JP2000238854A - Freeze-drying container and composite container including the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a highly sterile freeze-drying container in a manufacturing process by constituting a lid member of a filter impermeable to bacteria. SOLUTION: The freeze-drying container 1 has a lid member 4 comprising a filter 5 impervious to bacteria. During a manufacturing process, a cup member 3 is sterilely filled with solution of antibiotic 2 in a highly clean sterile chamber. Then the lid member 4 which has gone through dust-free and sterilization treatment is attached to an opening 3A of a cup-like member 3 by a peelable heat seal and frozen in a freeze-drying device, so that moisture is vaporized and removed by reduced pressure. Steam gas comes out into the device through the filter 5. Since the freeze-drying container 1 has its solution free from direct contact with an atmosphere during freezing and drying of the solution, sterile or dust-free control during its operation period is extremely easy. Since the internal steam gas is discharged through the filter 5 during drying, there is no problem in drying.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a lyophilization container for lyophilizing contents and a composite container suitably utilizing the lyophilization container. More specifically, the present invention relates to a lyophilized container that can easily obtain a lyophilized product having high sterility in a manufacturing process, and a composite container that allows the lyophilized container to be used conveniently and safely.

[0002]

2. Description of the Related Art Medical drugs include freeze-dried products. Lyophilizates are usually provided in vials with rubber stoppers. The vial containing the lyophilized product is performed according to the following manufacturing process. First, a vial and a rubber stopper, which are glass containers, are washed, rinsed, dried, and then sterilized. Next, the vials and rubber stoppers are brought into a sterile and dust-free room. The vial is filled with the drug solution that has passed through the sterilization filter. A rubber stopper is attached to the vial filled with the drug solution in a half stoppered state. The vial is carried into a freeze-drying apparatus, and the drug solution in the vial is frozen and dried, and water is removed to produce a freeze-dried product. Next, the vial rubber stopper is completely stoppered from a half stoppered state, and is provided as a vial of a lyophilized product by covering an aluminum cap or the like.

When the above vial is used, a solution of the drug is required. Recently, a composite container in which the vial and the dissolving solution are combined has been proposed. In a conventional composite container, a storage container for a solution is formed of a resin container, and the resin container has a connection port with a vial in addition to an outlet through which a drip needle is pierced. And, between the vial and the connection port, a double-ended needle-type communication needle that pierces the vial rubber plug and pierces the rubber plug of the connection port is arranged. The connecting portion between the vial and the resin container has a structure in which the communicating needle is placed in an aseptic environment. At the time of use, the inside of the resin container and the inside of the vial can be aseptically used by inserting the communication needle into both rubber stoppers. Also, a method of manufacturing a medical container has been proposed in which a peelable weak seal portion is formed in each of the first container member and the second container member, and the weak seal portions are connected to each other (Japanese Patent Laid-Open No. 8-215285). Gazette). In such a medical container, a main component such as an infusion solution is stored in a second container member, and a freeze-dried product is stored in a first container member. The lyophilizate is manufactured in a separate lyophilization container and is aseptically transferred into the first container member. When the medical container is used, the weak seal is peeled off, and the infusion solution and the medicine are mixed.

[0004]

However, in the conventional freeze-drying of vials, due to the manufacturing process, it is necessary to strictly control and maintain a dust-free and sterile room at the time of filling, freezing, and drying of the chemical solution. . In particular, when frozen, the rubber stopper is in a half-plugged state, which lasts for a long time. For this reason, in the production process of the lyophilized product, it is often difficult to easily obtain a lyophilized product having high sterility. Further, in a conventional composite container, a portion having a communication needle is complicated, and a structure for maintaining a complicated connection portion aseptically is often very difficult. In the transfer type composite container, it is generally difficult to control and maintain dust-free and sterility in the operation process when transferring the freeze-dried product.

[0005] When a resin container member is connected to a container member in a composite container, there are mainly two types of connection structures or methods. In the first connection structure, the connection port of another container member is inserted into the connection port of one container member, and the two are connected by heat sealing from the outside of the connection port of one container member. The second connection structure abuts the connection port of one container member with the connection port of another container member, covers the butted portion with a connection sheet, and heat seals the connection sheet and the outer wall of each connection port to connect the two. Is what you do.
Conventionally, such connection between the container members is performed aseptically using a sterile chamber, thereby improving the sterility of the connection portion of the resin container. Further, in order to enhance the sterility of the connecting portion, it has been proposed to irradiate the connecting portion with an ultraviolet ray, a gamma ray, an electron beam or the like (Japanese Patent Laid-Open No. 9-10283).
No.). However, conventional sterilization of the connection portion by irradiation with ultraviolet light cannot achieve high sterility or sterility. That is, even if the connection wall or connection sheet of the connection port of one resin container is a polyolefin resin wall having transparency and no polar group or the like, ultraviolet rays do not sufficiently penetrate into the inside of the connection. In addition, gamma rays, electron beams, and the like can sufficiently penetrate the connecting wall because the irradiation rays are strong. However, there are many disadvantages with such radiation. The first is that the irradiation apparatus is large and is not suitable for a large-scale production line. Second, since X-rays and the like are generated as by-products from the apparatus, there is a disadvantage that the X-rays affect the contents of the container body other than the connection portion. Third, since the temperature of the connection portion may be increased, the heat seal at the connection portion may be broken.

Accordingly, it is an object of the present invention to provide a freeze-dried container in which a freeze-dried product having high sterility can be easily obtained in the production process. Another object of the present invention is to provide a composite container that does not require complicated operations such as transfer of a lyophilized product using the lyophilized container, and that the sterilization or sterility of the connection between the container members is sufficiently improved. It is an object of the present invention to provide a composite container which can be increased and which can be easily sterilized without causing any other trouble on a production line without causing breakage at the connection.

[0007]

SUMMARY OF THE INVENTION The present invention relates to a container for lyophilizing contents, a cup-shaped member for containing the contents, a lid member for sealing an opening of the cup-shaped member,
The above object has been attained by providing a lyophilization container characterized in that the lid member comprises a filter impermeable to bacteria.

The freeze-dried container of the present invention is one in which a solution to be freeze-dried is aseptically filled, and the solution is frozen and dried in the container. The freeze-drying container of the present invention comprises a cup-shaped member for accommodating contents, and a lid member for sealing an opening of the cup-shaped member. The cup-shaped member may be made of a metal such as aluminum or steel, or may be a ceramic such as glass,
Synthetic resin may be used. In consideration of the disposal of the container, a synthetic resin or the like is desirable. If the contents in the lyophilization container are pharmaceuticals, it is desirable that the cup-shaped member has such transparency that the contents can be checked. In this regard, the cup-shaped member is preferably made of glass or synthetic resin. The synthetic resin may be a thermoplastic resin or a thermosetting resin. Desirably, the molded synthetic resin of the cup-shaped member is a thermoplastic resin. Examples of the thermoplastic resin include general-purpose resins such as polyolefin resin, vinyl chloride, vinylidene chloride resin, polyester resin, polyvinyl alcohol resin, polyacrylonitrile resin, polyacrylic acid resin, and polyamide resin. Further, the resin wall may be formed in a single layer or a multilayer. Since the purpose of use of the container according to the present invention is mainly for accommodating a medical drug, the innermost layer that comes into contact with the drug in the container member is a resin layer that does not affect the drug and does not generate eluted substances. Desirably. As such a resin, a polyolefin-based resin is desirable, and examples thereof include low-, medium-, and high-density polyethylenes, lower olefin resins such as polypropylene, cyclic polyolefins having gas barrier properties and water vapor barrier properties, and copolymers thereof. Can be

The cover member may be entirely formed of a filter. Further, in order to make it easy to attach the lid member to the opening of the cup-shaped member, the filter may not be entirely formed, and the periphery of the filter may be constituted by another supporting or bonding member. It may have a multilayer structure. The above filter has a rejection of 99% or more at a particle size of 1.2 μm, more preferably a filter having a rejection of 99% or more at a particle size of 0.8 μm, preferably at least 99% at a particle size of 0.45 μm. Those having a rejection rate, in particular, a particle size of 0.22μ
It is desirable that the resin has a rejection of 99% or more in m. A filter having a rejection rate lower than the above range may not be able to sufficiently block bacteria, and if the rejection rate is in the above range, a sterilization maintaining effect can be expected. In particular, a particle size of 0.45μ
With an inhibition rate of 99% or more at m, most bacteria can be blocked, and at an inhibition rate of 99% or more at a particle size of 0.22 μm, an effect of removing particles by destruction of bacteria can be expected. The filter is desirably a material that can be subjected to ethylene oxide gas sterilization or high-pressure steam sterilization. Examples of such a material include polyolefin resins such as polyethylene and polypropylene, cellulose mixed esters, and polyvinylidene fluoride. Can be. The filter of the present invention may be a hydrophilic filter that allows an aqueous solution to pass through, or a hydrophobic filter that does not allow an aqueous solution to pass through. However, when a freeze-dried container is used for the composite container of the present invention described later, the container is limited to a hydrophobic filter. This is because the dissolving solution flows into the cup member when the composite container is used, and if the filter of the lid member is hydrophilic, the dissolving solution may flow out through the filter.

According to the freeze-drying container of the present invention, in the manufacturing process, the solution to be freeze-dried is filled in a cup-shaped member in a dust-free and sterile room, and the cup-shaped member is sealed with a lid member serving as a filter. Is done. If the filter is hydrophilic,
Before filling the lyophilized solution into the cup-shaped member, the opening of the cup-shaped member may be sealed with a lid member and sterilized. The lyophilized solution can be filled through a filter. In this case, since the cup-shaped member is not directly exposed to the outside air before filling, the sterility in the cup-shaped member is further enhanced. In the freeze-dried container having the above configuration, when the solution to be freeze-dried is frozen,
Since the solution does not come into direct contact with the outside air during drying, aseptic or dust-free management of the operation period is facilitated. At the time of drying, from the viewpoint of the function of the filter, the internal water vapor gas is easily discharged to the outside through the filter, so that there is no problem in drying. Furthermore, if a desiccant or an oxygen scavenger is disposed outside the lid member with the filter of the freeze-drying container, there is no danger that the contents will be deteriorated by the presence of oxygen or moisture during the storage period.

[0011] The freeze-dried container according to the second aspect of the present invention comprises:
The container according to claim 1, wherein the opening of the cup-shaped member and the lid member are adhered by a peelable heat seal. If the opening and the lid member can be easily attached by heat sealing, the sealing operation after filling the freeze-dried solution becomes extremely easy. Further, since the heat seal is peelable, it can be easily opened even during use.

A composite container according to a third aspect of the present invention is a composite container including the freeze-drying container according to the second aspect,
A resin sheet is provided at each of the opening and the lid member of the cup-shaped member of the freeze-drying container, and the heat-sealing portion that can be peeled off is formed on the resin sheet or the lid member. The bag-shaped member formed integrally or separately and formed of the resin sheet is connected to a container member containing a solution for dissolving the contents, and the container member is peeled off at the connection portion. It has a possible isolation seal portion, and is characterized in that it can communicate with the bag-shaped member when the isolation seal portion is opened in use.
Thereby, the object according to the present invention is achieved.

The opening of the above-mentioned freeze-drying container and the lid member are heat-sealed releasably via a resin sheet or a sheet-like lid member. Forming and sealing a peelable heat seal on a resin sheet is extremely simple in the manufacturing process. The resin sheets are integrally or separately formed in a bag shape, and the bag-shaped member made of the resin sheet is
It is connected to the container member described below. The resin sheets may be formed of two resin sheets, may be formed by bending and overlapping one resin sheet, or an inflation sheet may be used. Holes are formed in the sheet forming the resin sheet, and each hole serves as an opening portion of the cup-shaped member and a mounting portion of the filter, and a peripheral edge or an edge thereof is subjected to a heat seal that cannot be peeled off from each other, It is formed in a bag shape.

The resin sheet is made of a polyolefin resin, vinyl chloride, vinylidene chloride resin, polyester resin, polyvinyl alcohol resin, polyacrylonitrile resin, similar to the material of the container member for connection described later. It is a general-purpose resin such as a polyacrylic resin and a polyamide resin. Further, the resin wall may be formed in a single layer or a multilayer. Since the purpose of use of the container according to the present invention is mainly for accommodating a medical drug, the innermost layer that comes into contact with the drug is desirably a resin layer that does not affect the drug and does not generate eluted substances. . As such a resin,
Polyolefin-based resins are desirable, and examples thereof include low-, medium-, and high-density polyethylenes, and lower olefin resins such as polypropylene. In addition, as described later, the connection port of the bag-shaped member may be irradiated with a high-energy pulsed light from the outside. As such a resin, a resin such as a polyolefin-based resin is generally desirable, not a polymer having a polar group composed of chlorine, oxygen, nitrogen or the like.

The above-mentioned peelable heat seal portion or isolation seal portion is usually called a peel seal or a weak seal, and can be peeled off when a room or a container is pressed from the outside and the inside is kept at a constant pressure. It is a seal or the like that can be peeled off when the seal portion or the outer wall of the container is gripped and pulled. The peel strength of the peelable seal portion is such that the indoor pressure is 0.01 to 1.0 kgf.
/ Cm ² , in particular, a peeling strength at a pressure increase of 0.05 to 0.5 kgf / cm ² is desirable. If the strength is lower than the above range, the safety for maintaining an isolated state during production, transportation, storage, etc. is lacking. If the strength exceeds the above range, there is a possibility that the communication operation of the connecting portion cannot be easily performed at the time of use.

When forming the peelable hermetic seal between the walls or forming the non-peelable hermetic seal, the inner layer of the wall must be a blend of different resins in order to ensure that they are formed differently. It is desirable that In particular, it is desirable that the different resins be made of resin blends that have different thermal melting onset temperatures or biquad softening points and are not very compatible. By having such a blended material layer, it is possible to easily set the sealing temperature conditions for complete hermetic seal bonding with the same inner layer, but also to easily set the sealing temperature conditions for peel seal bonding. In particular, the relationship between the seal strength required for peel seal adhesion, that is, the easy peelability due to external force during use, and the seal strength that does not cause peeling during storage can be strictly set. In this method, a resin having different compatibility is melt-mixed in the inner layer and formed into a sheet to form a surface which is microscopically separated into portions having different thermal adhesiveness. Then, by deciding the thermal fusibility of the microscopic part between the surfaces of the sheet at an arbitrary temperature, the strength of the seal strength is accurately given,
The above effects are easily achieved.

The bag-like member made of the resin sheet is connected to a container member containing a solution for dissolving the contents at the time of use. The freeze-drying container is connected to the container member containing the lysing solution via the bag-shaped member that is the resin sheet. Therefore, the lyophilization container is included as a part of the composite container. The container member has a detachable isolation seal portion at the connection portion, and is connected to the bag-like member by opening the isolation seal portion during use. The container member is formed by blow molding, air pressure molding, vacuum molding, or injection molding, or is formed by appropriately cutting a film or sheet and sealing the peripheral edge by heat welding. As the resin used for the container member, the same resin as the resin sheet can be used as described above. The container member can be easily formed with a detachable seal portion and a non-peelable peripheral seal portion like the connection portion.

In the composite container constructed as described above, in the manufacturing process, the lyophilized product in the lyophilized container can be stored in a simple and highly sterile and safe state. In addition, the lyophilization container and the container member containing the lysis solution can be filled with the drug in different places. Therefore, it is possible to easily provide a filling facility for each type of antibiotic.
In addition, at the time of its use, the isolation seal portion is broken by pressing the container member from the outside, the inside of the connection portion is communicated, the inside of the bag-like member is filled with the solution, and the heat seal portion is further peeled. This allows the solution to flow through the lyophilization container. At the time of use, the drug in the lyophilization container can be easily dissolved aseptically in the dissolution solution. Then, such a mixed solution can be injected via a drip needle.

A composite container according to a fourth aspect of the present invention is the composite container according to the third aspect, wherein the connection portion is formed by heat sealing, and is connected aseptically or sterilized by irradiation. And The composite container of the present invention is a medical container or the like that stores an infusion solution, a dialysate, or the like to be injected into a body or the like. The contents are usually housed in a sterilized or aseptic condition. In order for such a sterilized or aseptically accommodated drug to be aseptically mixed at the time of use, high sterility or sterility is maintained in the connection between the bag-shaped member and the container member that are communicated during mixing. Must be connected in state.

The connection portion of the composite container is mainly constituted by inserting the connection port of the container member into the connection port of the bag-shaped member and heat-sealing the connection portion of the bag-shaped member from the outside of the connection port of the bag-shaped member so as not to be peeled off. The connection port is abutted with each other, and the abutted portion is covered with a connection sheet or the like, and is heat-sealed so as not to be peeled off. The connecting portion is preferably formed in a sterile room or the like, and the connecting portion is preferably sterilized by irradiation sterilization to the inside of the connection port or the inside of the connection sheet. If such a connection portion has high sterility or sterility, safety during use thereof is extremely enhanced. As the irradiation sterilization,
There are gamma irradiation, electron beam irradiation, irradiation sterilization by ultraviolet rays and the like. Among the above-mentioned irradiation sterilization, irradiation with a high-energy pulsed light beam described below is desirable.

According to a fifth aspect of the present invention, there is provided the composite container according to the fourth aspect, wherein the irradiation sterilization of the connection portion is an irradiation sterilization using a pulsed light beam for increasing the energy of a light emitting lamp by a pulse electric field processing apparatus. It is characterized by the following. The above-described pulse electric field processing apparatus is generally roughly divided into a charge supply circuit, a controller, a switch, and the like. Electrodes from the charge supply circuit have a high intensity electric field pulse, that is,
Supplied with an electric field strength of 2000 V / cm or more, preferably 5000 V / cm or more, and more preferably 10,000 V / cm or more. The light emitting lamp is connected to the pulse electric field processing apparatus, and the light emitting lamp emits a high-energy pulsed light beam.

The above-mentioned light-emitting lamp comprises a sealed tube and an inert filling gas. The light-emitting lamp can emit pulsed light in different wavelength ranges depending on the kind of glass material and the kind of gas of the sealed tube. Cerium glass, gel machine, quartz glass, sapphire glass and the like can be cited as the lamp glass of the above-mentioned light-emitting lamp, and particularly preferred are quartz glass and sapphire glass which can sufficiently contain an ultraviolet region. The sealing gas may include mercury, metahalide, xenon, etc.
Xenon, which emits pulsed light in a wide wavelength range close to natural light, is desirable. In order for the above-mentioned pulsed light to become the above-mentioned high-energy light, it is desirable that the emission time of the amplified pulse be 1/1000 second or less and 1/1000000000 second or more in view of the function of the pulse electric field processing apparatus. The pulse output intensity of the lamp, i.e. the energy of a single flash per unit area, can be monitored by a silicon photodiode as its ultraviolet (UV) amount. The output intensity (fluence), that is, the amount of light energy per unit area (J / cm ² ) can be represented by the monitor. The output intensity of the pulse light per single flash is in the range of 0.1 to 4.0 J / cm ² .

In the composite container of the present invention, the
In the middle, the contents are pre-sterilized or pre-sterilized in each resin container member.
Can be autoclaved. Soshi
Then, as a final step, the bag-like member and the container member are connected.
In this case, bring the above container members into a clean room.
Easy to connect or dock with heat seal etc.
Can be And the above-mentioned pulse
When illuminated, the rays are tens of thousands times stronger than sunlight.
Since there is a sufficient amount of light, enough light rays reach the inside of the connection section.
Permeate inside the connection part and stain inside the connection part when connecting or docking.
Trace amounts of viable microorganisms or bacteri that may be stained
Bacteria such as rear spores can be sterilized. In particular,
The instantaneous output intensity of the ultraviolet light in the pulsed light is normal mercury purple.
1000 times the continuous output intensity of outside line lamps
That is all. Actually, it is 10 at best with ordinary ultraviolet rays. ³Oh
Could only sterilize the
The number of pulsed rays is 10⁹Can sterilize more than the order
You.

[0024] By repeating a predetermined number of times of irradiation as by transmitting resin wall of the connecting portion sufficiently penetrate the pulse beam to the connection portion, sterilization in the ¹⁰⁶ order is fully enabled. Since the device for emitting the above-mentioned pulse light does not emit any inconvenient light at all, it does not affect the freeze-drying container and the container body in which the contents are stored. In addition, the device is extremely compact. Furthermore, since such a pulsed light beam is repeatedly irradiated instantaneously, there is no possibility that the connection portion will be in a high temperature state and the seal will be damaged. Therefore, the inside of the connection portion of the container is sufficiently sterilized by a simple device, and in the composite container in which the connection portion is sterilized in such a manner, the connection portion is distributed through the connection portion in combination with the high sterility of the lyophilization container. The contents at this time are not contaminated by bacteria, and excellent safety is obtained as a medical container.

The composite container according to claim 6 of the present invention is the composite container according to claim 5, wherein the pulse output intensity (single flash energy per unit area) of the lamp by the pulse electric field processing device is 1.25 J /. cm ² or more, and the total output received by the connection from the lamp is 2.
It is characterized by being at least 5 J / cm ² .

The pulse output intensity of the lamp, that is, the energy of a single flash per unit area, can be monitored by the silicon photodiode for the amount of ultraviolet rays (UV) as described above. In the present invention, the pulse output intensity is 1.25 J / cm ²
As described above, it is particularly desirable that it be 2.50 J / cm ² or more. If the output intensity is within the above range, the connecting portion inside until high energy of light to penetrate, and the inside of the bacteria adhering to the time of connection can be sterilized ¹⁰⁶ orders or more. If falls below the above range, it is possible to at most in the order of 10 ⁴ orders sterilization. Further, the output amount from the lamp to be illuminated in the connection part 2.5 J / cm ² or more, it is desirable in particular 4.0 J / cm ² or more. If the irradiation is performed within the above range, the inside of the connection portion is reliably sterilized, and the safety at the connection portion is sufficiently obtained.

The composite container according to claim 7 of the present invention is characterized in that, in the composite container according to claim 6, the lamp is made of xenon gas and quartz glass or sapphire glass. If the gas sealed in the lamp is xenon, light having a wavelength close to the natural wavelength, ultraviolet light, and other wide wavelengths can be emitted as compared with other gases, and the gas itself is suitable for pulsed light emission. If the sealing tube is quartz glass or sapphire glass, the wavelength range is 150 to 6000 n.
m, and the pulsed light can be used sufficiently for sterilization.

The composite container according to claim 8 of the present invention is the composite container according to claim 5, wherein the connection port of the container member is inserted into the connection port of the bag-shaped member or the connection port of the container member is inserted into the connection port of the container member. The connection port of the bag-shaped member is inserted, and the connection port of the bag-shaped member or the connection port of the container member has a wall thickness of 2 mm.
The connection portion is formed in a range of 0 to 1000 μm and heat-sealed from the outside of the wall. In the composite container according to the third aspect, as described above, the main structure of the connection portion is such that the connection port of the container member is inserted into the connection port of the bag-shaped member, and heat is applied from outside the overlapping connection portion. Sealed ones, or ones in which connection ports are abutted to each other as described later, the joints thereof are covered with a sheet or the like, and connected by a heat seal via the sheet can be cited.

When the connection port of the container member is inserted into the connection port of the bag-shaped member and heat-sealed, the inside of the connection port of the bag-shaped member may be exposed to outside air at the time of connection and may be contaminated. For this reason, it is necessary to penetrate the pulse light into the connection port. The thickness of the wall of the connection port of the bag-shaped member is preferably in the range of 20 to 1000 μm, particularly 50 to 400 μm. Within the above range, the pulsed light can penetrate into the connection port while maintaining high energy, thereby ensuring sterilization at such a place. If the thickness of the wall of the connection port is less than the above range, the mechanical strength of the connection portion or the mechanical strength of the container member will be weak. If the thickness of the wall of the connection port exceeds the above range, even if the wall is a polyolefin-based resin having transparency, the pulse light cannot penetrate into the connection port while maintaining high energy. The thickness of the resin wall containing a polar element such as vinyl chloride is desirably 300 μm or less in order not to sufficiently transmit light depending on the wavelength range. Note that a structure may be employed in which the isolation seal portion of the container member is not provided at the very end of the connection end but provided in the middle, and the connection port of the bag-shaped member is inserted into the connection port of the connection section of the container member.

The composite container according to a ninth aspect of the present invention is the composite container according to the fifth aspect, wherein the connection port of the bag-like member and the connection port of the container member abut, and the abutted connection port has a thickness of 20 mm. It is characterized in that the connection portion is formed by covering with a connection sheet in a range of up to 1000 μm and heat-sealing the connection sheet to an outer wall of each connection port. As described above, the connection portion can be configured via the connection sheet. In this case, the joint portion covered with the connection sheet may be exposed to the outside air at the time of the connection.
For this reason, if the connection sheet is also within the above-described range, the joint portion can be reliably sterilized by the pulsed light.

A composite container according to a tenth aspect of the present invention is the composite container according to the third aspect, wherein the container member is subjected to an autoclave sterilization process before being connected to the bag-shaped member. In the case of a medical container, when the contents are an infusion or a dialysate, it is desirable to carry out autoclave sterilization. On the other hand, contents that easily change such as antibiotics and chemicals must be filled aseptically rather than by autoclave sterilization. In the present invention, one container member containing a solution such as an infusion solution is subjected to autoclave sterilization before connection, and another container member filled aseptically can be easily connected thereto. And the sterilization of the connection part can be made surely, simply and safely.

[0032]

EXAMPLES Examples of the freeze-drying container and the composite container of the present invention will be described below in detail. 1 (A) and 1 (B) are a side view of a freeze-drying container of the present invention and a rear view of a lid member thereof. 2 (A) and 2 (B) are a plan view of the composite container of the present invention and a schematic partial cross-sectional view of a connecting portion thereof. FIG. 3 is a plan view of a bag-shaped member to which the freeze-drying container of the present invention is attached. FIG. 4 is a plan view showing a state where a cup member is attached to the bag-like member of FIG. FIG. 5 is a plan view in which a lid member is attached to the bag-like member of FIG. 4 to provide a freeze-drying container. FIG.
(A), (B), and (C) are schematic diagrams showing a process of attaching a freeze-drying container to a bag-like member and performing freeze-drying. FIG. 7 is a schematic diagram showing a step of irradiating the connection part of the composite container of FIG. 2 with irradiation. FIG. 8 is a schematic cross-sectional view of a connection portion and a freeze-drying container portion when the composite container of FIG. 2 is used.
FIG. 9 is a schematic cross-sectional view of the connecting portion showing another usage mode of the connecting portion of the composite container according to the present invention.

As shown in FIG. 1, a container 1 for freeze-drying an antibiotic 2, comprising a cup-shaped member 3 containing the antibiotic 2 and a lid member 4 for sealing an opening 3 A of the cup-shaped member 3. , The lid member 4 comprises a filter 5 which is impermeable to bacteria.

To further explain the freeze-drying container 1 of the present embodiment, the antibiotic 2 is aseptically filled in the cup-shaped member 3 in a solution state, and freeze-dried in the cup-shaped member 3. The cup-shaped member 3 is obtained by molding a plate-like material obtained by co-extrusion of different resins by air pressure molding. The inner layer resin is made of low density polyethylene, and the outer layer is an ethylene / cyclic olefin copolymer (manufactured by Mitsui Petrochemical Industries, Ltd.). Brand name Apel). The moisture permeability of the wall of the cup-shaped member 3 is 0.09 g / m ^2.
24 hours (temperature 40 ° C, RH 90%).

The lid member 4 for sealing the opening 3A of the cup-shaped member 3 comprises a donut-shaped support plate made of low-density polyethylene and a filter 5 supported by the support plate.
The filter 5 is formed by applying a polyethylene terephthalate fiber to a polyvinylidene fluoride-based filter, and is fixed to a support plate via the polyethylene terephthalate fiber. The filter 5 has a particle diameter of 0.22 μm, a rejection of 99% or more, and is impermeable to bacteria. The filter 5 is a hydrophobic filter that allows water vapor gas to pass substantially free, but does not allow any aqueous solution to pass therethrough. The bubble point of the filter 5 is 5 kg / cm ² . Medical containers are usually
Since a pressure-resistant wall of 1.0 g / cm ² or more is sufficient, the filter 5 is a water-resistant wall sufficient as the pressure-resistant wall. The lid member 4 and the opening 3A are bonded by a heat seal, and the heat seal portion is a peelable seal. The lid member 4 is provided with a knob 7 for opening.

In the manufacturing process of the freeze-dried container 1 of this embodiment, first, the cup-shaped member 3 is sufficiently dust-free and sterilized. Antibiotic 2 in cup member 3 in a clean room
Is filled aseptically. Next, the cup-shaped member 3 is formed by a heat seal from which the dust-free and sterilized lid member 4 can be peeled off.
Attached to the opening 3A. Next, the freeze-drying container 1 is carried into a freeze-drying apparatus having a reduced rank of cleanliness. The solution in the freeze-drying container 1 is frozen in the freeze-drying device, and the water is evaporated and removed under reduced pressure. The vapor gas escapes through the filter 5 into the device. Thereby, the antibiotic 2 which is a freeze-dried product is generated in the freeze-drying container 1. Next, a desiccant 6 is placed outside the filter 5.
Is arranged. Note that an oxygen scavenger or the like may be provided.

During storage, since the cup-shaped member 3 is made of a resin wall that is permeable to steam- and gas-resistant gas, moisture and oxygen in the container are very small even if they are transmitted. Such a small amount of moisture or oxygen easily passes through the filter 5 and is absorbed by the desiccant 6 or the oxygen scavenger. For this reason,
The inside of the cup-shaped member 3 is maintained at the same atmosphere as that of the desiccant room or the oxygen absorber room. Also, when using it,
By pulling the knob 7, the lid member 4 can be easily removed from the opening 3A. In the freeze-drying container 1, it can be seen that the solution does not come into direct contact with the outside air when the solution is frozen and dried, so that sterility or dust-free management during the operation period is extremely easy. At the time of drying, the internal steam gas is released to the outside through the filter 5, so that there is no problem in drying. Furthermore, if a desiccant 6 or a deoxidizer is disposed outside the lid member 4 having the filter 5 of the freeze-drying container 1, the antibiotic 2 may be deteriorated during storage by the presence of oxygen or moisture. Absent.

Next, an embodiment relating to the composite container of the present invention will be described with reference to FIGS. As shown in FIGS. 2 to 11, the composite container 10 of the present embodiment includes the freeze-dried container 1. The composite container 10 contains the lyophilized container 1
The resin sheets 16A and 16B are provided in the opening 3A and the lid member 4 of the cup-shaped member 3 respectively, and the peelable heat seal portion 24 is formed on the resin sheets 16A and 16B. , 16B are integrally formed in a bag shape, and the bag-like member 16 composed of the resin sheets 16A, 16B is used as a dissolving solution 14 for dissolving the antibiotic 2.
Is connected to the container member 18 containing the
Has a peelable isolation seal portion 28 at the connection portion 12,
During use, the isolation seal portion 28 is opened to communicate with the bag-like member 16.

The connecting portion 12 of the composite container 10 is heat-sealed, aseptically connected, and sterilized by irradiation. The irradiation sterilization of the connection portion 12 is irradiation sterilization by the pulsed light beam 34 with high energy of the light emitting lamp 40 by the pulse electric field processing device 42. The pulse output intensity (single flash energy per unit area) of the lamp 40 by the pulse electric field processing device 42 is set to 1.2.
5 J / cm ² or more, and the total output received by the connection section 12 from the lamp 40 is 2.5 J / cm ² or more. The lamp 40 is made of xenon gas and quartz glass. The connection port of the bag-like member 16 and the connection port of the container member 18 are abutted with each other.
The connection portions 13 are covered with connection sheets 13 in the range of 0 to 1000 μm, and the connection portion 13 is heat-sealed to the outer wall of each connection port to form the connection portion 12. The container member 1
8 is autoclaved before connecting to the bag-like member 16.

The present embodiment will be described in more detail. First, as shown in FIG. 2, the composite container 10 is a medical container. The composite container 10 roughly includes the freeze-drying container 1, a bag-like member 16, a container member 18, and a connection portion 12 covered with a connection sheet 13. The composite container 10 is manufactured at a separate place from the lyophilization container 1 attached to the bag-like member 16 and the container member 18 containing the lysing solution 14.

As shown in FIG. 3, the bag-like member 16 is formed from a two-layer inflation sheet by co-extrusion, and its inner layer is formed from a blend layer of a mixture of linear low-density polyethylene and polypropylene at a weight ratio of 2: 1. The outer layer of which comprises a layer of linear low density polyethylene. The inflation sheet has a folding diameter of 70 mm, an inner layer thickness of 50 μm, and an outer layer thickness of 200 μm. The inflation sheet is cut to a predetermined length, and one end of the cut open end is heat-sealed so as not to be peeled off. At the other end of the cut, a detachable seal portion 22 is formed. A substantially central portion of the inflation sheet is opened, and an attachment port 23 of the freeze-drying container 1 is formed. A peelable heat seal portion 24 is formed around the mounting opening 23. The non-peelable seal is performed at a seal temperature condition of 170 ° C., and the peelable seal is performed at a seal temperature condition of 140 ° C. The front sheet of the bag-like member 16 shown in FIG. 3 is a resin sheet 16A to which the opening 3A of the cup-shaped member of the freeze-drying container 1 is fixed, and the back sheet is the resin sheet to which the lid member 4 is fixed. 16B. Further, since the freeze-drying container 1 has substantially the same members and structure as the freeze-drying container in FIG. 1, detailed description thereof is omitted.

As shown in FIG. 4, the mounting opening 2 of the bag-like member 16 is formed.
The cup-shaped member 3 is attached to 3, and the opening 3 </ b> A of the cup-shaped member 3 is thermally bonded to a resin sheet 16 </ b> A which is a front sheet of the bag-shaped member 16. Such a heat-bonding seal is heat-sealed at a temperature of 130 ° C. so as not to lose the function of the peelable heat seal portion 24. Although not shown in FIG. 4, when the bag-like member 16 is subjected to the autoclave sterilization process with the cup-like member 3, the aseptic maintenance seal is detachably attached to the resin sheet 16 </ b> B which is the back sheet of the bag-like member 16. Then, the mounting port 23 is maintained aseptically. The sterilized bag-shaped member 16 and cup-shaped member 3 are carried into a high-purity, dust-free, sterile room so that the sterility-maintaining seal is at the top, and the sterility-maintaining seal is peeled off. The solution 2A of No. 2 is aseptically filled in the cup-shaped member 3.

As shown in FIGS. 5 and 6A, the cover member 4 is attached to the mounting opening 23 of the bag-like member 16 and the cover member 4 is supported on the resin sheet 16B which is the back sheet of the bag-like member 16. The sheet is heat bonded. Such a heat-sealing seal is set at 130 ° C.
The heat sealing is performed under the following temperature conditions. As shown in FIG. 6 (B), the solution 2A in the freeze-drying container 1 is carried into a freeze-drying device of semi-cleanliness, and is frozen and dried. 2 is generated.
As shown in FIG. 6 (C), a desiccant 6 is disposed on the lid member 4 of the freeze-drying container 1, and the outside of the filter 5 is hermetically covered with the desiccant 6. The bag member 16 including the freeze-dried container 1 in which the antibiotic 2 is aseptically stored is provided to a docking room for docking with the container member 18.
Although the cup-shaped member 3 was attached to the resin sheet 16A first, the lid member 4 was attached to the resin sheet 16B first, and then the cup-shaped member 3 filled with the solution was attached to the resin sheet 16A. Is also good. In addition, resin sheet 1
Although the diameter of each of the mounting ports 23 formed in 6A and 16B is made the same, the heat sealing part 24 may be formed in a part or the whole of the lid member 4 by making this diameter different.

As shown in FIG. 2, the container member 18 is formed from a two-layer inflation sheet by co-extrusion, and the inner layer is composed of a blend layer in which linear low density polyethylene and polypropylene are mixed at a weight ratio of 2: 1. The outer layer comprises a layer of linear low density polyethylene. The inflation sheet has a folding diameter of 70 mm, an inner layer thickness of 50 μm, and an outer layer thickness of 200 μm. The inflation sheet is cut to a predetermined length, and an outlet port 26 is inserted into one end of the cut open end, and the open end is sealed together with the outlet port 26 with a non-peelable seal. On the other hand, at the other open end, a detachable seal portion 28 is formed, and the container member 18 is formed. The solution 14 is filled into the container member 18 from the outlet port 26, and after filling, the outlet port 26 is sealed with a rubber stopper.
After sealing, the solution 14 is heated to 110 ° C. with the container member 18.
Is autoclaved. Thereby, the container member 18 is provided to a docking room for docking with the bag member 16.

As shown in FIG. 2, the composite container 10 is placed in a highly clean environment, and the ends of the isolation seal portions 22, 28 of the members 16, 18 are abutted against each other. Then, the butted portion is sandwiched between the two connection sheets 13, and the connection sheets 13 and the outer wall surfaces of the isolation seal portions 16, 18 sandwiched between the connection sheets 13 are heat-sealed so as not to be peeled off. The connection part 12 of the container 10 is formed. The connection sheet 13 is made of a transparent low-density polyethylene sheet having a thickness of 100 μm. In this case, while the outer wall surfaces of the isolation seal portions 22 and 28 are both made of polyethylene resin, the inner surface of each isolation seal portion 22 and 28 is a blend layer of linear low-density polyethylene and polypropylene. Therefore, such complete sealing of the inner wall surface and the outer wall surface, which cannot be separated, can be performed at a relatively low temperature so as not to impair the function of the isolation seal portions 22, 28 between the inner wall surfaces. Bar temperature 125 ° C
To 135 ° C.

After the docking is completed, the container 10 is moved to the moving conveyor 36 in the chamber for generating the high-energy pulse light 34.
It is carried in. As shown in FIG. 2 (B), the container 10 is sterilized by irradiating only the region L of the connection portion 12 with the high-energy pulse light 34. Portions of the container 10 other than the connection portion 12 are shielded by a shielding plate (not shown). Further, the container 10 is turned by the reversing device 38 on the moving conveyor 36.
The container 10 itself is inverted, and the region L of the connection portion 12 on the back surface is
Are also irradiated with the high energy pulse light 34.

The device for the high-energy pulsed light 34 includes a light-emitting lamp 40 and a pulse electric field processing device 42. The pulse electric field processing device 42 includes a charge supply circuit, a controller, and a switch unit, and supplies the lamp 40 with a pulse electric field intensity of 5000 V / cm or more. The light-emitting lamp 40 is composed of a sealed tube and an inert sealed gas, the sealed gas is xenon, and the sealed tube is made of quartz glass. For this reason, the light-emitting lamp instantaneously emits a high energy of about 20,000 times or more the natural light at a wavelength close to the natural light. The emission time of the amplified pulse from the pulse electric field processing device 42 is 2-3 / 1,000,000 (seconds).
It is.

The light emitting lamp 40 is provided with a light detector 44 for measuring the lamp life and the irradiation amount of the light from the connecting portion 12. The light detector 44 detects by measuring the output voltage of the reverse bias generated when the light hits the light of the photodiode. The output intensity (fluence) of the pulse light 34 by the light detector 44, that is, the energy of light per unit area is 2.1 J / cm ^2.
As described above, the total output amount received by the connection unit 12 is 10.5 J
/ Cm ² or more.

In the composite container 10 configured as described above, in the manufacturing process, freezing, drying, and storing of the antibiotic in the freeze-drying container 1 can be performed easily and in a state of high aseptic safety. In addition, the lyophilization container 1 and the container member 18 containing the lysing solution 14 can be filled with the medicine in different places. Therefore, a filling facility for each type of antibiotic 2 can be easily provided. When the container member 18 is used, the seal members 22 and 28 which can be peeled off by pressing the container member 18 from the outside are broken, and as shown in FIG. The inside of the freeze-drying container 1 can be circulated by filling the inside with the dissolving solution and peeling off the heat seal portion 24. At the time of use, antibiotic 2 in lyophilization container 1
Can be easily aseptically dissolved in the dissolving solution 14. Then, such a mixed solution can be injected via a drip needle.

The connecting portion 12 irradiated with the above-mentioned high-energy pulse light beam is not damaged at all. In addition, connection section 1
The resin wall in No. 2 did not undergo any oxidation or hydrophilicity, and the medical container 10 was sufficiently safe. By performing the following sterilization or sterility experiments, it can be understood that the sterility and sterility in the connection portion 12 are extremely high.

The lyophilized container 1 was filled with a sucrose solution having passed through a sterilizing filter as a control, frozen and dried according to the above-described embodiment, and a liquid thioglycolic acid medium I (Japanese Pharmacopoeia 13 (A medium according to the sterility test method of the general test method published in the Bureau) was sterilized at a temperature of 110 ° C. in an autoclave. Next, the members 16 and 18 were butted together and connected via the connection sheet 13. Before sealing the connection sheets 13 with each other,
The bacterium equivalent to 10 ⁷ (Ba
cillus subtile: ATCC 6633). Ten such containers were manufactured, and irradiation with the high-energy pulsed light was performed under the same conditions. Next, by pressing one of the container members 18, the members 16 and 18 were connected to each other. The connected vessel 10 was cultured at 31 ° C. for 14 days.
As a result, no breeding of bacteria was observed in all cases. Therefore, it can be seen that the connection portion 12 of the container 10 is surely sterilized.

In the above-described embodiment, the connecting portion 12 is formed by abutting the members 16 and 18 with each other. However, as shown in FIG. The connecting portion 73 may be formed by inserting the end of the isolation seal portion 28 of the container member 18 into the opening 71 by holding the opening 71 of the shaped member 16 with the clip 72.
Further, a structure in which the isolation seal portion 28 of the container member 18 is provided not in the vicinity of the connection end portion but in the middle, and the connection port of the bag-like member 16 is inserted into the connection port of the connection portion of the container member 18 may be used. .

[0053]

As described above, according to the freeze-drying container of the present invention, since the lid member is formed of a filter impermeable to bacteria, a freeze-dried product having high sterility can be easily obtained in the production process. Can. Further, the composite container of the present invention includes the freeze-drying container, and a resin sheet is provided at each of the opening and the lid member of the cup-shaped member of the freeze-drying container, and the heat-peelable resin sheet is peelable from the resin sheet. A seal portion is formed, the resin sheets are formed integrally or separately in a bag shape, and the bag member made of the resin sheet is a container member containing a solution for dissolving the contents when used. The container member has a detachable seal portion at the connection portion, and is opened so as to be in communication with the bag-shaped member at the time of use, so that the freeze-drying container No complicated operation such as transfer of freeze-dried product is required. In addition, it is possible to sufficiently enhance the sterility or sterility of the connection portion between the container members, and to cause the connection portion to inconvenience other portions on the production line without causing destruction at the connection portion. And can be easily sterilized.

[Brief description of the drawings]

1 (A) and 1 (B) are a side view of a freeze-drying container of the present invention and a rear view of a lid member thereof.

2 (A) and 2 (B) are a plan view of a composite container of the present invention and a schematic partial cross-sectional view of a connecting portion thereof.

FIG. 3 is a plan view of a bag-shaped member to which the freeze-drying container of the present invention is attached.

FIG. 4 is a plan view showing a state where a cup member is attached to the bag-like member shown in FIG. 3;

FIG. 5 is a plan view in which a lid member is attached to the bag-like member in FIG. 4 to provide a freeze-drying container.

6 (A), 6 (B) and 6 (C) are schematic views showing steps of attaching a freeze-drying container to a bag-shaped member and performing freeze-drying.

FIG. 7 is a schematic view showing a step of irradiating the connection part of the composite container of FIG. 2 with irradiation.

FIG. 8 is a schematic cross-sectional view of a connecting portion and a freeze-drying container portion when the composite container of FIG. 2 is used.

FIG. 9 is a schematic cross-sectional view of a connecting portion showing another use mode of the connecting portion of the composite container according to the present invention.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Freeze-drying container 2 Antibiotic 3 Cup member 4 Lid member 5 Filter 6 Desiccant 10 Composite container 12 Connection part 13 Connection sheet 14 Dissolution liquid 16 Bag-shaped member 18 Container member 22, 28 Peelable isolation seal part 34 High energy Light 40 Light emitting lamp 42 Pulse electric field processing device 44 Detector

Claims (10)

[Claims] 1. A freeze-drying container for freeze-drying contents, comprising: a cup-shaped member for accommodating the contents; and a lid member for sealing an opening of the cup-shaped member. A lyophilization container, wherein the lid member is formed of a filter impermeable to bacteria. 2. The freeze-drying container according to claim 1, wherein the opening of the cup-shaped member and the lid member are adhered by a peelable heat seal. 3. A composite container comprising the freeze-drying container according to claim 2, wherein a resin sheet is provided at each of an opening of the cup-shaped member and a lid member of the freeze-drying container.
The heat-sealable portion is formed on the resin sheet or the lid member, and the resin sheets are integrally or separately formed in a bag shape. The bag-shaped member made of the resin sheet is The container member is connected to a container member containing a solution for dissolving the contents, and the container member has a detachable seal portion at the connection portion, and communicates with the bag-like member by opening the separate seal portion at the time of use. A composite container characterized in that it is adapted to be used. 4. The composite container according to claim 3, wherein said connecting portion is formed by heat sealing, and is connected aseptically or sterilized by irradiation. 5. The composite container according to claim 4, wherein the irradiation sterilization of the connection part is irradiation sterilization by a pulsed light beam with a high energy of a light emitting lamp by a pulse electric field processing device. 6. The pulse output intensity (single flash energy per unit area) of the lamp by the pulse electric field processing device is set to 1.25 J / cm ² or more, and the total output received from the lamp by the connection portion is 2.5 J / cm ^2. The composite container according to claim 5, wherein the composite container is at least ² cm2. 7. The composite container according to claim 6, wherein said lamp is made of xenon gas and quartz glass or sapphire glass. 8. A connection port of said bag-like member is inserted into a connection port of said bag-like member, or a connection port of said bag-like member is inserted into a connection port of said container-member. The connection port of the container member has a wall thickness of 20 to 1000 μm.
6. The composite container according to claim 5, wherein the connection portion is formed by heat sealing from the outside of the wall. 9. The connection port of the bag-like member and the connection port of the container member are abutted against each other, and the abutted connection port has a thickness of 20 mm.
6. The composite container according to claim 5, wherein said connection portion is formed by covering with a connection sheet having a size in a range of from about to 1000 [mu] m and heat-sealing said connection sheet to an outer wall of each connection port. 10. The composite container according to claim 3, wherein the container member is subjected to an autoclave sterilization process before connecting to the bag-shaped member.