive and is preferably stored in a sterile state to prevent deterioration. Liquid L as food or pharmaceuticals is prone to deterioration due to post-sterilization treatment performed after production. Post-sterilization (also known as terminal sterilization), such as high-pressure steam, dry heat, radiation, ethylene oxide gas, and hydrogen peroxide gas plasma, cannot be applied to highly sensitive liquids. Such highly sensitive liquid L can be produced using a production line arranged in a sterile environment. That is, it can be produced by aseptic processing. To adjust the oxygen content of liquid L produced by aseptic processing, the entire space in which the liquid L production line is located can be replaced with an inert gas. However, filling the entire space in which the liquid L production line is located with an inert gas atmosphere requires a huge capital investment and may raise safety concerns for workers. Given the above background, the amount of oxygen in Liquid L has generally been adjusted by replacing the atmosphere inside the formulation container containing Liquid L with an inert gas.

In contrast, according to the invention of the present inventors described below, simply storing the liquid-containing first container 30L in the second container 40 can sufficiently reduce the oxygen concentration (%) in the first container 30 and the amount of oxygen dissolved (mg/L) in the liquid L in the first container 30. The effects resulting from the invention of the present inventors are remarkable and exceed the range predicted by the state of the art.

Note that the term "sterile state" as used herein refers to a product (liquid L) labeled "sterilized" or "sterile," the interior of a container containing such a product, and a pharmaceutical or other product (liquid L) for which "sterility" is a requirement for commercialization, and the interior of a container containing such a product. A product (liquid L) that meets the sterility assurance level (SAL) of ^10-6 as specified in JIS T0806:2014, and the interior of a container containing such a product, also fall under the category of "sterile state" as used herein. A product that does not grow bacteria when stored at room temperature (e.g., 20°C) or higher for four weeks, and the interior of a container containing such a product, and a product that does not grow bacteria when stored in a refrigerated state (e.g., 8°C or lower) for eight weeks or more, and the interior of a container containing such a product, also fall under the category of "sterile state." Furthermore, a drug in which bacteria do not grow when stored for two weeks at a temperature of 28°C or higher and 32°C or lower, and the inside of a container containing the drug, also fall under the "sterile state" used herein.

Next, we will explain the first container 30 that contains the liquid L. As described above, the first container 30 can seal the liquid L. In other words, 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. Alternatively, all gases may be permeable to the first container 30. Alternatively, only some gases containing oxygen, for example only oxygen, may be permeable to the first container 30.

The material constituting the oxygen-permeable portion has an oxygen permeability coefficient of 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, and even more preferably 1×10 ⁻¹¹ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or more. When the oxygen-permeable portion has multiple layers, it is preferable that the material constituting at least one layer has such a permeability coefficient, and it is more preferable that the materials constituting all layers have the above permeability coefficient. This promotes oxygen permeation through the first container 30, allowing the oxygen concentration in the first container 30 to be adjusted quickly.

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

When the object being measured is a resin film or resin sheet, the oxygen permeability coefficient is a value measured in accordance with JIS K7126-1. When the object being measured is rubber, the oxygen permeability coefficient is a value measured in accordance with JIS K6275-1. The oxygen permeability coefficient can be measured using an OXTRAN (2/21) permeability measuring device manufactured by MOCON Corporation in the United States at a temperature of 25°C and a humidity of 60% RH.

The area of the oxygen-permeable portion is preferably 1 ^mm2 or more, more preferably 10 ^mm2 or more, and even more preferably 30 ^mm2 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 several tenths of a mm or less. These factors promote gas permeation through the first container 30, and enable rapid adjustment of the oxygen concentration inside the first container 30.

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, and even more preferably 1×10 ⁻¹ (mL/(day×atm)) or more. This promotes oxygen permeation through the first container 30, allowing the oxygen concentration in the first container 30 to be adjusted quickly. 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×atm)) or less. This makes it possible to suppress leakage of water vapor and the like. Furthermore, it is possible to suppress the effect on the liquid in the first container 30 caused by the high gas permeation rate after the second container 40 is opened. 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. Changes in the oxygen concentration in the first container 30 are measured over time. From the changes in the oxygen concentration over time, the amount of oxygen that has entered the first container 30 per day can be calculated, thereby determining the amount of oxygen that permeates the entire first container 30.

For example, the configuration of the oxygen-permeable portion of the first container may be determined so that storing a first container 30 containing a liquid with an oxygen dissolution rate of 8 mg/L in the second container 40 for four weeks reduces the oxygen concentration (%) in the first container 30 by 5% or more.

The illustrated first container 30 includes a container body 32 having an opening 33 and a stopper 34 held in the opening 33 of the container body 32. The stopper 34 prevents leakage of the liquid L from the opening 33. In this example, the stopper 34 may be made of a material that is oxygen permeable and has the above-mentioned oxygen permeability coefficient (cm ³ (STP)·cm/(cm ² ·sec·Pa)). The oxygen permeability coefficient of the material constituting the stopper 34 may be higher than the oxygen permeability coefficient of the material constituting the container body 32. Alternatively, only a portion of the stopper 34 may be oxygen permeable. A portion of the stopper 34 may be made of an oxygen permeable material throughout its entire thickness. For example, the stopper 34 may be oxygen permeable throughout its entire thickness in a central portion spaced from the periphery, and have oxygen barrier properties in a peripheral portion surrounding the central portion.

In the illustrated example, the area of the opening 33, i.e., the opening area of the container body 32, is preferably 1 ^mm2 or more, more preferably 10 ^mm2 or more, and even more preferably 30 ^mm2 or more. Similarly, the thickness of the stopper 34 is preferably 3 mm or less, more preferably 1 mm or less, and even more preferably several tenths of a mm or less. This promotes oxygen permeation through the first container 30, allowing the oxygen concentration within the first container 30 to be quickly adjusted. Furthermore, from the viewpoint of ensuring flexibility and airtightness, the thickness of the stopper, for example, the thickness of a rubber stopper, may be 20 mm or less. Furthermore, from the viewpoint of being able to be punctured by a syringe needle or a straw, the thickness of the stopper, for example, the thickness of a rubber stopper, may be 1 mm or less.

An upper limit may be set on the area of the opening 33 from the viewpoint of suppressing 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 transmission rate after the second container 40 is opened. Specifically, the area of the opening 33 may be set to 5000 ^mm2 or less. From the viewpoint of ensuring strength, the thickness of the stopper, for example, the thickness of a rubber stopper, may be set to 0.01 mm or more.

The oxygen-permeable stopper 34 is not particularly limited and can have a variety of configurations. In the example shown, the stopper 34 is inserted into the opening 33 of the container body 32, sealing the opening 33. In addition to the stopper shown, a liquor bottle cap may also be used; more specifically, a stopper having a stopper body portion that is inserted into the opening 33 and a flange portion that expands in diameter from the stopper body portion. It is also possible to use a stopper that has an external or internal spiral and is attached to the container body portion by the interlocking of the spirals.

The stopper 34 may be made of silicone. Silicone is a substance with a siloxane bond as its main chain. The stopper 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 its main component, and is a rubber-like substance. Silicone rubber is a rubber-like substance with a siloxane bond as its main chain. Silicone rubber may be a thermosetting compound containing a siloxane bond. Examples of silicone rubber include methyl silicone rubber, vinyl-methyl silicone rubber, phenyl-methyl silicone rubber, dimethyl silicone 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 even 1×10 ⁻¹¹ (mL/(m ² ×day×atm)) or more. The oxygen permeability coefficient of silicone and that of silicone rubber are 1×10 ⁻⁹ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or less. Compared with natural rubber, silicone and silicone rubber have a hydrogen permeability coefficient that is about 10 times higher, an oxygen permeability coefficient that is about 20 times higher, and a nitrogen permeability coefficient that is about 30 times higher. Compared with butyl rubber, silicone and silicone rubber have a hydrogen permeability coefficient that is 70 times higher, an oxygen permeability coefficient that is 40 times higher, and a nitrogen permeability coefficient that is 650 times higher.

At least a portion of the plug 34 may be made of silicone. That is, the entire plug 34 or a portion thereof may be made of silicone or silicone rubber. For example, a portion of the plug 34 may be made of silicone or silicone rubber across its entire thickness. The portion may be the central portion of the plug 34, or part or all of the peripheral portion surrounding the central portion.

As shown in FIG. 2, the illustrated container body 32 has a bottom 32a, a body wall 32b, a neck 32c, and a head 32d, in that order. The bottom 32a and the body wall 32b mainly form the storage space for the liquid L. The head 32d forms the tip of the container body 32. The head 32d is thicker than the other parts. The neck 32c is located between the body wall 32b and the head 32d. The neck 32c has a narrower width, particularly a narrower diameter, than the body wall 32b and the head 32d. The container body 32 may be transparent so that the stored liquid L can be observed from the outside. Here, "transparent" means that the visible light transmittance, specified as the average value of the transmittance at each wavelength when measured using a spectrophotometer (Shimadzu Corporation's "UV-3100PC," compliant with JIS K 0115) within the measurement wavelength range of 380 nm to 780 nm, is 50% or more, and preferably 80% or more.

In the illustrated example, the container body 32 is made of a material with a smaller oxygen permeability coefficient than the material of the stopper 34. The container body 32 may have oxygen barrier properties. That is, the first container 30 may be oxygen permeable only in a portion thereof. Having oxygen barrier properties means that the first container 30 is made of a material with an oxygen permeability coefficient of 1×10 ⁻¹³ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or less. The structure with oxygen barrier properties may preferably be made of a material with an oxygen permeability coefficient of 1×10 ⁻¹⁷ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or less.

Examples of a container body 32 with oxygen barrier properties include a can made of metal, a container body with a metal layer formed by vapor deposition or transfer, and a glass bottle. Oxygen barrier properties can also be imparted to a container body 32 made using a resin sheet or resin plate. In this example, the resin sheet or resin plate may include a layer with oxygen barrier properties, such as ethylene-vinyl alcohol copolymer (EVOH) or polyvinyl alcohol (PVA). The container body 32 may also include a laminate including a metal vapor deposition film. A container body 32 made using a laminate, or a container body 32 made using glass or resin, can be imparted with transparency in addition to oxygen barrier properties. A transparent first container 30 or container body 32 is preferable because the liquid L contained therein can be observed 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 colorless or colored glass bottle. The container body 32 is formed, for example, from borosilicate glass. The first container 30 is a vial. The volume of the first container 30 that is a vial may be 1 mL or more, or 3 mL or more. The volume of the first container 30 that is a vial may be 500 mL or less, or 200 mL or less.

When the first container 30 is a vial, the oxygen permeability coefficient of the material making up the stopper 34 may be greater than the oxygen permeability coefficient of the glass making up the container body 32.

The illustrated first container 30 further includes a fastener 36. The fastener 36 prevents the stopper 34 from being removed from the container body 32. The fastener 36 is attached to the head 32d of the container body 32. As shown in Figures 1 and 2, the fastener 36 covers the periphery of the stopper 34. As a result, the fastener 36 prevents the stopper 34 from being removed from the container body 32 while leaving a portion of the stopper 34 exposed. The fastener 36 may be a sheet metal fixed to the head 32d. The fastener 36 may also be a cap that is screwed onto the head 32d.

The illustrated first container 30 can maintain a negative internal pressure under atmospheric pressure. That is, the first container 30 can contain a gas while maintaining the gas at a negative pressure under atmospheric pressure. Alternatively, the first container 30 may be capable of containing a gas while maintaining the gas at a positive pressure under atmospheric pressure. In these examples, the first container 30 may have sufficient rigidity to maintain its shape. However, the first container 30 may deform somewhat under atmospheric pressure when maintaining a negative or positive internal pressure. Examples of first containers 30 capable of maintaining a negative or positive internal pressure include the specific examples illustrated above and cans made of metal.

Next, we will explain the second container 40.

The second container 40 can be airtightly sealed, for example, by welding such as heat sealing or ultrasonic bonding, or by bonding using a bonding material such as an adhesive or glue. The second container 40 has oxygen barrier properties. Examples of second containers 40 with oxygen barrier properties include metal cans, containers with a metal layer formed by vapor deposition or transfer, and glass bottles. The second container 40 may also include a laminate with oxygen barrier properties. The laminate may include a resin layer with oxygen barrier properties, such as ethylene-vinyl alcohol copolymer (EVOH) or polyvinyl alcohol (PVA), or a metal vapor deposition film. At least a portion of the second container 40 may be transparent. A second container 40 using a laminate, or a second container 40 using glass or resin, can be imparted with transparency in addition to oxygen barrier properties. Giving the second container 40 transparency is advantageous in that the liquid-filled first container 30L contained therein can be observed from the outside of the second container 40.

The second container 40 has a volume sufficient to 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 perspective of adjusting the oxygen concentration in the first container 30 and the amount of oxygen dissolved in the liquid L, the second container 40 can accommodate a predetermined volume of gas that is determined taking into account the volume γ (mL) of the liquid L, etc. The predetermined volume will be described in detail later.

In the illustrated example, the second container 40 is made of a resin film with 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 opposite each other. The first gusset film 41c is folded 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 folded 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 to each other at their upper and lower edges. The films 41a-41d are hermetically joined, for example, by welding, such as heat sealing or ultrasonic bonding, or by joining with a bonding material, such as an adhesive or glue. However, instead of joining separate films, two or more adjacent films 41a-41d may be formed by folding a single film. As shown in FIG. 1, the gusset bag can form a rectangular bottom surface for the second container 40. By placing the first container 30 on the bottom surface, the first container 30 can be stably stored in the second container 40. However, instead of a gusset bag, the second container 40 may be a pouch having a bottom film in addition to the first main film 41a and the second main film 41b. The bottom can also be formed using such a pouch, allowing the first container 30 to be stably stored within the second container 40. In these examples, the film forming the second container 40 may be transparent.

As another example, as shown in FIG. 7, the second container 40 may have a container body 42 and a lid 44. The container body 42 has a storage portion 42a and a flange portion 42b. The storage portion 42a forms a rectangular parallelepiped storage space. The first container 30 is stored in this storage space. The storage portion 42a has a rectangular parallelepiped outer shape with one side open. The flange portion 42b is provided on the periphery of the opening of the storage portion 42a. The lid 44 is flat. The periphery of the lid 44 can be airtightly joined to the flange portion 42b of the container body 42. The container body 42 and the lid 44 may be formed from a resin plate with gas barrier properties. The lid 44 and the container body 42 may be transparent. The thickness of the resin plate with gas barrier properties may be 0.05 mm to 2 mm or 0.1 mm to 1.5 mm. The second container 40 can maintain a negative internal pressure under atmospheric pressure. That is, the second container 40 can contain a gas while maintaining the gas at a negative pressure under atmospheric pressure. The second container 40 may also be capable of containing a gas while maintaining a positive pressure under atmospheric pressure. The second container 40 has sufficient rigidity to maintain its shape. However, the second container 40 may deform somewhat under atmospheric pressure when maintaining a negative or positive internal pressure.

The container set 20 is made up of the liquid-containing first container 30L and second container 40 described above. The container set 20, which has the liquid-containing first container 30L and second container 40, is used to obtain the liquid-containing combination container 10L. The first container 30 and container set 20 are used to obtain the combination container 10.

Next, we will explain the manufacturing method of the liquid-filled combination container 10L. By manufacturing the liquid-filled combination container 10L, a liquid-filled first container 30L with an adjusted oxygen concentration is obtained.

First, a first container 30L containing liquid and a second container 40 before closing are prepared. The first container 30L containing liquid is manufactured by filling the first container 30 with liquid L. For example, liquid L, such as food or medicine, is manufactured using a manufacturing line installed in a sterile environment maintained at positive pressure. The internal pressure of the first container 30L containing liquid obtained in this way becomes positive pressure, similar to the manufacturing environment.

As shown in Figure 3, the second container 40 before closing has an opening 40a remaining for accommodating the first container 30L containing liquid. In the second container 40 shown in Figure 1, for example, the upper edges of the films 41a to 41d are not joined to each other to form the opening 40a. In the second container 40 shown in Figure 7, a container body 42 is prepared without a lid 44 attached. Then, as shown in Figure 3, the first container 30L containing liquid is placed in the second container 40 through the opening 40a.

Then, 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 a supply pipe 55. The supply pipe 55 passes through the opening 40a and enters the second container 40. The outlet 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. In other words, the liquid-filled first container 30L is placed in an inert gas atmosphere. Note that 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.

It is possible to fill the second container 40 with inert gas and place the first container 30L containing liquid in the second container 40 in either order, or to perform these steps simultaneously.

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

Instead of supplying inert gas from the supply pipe 55, the second container 40 containing the liquid-containing first container 30L may be closed under an inert gas atmosphere. This method also allows the liquid-containing first container 30L to be sealed within the second container 40 together with the inert gas.

The steps up to closing the second container 40 may also be carried out in a sterile environment. That is, the liquid-filled first container 30L, which has been manufactured in a sterile environment, and the second container 40, which has been sterilized or manufactured in a sterile environment, are brought into a sterile environment, such as a sterile chamber. If this chamber is separated from the atmosphere and contains an inert gas atmosphere, the supply of inert gas via the supply pipe 55 can be omitted. Then, in a sterile environment, the second container 40 containing the liquid-filled first container 30L is closed. Therefore, the inside of the second container 40 containing the liquid-filled first container 30L is also sterile. That is, the liquid-filled first container 30L can be stored in the second container 40 in a sterile environment.

The liquid-filled first container 30L is then stored in the second container 40. As described above, the second container 40 has oxygen barrier properties. Therefore, oxygen permeation through the second container 40 is effectively suppressed. On the other hand, at least a portion of the first container 30 is permeable to oxygen. Furthermore, the second container 40 is filled with an inert gas, and the oxygen concentration within the second container 40 is very low. In this liquid-filled combination container 10L, oxygen within the first container 30 permeates the first container 30 and moves into the second container 40. As oxygen moves from the first container 30 to the second container 40, the oxygen concentration within the second container 40 increases and decreases. At the final equilibrium state where oxygen permeation through the first container 30 is balanced, the oxygen concentration within the first container 30 can match the oxygen concentration within the second container 40.

In addition, as the oxygen concentration in the first container 30 decreases, the oxygen partial pressure in the first container 30 decreases. As the oxygen partial pressure in the first container 30 decreases, the saturated solubility (mg/L) of oxygen in the liquid L in the first container 30 also decreases. As a result, the amount of oxygen dissolved in the liquid L (mg/L) decreases.

Incidentally, in order to sufficiently reduce the oxygen concentration (%) of the liquid L and the amount of oxygen dissolved (mg/L) in the liquid L, it is preferable to fill the second container 40 with a large amount of inert gas together with the liquid-containing first container 30L and then 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 then close the first container 30. That is, it is preferable that the maximum usable 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, be large. Furthermore, assuming that the inside of the first container 30 is replaced with an inert gas, it is preferable that the maximum usable 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 , be large. The maximum usable volume EV _2MAX (mL) of the second container 40 is the maximum volume of gas that can be contained in the second container 40 when the second container 40 contains only the liquid-containing first container 30L and gas. The maximum usable 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 usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be (2.56×10 ⁻⁴ × (β×T/α)) times or more the volume γ (mL) of the liquid L contained in the first container 30. Here, T is the temperature (K) of the environment in which the liquid-containing combination container 10L is placed. T can also be said to be the temperature (K) of the storage space of the liquid-containing combination container 10L, i.e., the inside of the second container 40. β is the saturated solubility (mg/L) of oxygen in the liquid L in an air atmosphere under atmospheric pressure at temperature T (K). α is the oxygen concentration (%) in the second container 40. α may also be the oxygen concentration (%) in the second container 40 in an equilibrium state.

Note that the maximum volume V _1MAX (mL) and the maximum volume V _2MAX (mL) refer to the maximum volume when the volume of the target container 30, 40 changes due to deformation, etc. Therefore, when the volume of the target container 30, 40 is constant, 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 the liquid L with a volume of γ (mL) placed in an air atmosphere at a temperature T (K) is expressed as follows: As an example, the amount of oxygen expressed as follows may be the maximum amount of oxygen that can be dissolved in the liquid L with a volume of γ (mL) that is produced in an air atmosphere at a temperature T (K) and stored in the first container 30.
Molecular weight of oxygen: β×γ/1000 (mg)
Molar amount of oxygen: β×γ/1000/32 (mmol)
It is then assumed that the maximum amount of oxygen dissolved in the liquid L is completely degassed from the liquid L, the solubility of oxygen becomes 0 (mg/L), and the oxygen concentration in the first container 30 and the second container 40 becomes α (%). Under this assumption, immediately after the second container 40 containing the first container 30 is closed, no oxygen gas is contained in the first container 30 and the second container 40. At this time, the volume Vx (mL) of oxygen in the first container 30 and the second container 40 is determined as follows using the equation of state:
Vx = nRT/P
= (β×γ/1000/32)×0.082×T/(α/100)
=2.56× ^10-4 ×(β×T/α)×γ(mL)
In this equation of state, the gas constant is 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 the volume of oxygen in the liquid-filled combination container 10L in a state in which all of the oxygen dissolved in the liquid L has been degassed from the liquid L. Therefore, by designing the sum of the maximum available volume EV _1MAX (mL) of the first container 30 and the maximum available volume EV _2MAX (mL) of the second container 40 to be at least 2.56×10 ⁻⁴ × (β×T/α) times the volume γ (mL) of the liquid L, the maximum amount of oxygen that can be dissolved in the liquid L can be present in the first container 30 and the second container 40 as a degassed gas. This makes it possible to sufficiently reduce the amount of oxygen dissolved in the liquid L (mg/L) and to sufficiently reduce the amount of dissolved oxygen in the liquid L.

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

Based on the above considerations, the volumes of the first container 30 and the second container 40 may be determined from the target oxygen concentration in the liquid-containing combination container 10L and the target amount of dissolved oxygen (mg/L) in the liquid L. Furthermore, the total volume of gas contained in the first container 30 and the second container 40 may be determined from the target oxygen concentration in the liquid-containing combination container 10L and the target amount of dissolved oxygen (mg/L) in the liquid L.

For example, the volumes of the containers 30, 40 and the volumes of the gases contained in the containers 30, 40 may be determined so that the oxygen concentrations 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 usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be greater than (2.56×10 ⁻⁴ ×β×T) times the volume γ (mL) of the liquid L contained in the first container 30. More specifically, if the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, the oxygen saturation solubility β of water, which is the solvent, is 8.84 (mg/L). In this specific example, the sum of the maximum usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be greater than 0.663 times the volume γ (mL) of the liquid L. Furthermore, the first container 30 and the second container 40 may contain a total volume of gas that is greater than (2.56×10 ⁻⁴ × β×T) times the volume γ (mL) of the liquid L contained in the first container 30. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, the first container 30 and the second container 40 may contain a total volume of gas that is greater than 0.663 times the volume γ (mL) of the liquid L contained in the first container 30.

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

Furthermore, the volumes of the containers 30, 40 and the volumes of the gases contained in the containers 30, 40 may be determined so that the oxygen concentrations 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 may be set to be (5.12×10 ⁻⁴ ×β×T) times or more the volume γ (mL) of the liquid L contained in the first container 30. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, 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 may be set to be 1.32 times or more the volume γ (mL) of the liquid L. Furthermore, the first container 30 and the second container 40 may contain a total volume of gas that is at least (5.12×10 ⁻⁴ × β×T) times the volume γ (mL) of the liquid L contained in the first container 30. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, the first container 30 and the second container 40 may contain a total volume of gas that is at least 1.32 times the volume γ (mL) of the liquid L contained in the first container 30.

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

Furthermore, the volumes of the containers 30, 40 and the volumes of the gases contained in the containers 30, 40 may be determined so that the oxygen concentrations 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 may be set to be (1.28×10 ⁻³ ×β×T) times or more the volume γ (mL) of the liquid L contained in the first container 30. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, 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 may be set to be 3.32 times or more the volume γ (mL) of the liquid L. Furthermore, the first container 30 and the second container 40 may contain a total volume of gas that is at least (1.28×10 ⁻³ ×β×T) times the volume γ (mL) of the liquid L contained in the first container 30. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, the first container 30 and the second container 40 may contain a total volume of gas that is at least 3.32 times the volume γ (mL) of the liquid L contained in the first container 30.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K, which is the refrigerated state, the oxygen saturation solubility β of water, which is the solvent, is 13.04 (mg/L). In this specific example, the sum of the maximum available volume EV _1MAX (mL) of the first container 30 and the maximum available volume EV _2MAX (mL) of the second container 40 may be greater than 4.61 times the volume γ (mL) of the liquid L. Furthermore, the first container 30 and the second container 40 may together contain a volume of gas that is greater than 4.61 times the volume γ (mL) of the liquid L contained in the first container 30.

It is also possible that oxygen is present in the space not occupied by the liquid L in the first container 30, the so-called head space HS, during the manufacturing of the liquid-filled first container 30L. For example, if the liquid L is placed in the first container 30 and the first container 30 is closed in an air atmosphere, air will be present in the head space HS of the first container 30. That is, the oxygen concentration in the liquid-filled first container 30L will be approximately 21.0%. In other words, in the initial state, the liquid-filled first container 30L will contain oxygen dissolved in the liquid L and oxygen as a gas in the head space HS. In this case, the amount of oxygen in the head space HS is determined as follows.
Molar amount of oxygen: 0.210 × EV _1MAX / 0.082 / T (mmol)
Here, EV _1MAX is the maximum usable 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 is the maximum volume (mL) of the headspace HS. The volume of oxygen present in gas form in the headspace HS expands to _{(EV 1MAX ×} 21.0/α) (mL) in an equilibrium state where the oxygen concentration is α (%).

The above-mentioned volume γ (mL) of liquid L multiplied by (2.56×10 ⁻⁴ × (β×T/α)) is the volume of gas in the liquid-containing combination container 10L in a state in which all of the oxygen dissolved in liquid L has been degassed from liquid L. Therefore, the sum of the maximum usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be set to be equal to or greater than the sum of the value obtained by multiplying the volume γ (mL) of liquid L by (2.56×10 ⁻⁴ × (β×T/α)) and the value obtained by multiplying the maximum usable volume EV _1MAX (mL) of the first container 30 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 container 30 and the second container 40 as degassed gas, together with the oxygen that was present in the headspace HS. This allows the amount of oxygen dissolved in liquid L to be sufficiently reduced, and the amount of dissolved oxygen in liquid L to be sufficiently reduced.

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

When considering the oxygen in the air present in the headspace HS during the production of the first liquid-containing container 30L, the volumes of the first container 30 and the second container 40 may be determined from the target oxygen concentration in the liquid-containing combination container 10L and the target amount of oxygen dissolved (mg/L) in the liquid L. Furthermore, the total volume of gas contained in the first container 30 and the second container 40 may be determined from the target oxygen concentration in the liquid-containing combination container 10L and the target amount of oxygen dissolved (mg/L) in the liquid L.

For example, the volumes of the containers 30, 40 and the volumes of the gases contained in the containers 30, 40 may be determined so as to reduce the oxygen concentrations in the first container 30 and the second container 40 to less than 1%. In this example, the sum of the maximum usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be greater than the sum of the volume γ (mL) of the liquid L contained in the first container 30 multiplied by (2.56×10 ⁻⁴ ×β×T) and the maximum usable volume EV _1MAX (mL) of the first container 30 multiplied by 21.0. More specifically, when the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, the oxygen saturation solubility β of water 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 may be greater than the sum of 0.663 times the volume γ (mL) of the liquid L and 21.0 times the maximum effective volume EV _1MAX (mL) of the first container 30. Furthermore, the first container 30 and the second container 40 may together contain a volume of gas that is greater than the sum of 2.56×10 ⁻⁴ ×β×T) times the volume γ (mL) of the liquid L contained in the first container 30 and 21.0 times the maximum effective volume EV _1MAX (mL) of the first container 30. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, the first container 30 and the second container 40 may contain a volume of gas that is greater than the sum of 0.663 times the volume γ (mL) of the liquid L contained in the first container 30 and 21.0 times the maximum effective volume EV _1MAX (mL) of the first container 30.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K, which is the temperature in a refrigerated state, the oxygen saturation solubility β of water, the solvent, is 13.04 (mg/L). In this specific example, the sum of the maximum usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be greater than the sum of 0.921 times the volume γ (mL) of the liquid L and 21.0 times the maximum usable volume EV _1MAX (mL) of the first container 30. Furthermore, the first container 30 and the second container 40 may collectively contain a volume of gas greater than the sum of 0.921 times the volume γ (mL) of the liquid L contained in the first container 30 and 21.0 times the maximum usable volume EV _1MAX (mL) of the first container 30.

Furthermore, the volumes of the containers 30, 40 and the volumes of the gas contained in the containers 30, 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 usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be set to be equal to or greater than the sum of the 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) and the value obtained by multiplying the maximum usable volume EV _1MAX (mL) of the first container 30 by 41.9. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, 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 may be equal to or greater than the sum of 1.32 times the volume γ (mL) of the liquid L and 41.9 times the maximum effective volume EV _1MAX (mL) of the first container 30. Furthermore, the first container 30 and the second container 40 may together contain a volume of gas equal to or greater than the sum of 5.12×10 ⁻⁴ ×β×T) times the volume γ (mL) of the liquid L contained in the first container 30 and 41.9 times the maximum effective volume EV _1MAX (mL) of the first container 30. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, the first container 30 and the second container 40 may contain a volume of gas that is equal to or greater than the sum of 1.32 times the volume γ (mL) of the liquid L contained in the first container 30 and 41.9 times the maximum effective volume EV _1MAX (mL) of the first container 30.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K, which is the temperature in a refrigerated state, the oxygen saturation solubility β of water, the solvent, is 13.04 (mg/L). In this specific example, the sum of the maximum usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be greater than the sum of 1.84 times the volume γ (mL) of the liquid L and 41.9 times the maximum usable volume EV _1MAX (mL) of the first container 30. Furthermore, the first container 30 and the second container 40 may collectively contain a volume of gas greater than the sum of 1.84 times the volume γ (mL) of the liquid L contained in the first container 30 and 41.9 times the maximum usable volume EV _1MAX (mL) of the first container 30.

Furthermore, the volumes of the containers 30, 40 and the volumes of the gas contained in the containers 30, 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 usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be set to be equal to or greater than the sum of the 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) and the value obtained by multiplying the maximum usable volume EV _1MAX (mL) of the first container 30 by 105. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, 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 may be equal to or greater than the sum of 3.32 times the volume γ (mL) of the liquid L and 105 times the maximum effective volume EV _1MAX (mL) of the first container 30. Furthermore, the first container 30 and the second container 40 may together contain a volume of gas equal to or greater than the sum of 1.28×10 ⁻³ ×β×T) times the volume γ (mL) of the liquid L contained in the first container 30 and 105 times the maximum effective volume EV _1MAX (mL) of the first container 30. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is 293 K, which is approximately room temperature, the first container 30 and the second container 40 may contain a volume of gas that is equal to or greater than the sum of 3.32 times the volume γ (mL) of the liquid L contained in the first container 30 and 105 times the maximum effective volume EV _1MAX (mL) of the first container 30.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K, which is the temperature in a refrigerated state, the oxygen saturation solubility β of water, the solvent, is 13.04 (mg/L). In this specific example, the sum of the maximum usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX (mL) of the second container 40 may be greater than the sum of 4.61 times the volume γ (mL) of the liquid L and 105 times the maximum usable volume EV _1MAX (mL) of the first container 30. Furthermore, the first container 30 and the second container 40 may collectively contain a volume of gas greater than the sum of 4.61 times the volume γ (mL) of the liquid L contained in the first container 30 and 105 times the maximum usable volume EV _1MAX (mL) of the first container 30.

As described above, by storing the liquid-filled first container 30L in the second container 40, the oxygen concentration of the gas contained in the liquid in the first container 30 can be reduced. In addition, the amount of dissolved oxygen in the liquid L in the first container 30 can also be reduced. On the other hand, highly sensitive liquids L, such as food and medicines, can be decomposed by oxygen. By storing the liquid L in the first container 30 stored in the second container 40, it is possible to suppress the decomposition of the liquid L by oxygen. In other words, this embodiment, which allows the oxygen concentration in the first container 30 to be adjusted after the liquid L is sealed, is suitable for highly sensitive liquids L, such as food and medicines.

It is believed that the amount of dissolved oxygen in the liquid stored in the container can be reduced by producing the liquid in an atmosphere substituted with an inert gas and storing the liquid in a container with oxygen barrier properties. However, installing the entire liquid production line in an atmosphere substituted with an inert gas requires extensive modifications to the manufacturing equipment and a huge capital investment. Furthermore, in the field of expensive chemicals, the chemicals are often freeze-dried and stored in powder form to ensure stability against temperature, oxygen, moisture, light, etc. However, converting liquid chemicals into powder form for storage and then converting the powdered chemicals back into liquid form when used has significant disadvantages in terms of effort, time, and cost.

In contrast, according to this embodiment, a first container filled with liquid can be manufactured in the conventional manner using existing equipment, etc. Therefore, equipment modifications and capital investment can be avoided. This is particularly useful when applied to liquids such as chemicals, as it eliminates the need for approval applications to public institutions regarding changes to manufacturing equipment or manufacturing processes. It also eliminates the need for the labor of freezing and drying the liquid L or turning a powder back into a liquid. Furthermore, there are no special restrictions on the first container 30. Therefore, materials that are widely used as containers for food, medicines, etc. due to their low elution amounts, such as glass and resins such as polyethylene and polypropylene, can be used as materials for the first container.

Additionally, in the above-described specific example, the first container 30 includes a container body 32 and a stopper 34. This first container 30 may be a vial. However, conventionally, vials containing liquids, particularly vials containing liquids under sterile conditions, are made of butyl rubber or fluororubber, which have low oxygen permeability and even oxygen barrier properties. In contrast, in the above-described specific example, oxygen is permeable through the stopper 34. That is, the oxygen permeability coefficient (cm ³ (STP)·cm/(cm ² ·sec·Pa)) of the material constituting the stopper 34 is set to be high. Specifically, the stopper 34 is made of silicone or silicone rubber. Furthermore, the oxygen permeability coefficient of the silicone or silicone rubber constituting the stopper 34 is higher than the oxygen permeability coefficient of the material constituting the container body 32. According to this specific example, oxygen permeates the stopper 34 and moves out of the first container 30. Therefore, oxygen permeability can be easily imparted to existing containers, such as vials, that have been used in the past.

In this specific example, the time required to reach equilibrium depends on the amount of oxygen permeable through the stopper 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 stopper 34 as described above, the time required for oxygen permeation through the first container 30 to reach equilibrium after the first container 30 is placed inside the second container 40 can be shortened. This makes it possible to suppress decomposition of the liquid L due to oxygen.

Furthermore, the maximum effective volume _EV1MAX of the first container 30, obtained by subtracting the volume γ of the liquid L from the maximum volume _V1MAX of the first container 30, may be 20 mL or less, or may be 5 mL or less. The volume of gas contained in the first container 30 together with the liquid L may be 20 mL or less, or may be 5 mL or less. With this type of liquid-filled combination container 10L, the time required for oxygen permeation through the first container 30 to reach equilibrium after the second container 40 containing the first container 30 is closed can be shortened. This makes it possible to suppress decomposition of the liquid L due to oxygen.

Similarly, the volume of the liquid L contained in the first container 30 may be 20 mL or less, or 5 mL or less. With this type of liquid-filled combination container 10L, the time required for oxygen permeation through the first container 30 to reach equilibrium after the second container 40 containing the first container 30 is closed can be shortened. This reduces decomposition of the liquid L due to oxygen. Furthermore, by setting an upper limit on the amount of liquid in the first container 30 in this manner, it is possible to prevent the second container 40 from becoming larger and reducing the ease of handling of the combination container 10. This type of container is suitable for storing highly concentrated tea or broth concentrates in the first container as liquids, or for storing expensive, highly pharmacologically active chemicals in the first container as liquids.

Furthermore, upper and lower limits may be set for the ratio (%) of the maximum usable volume _EV1MAX of the first container 30, calculated by subtracting the volume γ of the liquid L from the maximum volume _V1MAX of the first container ₃₀ , to the maximum usable volume _EV2MAX of the second container 40, calculated by subtracting the volume occupied by the first container 30 from the maximum volume V2MAX of the second container 40. This ratio may be set to 50% or less, or 20% or less. Setting such an upper limit reduces the oxygen concentration in the first container 30. Furthermore, it is possible to ensure sufficient storage space for the first container 30 within the second container 40, making it easier to store the first container 30 within the second container 40. Furthermore, it is possible to shorten the time required for oxygen permeation through the first container 30 to reach equilibrium after closing the second container 40 containing the first container 30. This reduces decomposition of the liquid L due to oxygen. Furthermore, this ratio may be set to 5% or more, or 1% or more. By setting the lower limit in this manner, the second container 40 does not become too large relative to the first container 30, and deterioration in the handleability of the combination container 10 can be suppressed.

Whether oxygen permeation through the first container 30 is in equilibrium is determined based on the oxygen concentration within the first container 30. This determination is made when the difference between the oxygen concentration value (%) within the first container 30 at a certain point in time and the oxygen concentration value (%) within the first container 30 24 hours prior to that point in time is within ±5% of the oxygen concentration value (%) within the first container 30 at that point in time.

In this manner, a liquid-filled first container 30L and a liquid-filled combination container 10L with adjusted oxygen concentrations and dissolved oxygen amounts can be obtained. In an equilibrium state where oxygen permeation through the first container 30 is balanced, the oxygen concentrations in the first container 30 and the second container 40 may be, for example, less than 1%. In conventional technology, simply replacing the air with an inert gas often made it difficult to reduce the oxygen concentration (%) in the headspace HS in the first container 30 due to the presence of liquid L in the first container 30. As a result, it was difficult to reduce the large amount of dissolved oxygen in liquid L. In contrast, according to one specific example of the above-described embodiment, the second container 40 contains the liquid formulation-containing container 30LF and gas, eliminating the need to directly contain liquid L. This allows the oxygen concentration in the second container 40 to be sufficiently reduced. Therefore, by adjusting the volume of the second container 40, the oxygen concentration in the first container 30 at equilibrium can be less than 1%, preferably 0.5% or less, and more preferably 0.2% or less. This effect is ideal when the liquid L is a highly sensitive chemical or food.

In contrast, it is possible to avoid using the second container 40 and instead secure a large maximum usable volume _EV1MAX of the first container 30 (calculated by subtracting the volume γ of the liquid L from the maximum volume _V1MAX of the first container 30) and fill the first container 30 with an inert gas. However, in this case, the excess space within the first container is larger than the liquid volume γ (mL), making it difficult to drain the liquid from the first container. Furthermore, the liquid may be spread within the first container, accelerating oxygen degradation. Furthermore, when applied to liquids such as food, this can discourage purchasing and reduce product appeal. When applied to liquids such as medicines, it can be difficult to check the state of the liquid within the first container and extract the appropriate amount of liquid from the first container.

If it takes a long time for the oxygen concentration or dissolved oxygen amount to decrease, deterioration of the liquid L due to oxygen will progress. The period or time from closing the second container 40 until oxygen permeation through the first container 30 reaches equilibrium is preferably within four weeks. If equilibrium is reached within four weeks, for example, if the oxygen concentration in the second container 40 is less than 1%, deterioration of the liquid L as a chemical can be effectively suppressed. For more sensitive liquids L, the period until equilibrium is reached is preferably within 20 days, more preferably within one week, and even more preferably within three days. On the other hand, it takes a certain amount of time for the liquid L to reach equilibrium, which reduces the dissolved oxygen amount to a certain extent. To effectively adjust the dissolved oxygen amount, the period or time from closing the second container 40 until oxygen permeation through the first container 30 reaches equilibrium may be set to one hour or more.

The Fibox3 oxygen meter from PreSens, Germany, is an example of a measuring device that can be used to determine oxygen concentration (%) and dissolved oxygen amount (mg/L). The Fibox3 oxygen meter can measure the oxygen concentration and dissolved oxygen amount non-contact without destroying the container, for example, for a combination container containing a liquid formulation shown in Figure 1 or a formulation container containing a liquid formulation shown in Figure 2. Alternatively, the Microx4 oxygen meter from PreSens, Germany, can be used to measure oxygen concentration (%) and dissolved oxygen amount (mg/L). The Microx4 oxygen meter is a needle-type device. The Microx4 oxygen meter can measure the oxygen concentration and dissolved oxygen amount in a container by inserting a needle into the container.

The first container 30 may be stored in the second container 40 until oxygen permeation through the first container 30 reaches equilibrium. The first container 30 may be stored in the second container 40 until the oxygen concentration in the second container 40 increases to a predetermined value. The first container 30 may be stored in the second container 40 until the oxygen concentration in the first container 30 decreases to a predetermined value. The first container 30 may be stored in the second container 40 until the amount of oxygen dissolved in the liquid L in the first container 30 decreases to a predetermined value. The first container 30 may be stored in the second container 40 until the liquid L in the combination container 10 is to be used. Furthermore, the liquid-filled combination container 10L may be circulated while the first container 30 is stored in the second container 40.

Next, we will explain how to use the liquid-filled combination container 10L.

When using the liquid L contained in the combination container 10, first open the second container 40. Next, remove the liquid-containing first container 30L from the opened second container 40. The liquid L can then be removed from the liquid-containing 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 then removing the stopper 34 from the container body 32. This allows the liquid L in the first container 30 to be used.

Alternatively, as shown in FIG. 6, the liquid L may be a medicine injected into the syringe 60. 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 protruding from the cylinder body 63. The cylindrical needle 64 allows access to the space in the cylinder body 63 for storing the liquid L. The piston 66 has a piston body 67 and a gasket 68 held by the piston body 67. The gasket 68 may be made of rubber or the like. The gasket 68 is inserted into the cylinder body 63 to define a storage space for the liquid L within the cylinder body 63.

It is preferable that the pressure inside the first liquid-containing container 30L be adjusted. As an example, it is preferable that the pressure inside the first liquid-containing container 30L be maintained low, and in particular, that it be maintained at a negative pressure. This example effectively prevents unintended leakage of the liquid when the first liquid-containing container 30L is stored, and prevents the liquid L from splashing when the first container 30L is opened. The problem of container leakage and splashing is more serious with toxic liquids, such as highly pharmacologically active drugs. Furthermore, in the example shown in Figure 6, if the first liquid-containing container 30L is under positive pressure, the liquid L will automatically enter the syringe 60. In this case, it becomes difficult to inject the desired amount of liquid L into the syringe 60 with high precision.

On the other hand, highly sensitive liquids, such as food and pharmaceuticals, that are degraded by post-production sterilization processes using gas, heat, gamma rays, etc., are manufactured in a sterile environment and sealed in containers. In other words, liquids that cannot be sterilized using terminal sterilization methods are manufactured using aseptic processing. This sterile environment is typically maintained at a predetermined positive pressure to prevent the entry 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 it is closed.

The specific example described above addresses this problem. As described above, the first container 30L containing the liquid is stored in the second container 40. During this storage, the oxygen concentration in the second container 40 decreases due to inert gas replacement, causing oxygen in the first container 30 to permeate the first container 30 and move into the second container 40. This allows the pressure in the first container 30 to be reduced. In other words, the pressure in the first container 30 containing the liquid L can be adjusted after the first container 30 is closed and the liquid L is sealed inside.

From the perspective of adjusting the internal pressure of the first container 30, a second container 40 capable of containing a gas while maintaining a negative pressure may be used. For example, the second container 40 shown in FIG. 7 may be used, and the second container 40 containing the first container 30 may be closed under an inert gas atmosphere maintained at a negative pressure. The pressure inside the closed second container 40 becomes less than atmospheric pressure. In this case, oxygen transmission from the first container 30 to the second container 40 is promoted. In particular, the pressure inside the first container 30 can be significantly adjusted by ensuring a large volume of the second container 40 or by significantly reducing the initial pressure of the second container 40. As a result, the pressure inside the first container 30, which is initially positive pressure, can be adjusted to negative pressure by storing the first container 30 inside the second container 40. This makes it possible to manufacture a pressure-adjusted liquid-filled first container 30L without relying on the method for producing the liquid L or the method for sealing the liquid L into the first container 30.

In addition, by adjusting the pressure inside the liquid-containing first container 30L, it is possible to extract the desired amount of liquid L from the first container 30. From the perspective of being able to extract the desired amount of liquid L from the first container 30 with high precision, the volume of liquid L contained in the first container 30 may be set to 0.5 mL or more, and more preferably 1 mL or more.

In addition, closing the second container 40 under negative pressure promotes oxygen permeation through the first container 30. Therefore, the time required for oxygen permeation through the first container 30 to reach equilibrium after the second container 40 containing the liquid-containing first container 30L is closed can be shortened.

Note that negative pressure refers to pressure less than atmospheric pressure, or 1 atm. Positive pressure refers to pressure greater than atmospheric pressure, or 1 atm. Note that whether or not a container is under negative pressure can be determined using a pressure gauge if the container is equipped with one. If the container is not equipped with a pressure gauge, it can also be determined using a syringe. Specifically, when a syringe needle is inserted into a target container, it can be determined by determining whether or not the liquid or gas contained in the syringe flows into the container when only atmospheric pressure is applied to the syringe piston. If the liquid or gas contained in the syringe flows into the container, it is determined that the container was under negative pressure. Similarly, whether or not a container is under positive pressure can be determined using a pressure gauge, but it can also be determined using a syringe. Specifically, when a syringe needle is inserted into a target container, it can be determined by determining whether or not the liquid or gas contained in the container flows into the syringe when only atmospheric pressure is applied to the syringe piston. If the liquid or gas contained in the container flows into the syringe, it is determined that there was positive pressure inside the container.

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

In this embodiment, oxygen within the first container 30 can pass through the first container 30 and move into the second container 40. By replacing the atmosphere within the second container 40 with an inert gas, the oxygen concentration (%) within the first container 30 can be reduced. As the oxygen concentration (%) within the first container 30 decreases, the amount of oxygen dissolved in the liquid L (mg/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. Meanwhile, the liquid-filled first container 30L may be responsible for ensuring the sterility of the interior and the contained liquid L. In this way, the storage environment required for the liquid L is efficiently achieved by combining the first container 30 and the second container 40. With the combination container 10 and container set 20, the storage environment required for the liquid L can be achieved inexpensively and easily with a high degree of flexibility.

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

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 may be greater than 0.663 times the volume γ (mL) of the liquid L. According to this example, in an air atmosphere at a temperature of 293 K and atmospheric pressure, the oxygen concentration in the second container 40 can be reduced to less than 1%.

Furthermore, in this embodiment, when the first container 30 is housed inside the second container 40 and the second container 40 is closed, the first container 30 and the second container 40 may house a total volume of gas that is greater than (2.56×10 ⁻⁴ ×β×T) times the volume γ (mL) of the liquid L. 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 housed inside the second container 40 and the second container 40 is closed, the first container 30 and the second container 40 may house a total volume of gas that is greater than 0.663 times the volume γ (mL) of the liquid L. According to this example, the oxygen concentration in the second container 40 can be reduced to less than 1% in an air atmosphere at a temperature of 293 K and atmospheric pressure.

According to the above embodiment, the amount of oxygen dissolved in the liquid L can be reduced, and decomposition of the liquid L due to oxygen can be suppressed. For example, in an application in which a medicine is stored in the first container as a liquid, the loss of the pharmacological ingredient over a three-year period can be reduced to 5% or less, more preferably 3% or less, and even more preferably 1% or less.

If the capacity for storing a large amount of gas were secured using only the first container without using a second container, the excess space within the first container would be larger than the liquid volume γ (mL), making it difficult to remove the liquid from the first container. Furthermore, the liquid would be agitated within the first container, potentially accelerating deterioration due to oxygen. Furthermore, when used with liquids such as food, this would discourage consumers and reduce product appeal. When used with liquids such as medicines, it would be difficult to check the state of the liquid within the first container and remove the appropriate amount of liquid from the first container. In contrast, according to the above-described embodiment, the liquid-filled combination container 10L includes a second container 40 in addition to the liquid-filled first container 30L. Therefore, the excess space within the first container 30 where liquid L is not contained can be reduced. Furthermore, because the second container 40 does not directly contain liquid L, the internal atmosphere of the second container 40 can be easily replaced with an inert gas.

As a specific example of the above-described embodiment, the volume γ (mL) of the liquid L may be greater than half the maximum volume (mL) of the first container 30. By reducing the space within the first container 30 where the liquid L is not contained, the so-called headspace HS, in this way, the amount of oxygen gas remaining in the first container 30 can be reduced when the first container 30 containing the liquid L is closed. This makes it possible to suppress decomposition of the liquid L due to oxygen. Furthermore, the first container 30 that is ultimately removed from the second container 40 can be made smaller, improving the handleability of the first container 30. Furthermore, it is possible to facilitate removal of the liquid L from the first container 30.

More preferably, the volume γ (mL) of the liquid L contained in the first container 30 may be set to 97.5% or more of the maximum volume V1MAX ₍ (mL) of the first container 30. According to this example, the number of moles of dissolved oxygen dissolved in the liquid L in the first container 30 will be greater than the number of moles of oxygen in the headspace HS of the first container 30. As described above, it is difficult to sufficiently reduce the amount of dissolved oxygen dissolved in the liquid L by inert gas substitution. Therefore, this embodiment is particularly useful for a liquid-filled first container 30L in which the volume γ (mL) of the liquid L is 97.5% or more of the maximum volume V1MAX ₍ (mL) of the first container 30.

As a specific example of the above-described embodiment, the sum of the maximum usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX of the second container 40 may be equal to or greater than the sum of the value obtained by multiplying the volume γ (mL) by (2.56×10 ⁻⁴ × (β×T/α)) and the value obtained by multiplying the maximum usable volume EV _1MAX (mL) of the first container 30 by (21.0/α). By using a first container 30 and a second container 40 having such volumes, the first container 30 and the second container 40 can accommodate a sufficient volume of gas. By storing the liquid-filled first container 30L with air contained in the headspace HS in the second container 40, the oxygen concentration in the second container 40 can be reduced to α (%) or less in an equilibrium state in which oxygen permeation through the first container 30 is balanced.

As a more specific example, the sum of the maximum usable volume EV _1MAX (mL) of the first container 30 and the maximum usable volume EV _2MAX of the second container 40 may be greater than the sum of 0.663 times the volume γ (mL) of the liquid L and 21.0 times the maximum usable volume EV _1MAX (mL) of the first container 30. According to this example, by storing the liquid-filled first container 30L with air accommodated in the head space HS in the second container 40, the oxygen concentration in the second container 40 can be reduced to less than 1% in an air atmosphere at a temperature of 293 K and atmospheric pressure.

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

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 a lower limit on the amount of liquid in the first container 30 in this way, a certain amount of liquid can be removed from the first container 30, reducing error in the amount removed.

In a specific example of the above-described embodiment, the first container 30 includes a container body 32 having an opening 33 and a stopper 34 closing the opening 33. The material constituting the stopper 34 may have an oxygen permeability coefficient of 1×10 ⁻¹² (mL/(m ² ×day×atm)) or more. The stopper 34 may be made of silicone rubber. The oxygen permeability coefficient (mL/(m ² ×day×atm)) of the material constituting the stopper 34 may be greater than the oxygen permeability coefficient (mL/(m ² ×day×atm)) of the material constituting the container body 32. According to this specific example, oxygen permeates through the stopper 34 and moves out of the first container 30. Therefore, oxygen permeability can be imparted to a region of the first container 30 exposed to the liquid L, such as a so-called headspace HS. This allows oxygen to permeate smoothly through the first container 30, thereby shortening the time required for oxygen permeation through the first container 30 to reach equilibrium after the first container 30 is placed in the second container 40.

In one specific example of the above-described embodiment, the container body 32 may have oxygen barrier properties. Oxygen that has permeated the first container 30 enters an area separated from the liquid L, such as the headspace HS within the first container 30. Therefore, dissolution of oxygen that has permeated the first container 30 into the liquid L can be suppressed.

One embodiment has been described with reference to specific examples, but the above-mentioned specific examples do not limit the embodiment. The above-mentioned embodiment can be implemented with various other specific examples, and various omissions, substitutions, modifications, additions, etc. can be made without departing from the spirit of the embodiment.

An example of a modification will be described below with reference to the drawings. In the following description and the drawings used in the following description, parts that can be configured similarly to the above-mentioned specific example will be designated by the same reference numerals as those used for the corresponding parts in the above-mentioned specific example, and duplicate descriptions will be omitted.

In the above specific example, the specific configuration of the first container 30 was described, but this is not limiting and various containers may be used. For example, as shown in FIG. 8, the stopper 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 using, for example, a bonding material or by welding. The stopper 34 may be oxygen permeable or may have oxygen barrier properties.

Figure 9 shows another modified example of the first container 30. The first container 30 shown in Figure 9 is a syringe 60. Similar to the syringe already described with reference to Figure 6, the syringe 60 shown in Figure 9 has a cylinder 62 and a piston 66. The cylinder 62 has a glass or resin cylinder body 63 and a metal needle 64. The cylinder 62 is the container body 32 of the first container 30 and forms a storage space for the liquid L. The piston 66 has a glass or resin piston body 67 and a gasket 68 disposed within the opening 33 of the cylinder 62. The gasket 68 is the stopper 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 further has a cap 69. The cap 69 is removably attached to the needle 64. The cap 69 prevents leakage of the liquid L from the needle 64 and seals the liquid L in the syringe 60. In the example shown in Figure 9, by using the syringe 60 as the first container 30, the syringe 60 can be used on a patient or the like after being removed from the second container 40.

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

In the example shown in Figure 9, oxygen passes through the gasket 68, causing oxygen to be expelled from the interior of the first container 30, which is partitioned by the cylinder body 63 and the gasket 68. This reduces the oxygen concentration within the syringe 60, and the amount of dissolved oxygen in the liquid L decreases. As a result, decomposition of the liquid L due to oxygen can be effectively suppressed.

In the specific example described above, the first container 30 has a container body 32 and a stopper 34, and the stopper 34 is gas permeable. However, at least a portion of the container body 32 may be gas permeable, and the stopper 34 may have gas barrier properties. Furthermore, 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: Fixing device, 40: Second container, 40a: Opening, 41a: First main film, 41b: Second main film, 41c: First gusset film, 41d: Second gusset film, 42: Container body, 42a: Storage section, 42b: Flange section, 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 of volume γ (mL) and at least a portion of which is oxygen permeable;
a second container that houses the first container and has oxygen barrier properties;
the sum of 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) of the first container from the maximum volume (mL) of the second container is equal to or greater than (2.56×10 ⁻⁴ × (β×T/α)) times the volume γ (mL), where T is the temperature (K) of the environment, β is the saturated solubility (mg/L) of oxygen in the liquid in an air atmosphere under atmospheric pressure at the temperature T (K), and α is the oxygen concentration (%) in the second container;
the first container is a vial bottle having a glass container body with an opening and a stopper containing silicone that closes the opening,
The liquid-filled combination container , wherein the amount of oxygen permeating the entire first container is 1×10 ⁻² (mL/(day×atm)) or more and 100 (mL/(day×atm)) or less . The liquid-filled combination container according to claim 1, wherein the oxygen concentration α is less than 1%. A liquid-containing combination container as described in claim 1 or 2, wherein the sum of 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 is greater than or equal to the sum of the value obtained by multiplying the volume γ (mL) by (2.56 x 10 ^-4 x (β x T/α)) and the value obtained by multiplying the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container by (21.0/α). a first container containing a liquid of volume γ (mL) and at least a portion of which is oxygen permeable;
a second container that houses the first container and has oxygen barrier properties;
the sum of 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 is equal to or greater than (2.56×10 ⁻⁴ ×β×T) times the volume γ (mL), where T is the temperature (K) of the environment, and β is the saturated solubility (mg/L) of oxygen in the liquid in an air atmosphere under atmospheric pressure at the temperature T (K);
the first container is a vial bottle having a glass container body with an opening and a stopper containing silicone that closes the opening,
The liquid-filled combination container , wherein the amount of oxygen permeating the entire first container is 1×10 ⁻² (mL/(day×atm)) or more and 100 (mL/(day×atm)) or less . The liquid-containing combination container according to claim 3, wherein the sum of 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 is greater than or equal to the sum of the value obtained by multiplying the volume γ (mL) by (2.56 x 10 ^-4 x β x T) and the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container by 21.0. A liquid-filled combination container according to any one of claims 1 to 5, wherein the volume γ (mL) is greater than half the maximum volume (mL) of the 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. The liquid-filled combination container according to any one of claims 1 to 8, wherein the first container is capable of containing gas while maintaining a negative pressure. a first container containing a liquid of volume γ (mL) and at least a portion of which is oxygen permeable;
a second container capable of accommodating the first container and having oxygen barrier properties;
the sum of 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 is greater than 0.663 times the volume γ (mL);
the first container is a vial bottle having a glass container body with an opening and a stopper containing silicone that closes the opening,
The container set , wherein the amount of oxygen permeating through the entire first container is 1×10 ⁻² (mL/(day×atm)) or more and 100 (mL/(day×atm)) or less . The container set described in claim 10, wherein the sum of 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 is greater than the sum of the value obtained by multiplying the volume γ (mL) by 0.663 and the value obtained by multiplying the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container by 21.0. The container set described in claim 10 or 11, wherein the volume γ (mL) is greater than half the maximum volume (mL) of the first container. The container set described in any one of claims 10 to 12, wherein the volume γ is 0.5 mL or more. The container set described in any one of claims 10 to 13, wherein the volume γ is 20 mL or less. The container set described in any one of claims 10 to 14, wherein the first container is capable of storing 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 liquid of volume γ (mL) and is at least partially oxygen permeable;
the second container has oxygen barrier properties,
When the first container is contained and the second container is closed, the first container and the second container contain a total volume of gas that is greater than (2.56×10 ⁻⁴ ×β×T) times the volume γ (mL), where T is the temperature of the environment (K), and β is the saturated solubility (mg/L) of oxygen in the liquid in an air atmosphere under atmospheric pressure at the temperature T (K);
the first container is a vial bottle having a glass container body with an opening and a stopper containing silicone that closes the opening,
The method for manufacturing a liquid-filled container , wherein the amount of oxygen permeating the entire first container is 1×10 ⁻² (mL/(day×atm)) or more and 100 (mL/(day×atm)) or less . 17. The method for manufacturing a liquid-filled container according to claim 16, wherein, when the first container is housed and the second container is closed, the first container and the second container together contain a volume of gas that is greater than the sum of the volume γ (mL) multiplied by (2.56×10 ⁻⁴ ×β×T) and the maximum volume (mL) of the first container minus the volume γ (mL) multiplied by 21.0. The method for manufacturing a liquid-filled container according to claim 16 or 17, wherein the volume γ (mL) is greater than half the maximum volume of the 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 is capable of containing gas while maintaining a negative pressure.