JPS5980256A - Plastic container filled with drug generating no deterioration for long period time - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to a plastic container containing a chemical solution, and more particularly to a method for manufacturing a plastic container containing a drug solution that does not deteriorate over a long period of time.

[Prior art and problems]

In recent years, in order to trace in-hospital infections during the administration of injectable infusions, progress has been made toward so-called closed systems in which infusions can be administered in a sealed system without the use of ventilation needles. In order to achieve such a closed system, it is necessary to use a flexible plastic container instead of the conventional glass bottle or glass ampoule as a container for the infusion solution.

This is because the closed system utilizes the flexibility of the container for infusion.

As in the past, such plastic containers containing chemical solutions need to be sterilized before use. This sterilization is generally performed by so-called high-pressure steam sterilization, which is performed in saturated steam at high temperatures. However, even plastic materials such as polyvinyl chloride, which have low gas permeability at room temperature, become highly permeable during high-pressure steam sterilization, and oxygen present in the surrounding atmosphere passes through the container wall made of plastic material into the container. It invades and alters the contents. There is a particularly high risk of deterioration when the content liquid contains components that are easily deteriorated by oxygen, such as high-concentration amino acid infusions containing tryptophan or fat emulsions for infusion.

Further, even if the container is sterilized in this way, if the sterile state on the surface of the container is not maintained during storage, it will cause inconvenience during use.

■Purpose of the Invention Therefore, an object of the present invention is to provide a plastic container containing a drug solution, in which the drug solution does not deteriorate over a long period of time, and the sterile state of the container surface is maintained over a long period of time.

According to the present invention, the above object is to provide a container made of a flexible plastic material having heat resistance that can withstand the heat of high-pressure steam sterilization, in which a chemical solution containing a component that is easily deteriorated by oxygen can be stored in a high-pressure steam sterilized state. and a first packaging material made of a plastic material that has heat resistance and gas permeability that can withstand the heat of placing in a steam autoclave to package the drug solution container. A plastic container containing a drug solution that does not deteriorate over a long period of time, characterized by comprising a container containing a drug solution, and a second packaging material having high oxygen gas impermeability for further packaging the packaged container containing a drug solution. achieved by.

It is preferable that the packaging with the second packaging material be carried out by vacuum packaging or under a nitrogen atmosphere.

Typically, the container is formed of polyvinyl chloride or crosslinked ethylene-vinyl acetate copolymer.

The medicinal solution includes at least one type of high-calorie IJ-containing tryptophan-containing amino acid, amino acid infusion, and fat emulsion.
and liquid components (ie, parenteral nutrition components).

Examples of the first packaging material include polypropylene, high-density polyethylene or polyester, a laminate film with an inner layer of unoriented polypropylene film and an outer layer of biaxially oriented polypropylene film, or a laminate film with an inner layer of unoriented polypropylene film and a nylon film. There is a laminate film whose outer layer is a biaxially oriented polypropylene film with intermediate binding.

The second packaging material is preferably 0.1 ((c).

crn/caSec, crnf(g)X 10”
(35°C, dry) Has an oxygen permeability coefficient of 1 or less. Examples of such materials include a three-layer laminate film having a polyvinyl alcohol film as an intermediate layer and a laminate film having an aluminum layer.

It is preferable that the packaging using the first and second packaging materials is performed by heat-sealing, and that the second packaging material is heat-sealed to the first packaging material at a predetermined portion.

A first notch is provided in the heat-sealed portion of the first packaging material, and a second notch is provided at a position corresponding to the first notch in the heat-sealed portion of the second packaging material. Conveniently, the first and second packaging materials are opened along the first and second cuts.

■Detailed Description of the Invention The present inventors have conducted various research in order to develop a plastic container containing a drug solution that does not deteriorate in quality during sterilization or even after sterilization, and in which the sterile state of the container surface is maintained for a long period of time. As a result, a plastic container containing five liquids was used as the first
By performing high-pressure steam sterilization while packaged with the packaging material of It is also important to note that by performing autoclaving in a saturated steam atmosphere substantially free of oxygen, even when sterilizing the container and the
Even if the packaging material becomes permeable to oxygen, the quality of the drug solution does not change, and the quality of the drug solution does not change over a long period of time by further packaging it with a second packaging material that is impermeable to oxygen gas after cooling. The inventors discovered that this problem could be eliminated, and based on this knowledge, they completed this invention.

In addition, among the medicinal solutions, amino acid infusion preparations are stored for 2 years at 42%
0? If the visible light transmittance of IJ is 95 or higher and the amount of dissolved oxygen is 21)I)m or less, it can be said that there has been no deterioration, and in the case of fat emulsions, no coloration is observed with the naked eye after 2 years of storage. If no fat particles with a particle size of 7 μm or more are observed by microscopic observation and the amount of dissolved oxygen is 2 ppm or less, it can be said that there is no deterioration.

As mentioned above, in this invention, since the container containing the drug solution is subjected to high-pressure steam sterilization, it has a heat resistance that can withstand the sterilization temperature (i.e., it does not melt, deform, or change in quality during the sterilization). It must be made of a flexible plastic material that does not deteriorate or deteriorate. Further, it is desirable that this plastic material has low oxygen gas permeability under normal ambient temperatures (1° C. to 30° C.). Further, since the plastic container is preferably obtained by heat-sealing a plastic sheet or a flat tube and applying high-frequency induction heating, it is desirable that the material has high-frequency sealing properties. In addition to this, it is advantageous to be able to observe the drug solution with the naked eye, so it is preferred that the container be made of a transparent or translucent plastic material.

Plastic materials that satisfy the above conditions include polyvinyl chloride, crosslinked ethylene-vinyl acetate copolymer, high-density polyethylene, and the like. Ethylene-vinyl acetate (
The EVA) copolymer is crosslinked with electron beams, gamma rays, etc. so that the crosslinking ratio (gel fraction) is 50 or more in order to have a specified heat resistance, and from the viewpoint of flexibility, it is crosslinked with a gel fraction of 10 to 20.
It is preferred to have a vinyl acetate content of % by weight. In addition, since the EVA copolymer loses high-frequency fusion properties when the above-mentioned crosslinking rate is achieved, it is preferable to form a container with an uncrosslinked EVA copolymer and crosslink it by irradiating the container with an electron beam or the like.

The drug solution contained in the above-mentioned plastic container, which contains components that are easily altered by oxygen, contains at least one high-calorie 11-solution component (transparenteral nutrition component) and a high concentration (10 to 12% by weight) of tryptophan. ) Includes amino acid infusions and fat emulsions. These medicinal solutions can be prepared by conventional methods. In addition, other medicinal solutions include a blood preservation solution contained in a blood bag.

The first packaging material for packaging the plastic container containing the drug solution before high-pressure steam sterilization is gas permeable during high-pressure steam sterilization, and almost the same requirements as those for the plastic material forming the container, such as heat resistance, are applied. Since the first packaging material is a plastic material that is permeable to gases (oxygen gas and water vapor) during high-pressure steam sterilization, there is a possibility that oxygen remaining in the plastic container and the first packaging material may remain in the plastic container. During high-pressure steam sterilization according to the present invention, oxygen that may remain between the two is permeated through the first packaging material and discharged into a sterile atmosphere with a low oxygen partial pressure,
A higher degree of sterilization is achieved by the introduction of high temperature steam.

Alternatively, even if the moisture in the drug solution passes through the wall of the plastic container and migrates to the surface, the moisture will migrate to the surface of the first packaging material through the wall of the first packaging material during cooling, so the plastic container and the first packaging Almost no moisture remains between the materials. Note that this first packaging material preferably exhibits high gas impermeability under normal atmospheric temperatures.

Preferred examples of the first packaging material include monolayer films such as polypropylene film, high-density polyethylene film, and polyester film, unstretched polypropylene (
cpp) film as an inner layer and biaxially oriented polypropylene (
laminated film with filtrate as the outer layer, biaxially oriented polypropylene (CPP) film as the inner layer and nylon film as the middle layer.
It is a plastic laminate film such as a laminate film having an outer layer of OPP) film. The first packaging material may consist of a number of separate films, in which case deep-draw vacuum packaging is preferred.

After drying, the second packaging material for double wrapping the plastic container containing the drug solution is a material that is highly impermeable to oxygen gas. Preferably, this second packaging material has an oxygen permeability coefficient of 0.1 ((cocm/-5ec, LMug)
x 10" (35°C, dry)). In addition, it is desirable that the heat fusion property is good.

Such second packaging materials include polyvinyl alcohol films and surlaminate films with an aluminum layer. Polyvinyl alcohol has extremely high impermeability (barrier properties) to oxygen gas due to hydrogen bonding between its hydroxyl groups. In order to improve the heat-sealability of this polyvinyl alcohol film, it is preferable to laminate a plastic film having heat-sealability, such as an unstretched polypropylene (CPP) film, on its inner layer. Furthermore, in order to eliminate the influence of moisture in the external atmosphere on the polyvinyl alcohol film,
It is desirable to laminate another plastic film as an outer layer on the polyvinyl alcohol film of the above laminate. Examples of such plastic films as the outer layer include biaxially oriented polypropylene (OPP) films, polyester films, biaxially oriented nylon films, and polyvinylidene chloride films. A laminate film having such a polyvinyl alcohol film as an intermediate layer is commercially available from Kuraray Co., Ltd. under the trade name EVAL, for example. Examples of the laminate film having an aluminum layer include polyester film, polypropy L/7 film, or high-density polyethylene film laminated with aluminum foil on the surface.

Hereinafter, this invention will be explained in more detail with reference to the drawings.

In order to obtain the plastic container containing the drug solution of this invention,
As shown in FIG. 1A, a flexible plastic container 11 is made of the previously described plastic material. This container 11 can be manufactured, for example, by overlapping two desired plastic sheets and heat-sealing their peripheral edges 12. A chemical solution port 13 communicating with the interior of the container 11 is provided at one end of the container 11, and the previously described chemical solution 16 is introduced into the container 11 from there. Further, the container 11 may have a relatively wide seal portion 14 at a position facing the port 13, and a suspension hole 15 is provided in the seal portion 14 for suspending the container 1 from a suitable support member. can be formed.

After the medicine 16 is placed in the container 11, the port 13 is sealed with a suitable sealing member 1 by heat sealing, high frequency welding, etc.
7 to be sealed.

Next, the container 11 containing the drug solution 16 is packaged with the first packaging material described above. This package 18 is preferably vacuum packaged. The package 18 is obtained, for example, by overlapping two plastic films for the first packaging material and heat-sealing the peripheral edge 19 thereof. At this time, it is preferable to form one or more notches 20 in at least one edge of the heat-sealed part 19.10 Next, the packaged plastic container containing the drug solution shown in FIG. This can be carried out in the absence of oxygen.

This sterilizer 30 includes an autoclave 31 in which sterilization is performed. One end of the autoclave 3 is connected by a line 35 via a valve 38 to a steam supply source, for example a boiler 32. Further, a supply source 33 of a gas inert to the chemical solution, preferably nitrogen, is connected to the autoclave 3 via a line 37, a valve 40, an inert gas reservoir 34, a line 36, and a valve 39. The storage tank 34 may not be provided (in that case, the line 36 and the valve 3
9 is also unnecessary).

Furthermore, an exhaust valve 42 is connected to the autoclave 31 and a cooling water source 43 is connected to the autoclave 3 via a line 44 and a valve 45.

For sterilization, a plurality of packaged plastic containers containing a drug solution are housed in an autoclave 3. Then, steam is introduced into the autoclave 31 from the boiler 32 for a predetermined period of time (for example, 2 to 10 minutes), and substantially all the oxygen and air present in the autoclave 3 are exhausted from the exhaust valve 42. Then, close the exhaust valve 42,
Steam at a predetermined temperature is transferred from the boiler 32 to the autoclave 3.
1, saturate it and sterilize it. The saturated steam temperature during sterilization is generally 100℃ to 130℃, usually 1
The temperature is 15° C. to 126° C., and the treatment is carried out for 10 minutes to 40 minutes. The pressure inside the autoclave during sterilization is about 12 to 2 = OKg/ca in gauge pressure, and in order to ensure this pressure during sterilization, inert gas is supplied from the gas source 33 through the valve 40 into the autoclave 31 as appropriate. Introduce.

After sterilization, a predetermined amount of cooling water is introduced into the autoclave 31 from the cooling water source 43 to sufficiently cool the chemical solution contained in the container. On the other hand, packaging using the second packaging material described above is preferably carried out as soon as possible after taking out the plastic container containing the drug solution from the autoclave 3. On the other hand, it is preferable to use a laminate film having a polyvinyl alcohol film as the second packaging material. and,
It has low heat resistance, so after sterilization, the plastic container containing the drug solution should be kept in an autoclave (usually at 40°C).
below) and die. In any case, during this cooling,
The pressure inside the autoclave 31 decreases relatively rapidly, and on the other hand, the chemical liquid is not cooled down that quickly, so there is a risk that the bag may break due to the pressure of the still hot chemical liquid. To prevent this, the sterilization pressure must be substantially maintained in the autoclave 31 during this cooling. To this end, in the present invention, an inert gas is introduced into the autoclave 31 from the inert gas source 33 during cooling to maintain the pressure during sterilization. Once the chemical solution has cooled down sufficiently, open the exhaust valve 42.
The gas inside the autoclave 3 is discharged from the autoclave 3 to bring it to normal pressure.

When the drug solution has been sufficiently cooled in this way, the packaged plastic container containing the drug solution is taken out from the autoclave 3, the moisture on the surface of the package 18 is sufficiently wiped off or dried, and then it is packaged with a second packaging material. This packaging is preferably carried out in an oxygen-poor atmosphere to minimize the amount of oxygen present within the packaging. It is best to do this in a warm atmosphere. For this packaging, either two pieces of second packaging material film are tied together and the periphery is heat-sealed, or
Alternatively, as shown in FIG. 1B, both ends 22 of the tubular film 21 are heat sealed. In this case, the peripheral seal 22 is located at a distance from the area of the first packaging 18, and the peripheral edge 19 of the first packaging 18, in which the notch 20 is formed, is located at a distance from the area of the first packaging 18. It is preferable to seal both parts in common at the portion overlapping with the body 21. This common sealing section 23 is performed before sealing the peripheral edge 22 of the second package 21.

Then, the first part of the peripheral seal part 22 of the second package 2 is
A notch 24 is provided at a position corresponding to the notch 20 of the package 18.
If this is provided, it is possible to read and write double packages at once, which is extremely convenient.

Example 1 A 2% amino acid (tryptophan-containing) infusion solution of OM+&i was prepared in a conventional manner and filled into a flexible polyvinyl chloride bag. This bag containing the chemical solution was vacuum packaged with a two-layer laminate film having an outer layer of a biaxially stretched polypropylene film (thickness: 30 μm) and an inner layer of an unstretched polypropylene film (thickness: 20 μm). The packaged drug solution-containing bag was sterilized and cooled in the same manner as described in connection with FIG. Sterilization was performed at 115°C for 30 minutes. After cooling, the sample was taken out of the autoclave, water droplets on the surface of the first package were wiped off, and a polyvinylidene chloride film (thickness 20μ) was used as the outer layer, a polyvinyl alcohol film (thickness 20μ) was used as the middle layer, and an unstretched polypropylene film was prepared. It was further packaged with a three-layer laminate film having an inner layer of At this time, first, common heat sealing as shown in FIG. 1B was performed, and then vacuum packaging was performed using a pillow packaging machine. In this way, a desired double-wrapped plastic bag containing a drug solution was obtained without tearing the bag.

Comparative Example Example 1 except that the final (second) packaging was not performed.
A plastic bag containing a drug solution was obtained in the same manner as above.

Example 2 The first packaging was made of a two-layer laminate film with a biaxially oriented polypropylene film (thickness 30μ) as an outer layer and an unstretched polypropylene film (thickness 30p) as an inner layer, and a biaxially oriented polypropylene film (thickness 30μ) as an inner layer. 30μ) as the outer layer and a nylon film (30μ thick) as the middle layer. ・Stretched polypropylene film (30μ thick)
The inner layer is a three-layer laminate film, which is used as the top material and the bottom material, respectively. 15 tt) as the middle layer and unstretched polypropylene film y-, (thickness 50μ) as the inner layer.
A double-wrapped plus deck bag containing a drug solution was obtained in the same manner as in Example 1, except that a straw laminate film was used.

In order to investigate the storage stability of the medicinal solutions in the bags obtained in Examples 1 and 2 and Comparative Examples, a storage test was conducted in air, and the visible light (420 nm) transmittance (chi) and dissolved oxygen amount (chi) of the medicinal solutions were determined. ppm) was measured. The results are shown in the table below.

■Specific Effects of the Invention As stated in 2, according to the present invention, since the Steam-O-I/crepe sterilization of the plastic container containing the drug solution is performed after packaging it with the first packaging material, the outside air is used after sterilization. The surface of the plastic container will not be contaminated and will remain sterile even if it comes into contact with the container. In addition, since sterilization is carried out in saturated steam without the presence of oxygen, the chemical solution does not come into contact with oxygen during sterilization and does not deteriorate in quality. In addition, since cooling after sterilization is carried out while substantially maintaining the pressure during sterilization by introducing an inert gas, the plastic container will not be damaged, and since there is no oxygen, the chemical solution will not change in quality. do not have. Finally, the oxygen gas barrier
Since the drug solution is packaged using a second packaging material with high properties, the drug solution does not come into contact with the external atmosphere and does not deteriorate even if stored for a long period of time. In particular, when packaging with this second packaging material is performed in an atmosphere with little oxygen, deterioration of the chemical solution can be further prevented. Thus, according to the present invention, a plastic container containing a chemical solution that does not deteriorate over a long period of time can be stably obtained.

[Brief explanation of the drawing]

1A and 1B are plan views showing the method for obtaining a plastic container containing a chemical solution according to the present invention in the order of steps;
The figure is a diagram schematically showing a sterilization device used to obtain a plastic container containing a drug solution according to the present invention. 1 No... Plus deck container, 16... Chemical solution, 18.
・First packaging body, 21...Second packaging body, 20° 24
- Notch, 23... Common seal portion, 3... Autoclave, 32... Boiler, 33... Inert gas source, 43... Cooling water source.

Claims (1)

[Scope of Claims] (1) A container made of a flexible plastic material with heat resistance that can withstand the heat of high-pressure steam sterilization, in which a chemical solution containing components that are easily deteriorated by oxygen is stored in a high-pressure steam sterilized state. and a first packaging material made of a plastic material having heat resistance and gas permeability capable of withstanding the heat of high-pressure steam sterilization and packaging the container containing the drug solution. 1. A plastic container containing a drug solution that does not deteriorate over a long period of time, comprising a container containing a drug solution and a second packaging material having high oxygen gas impermeability for further packaging the packaged container containing a drug solution. (2) The container according to claim 1, wherein the packaging using the second packaging material is vacuum packaging. (3) The container according to claim 1 or 2, wherein the packaging with the second packaging material is performed under a nitrogen atmosphere. (4) The container according to any one of claims 1 to 3, wherein the container is formed of polyvinyl chloride or a crosslinked ethylene-vinyl acetate copolymer. (5) The container according to any one of claims 1 to 4, wherein the drug solution is at least one high-caloric IJ-liquid component. (6) The container according to claim 5, wherein the drug solution is a high concentration amino acid infusion solution containing tryptophan. (7) The container according to claim 5, wherein the drug solution is a fat emulsion. (8) The container according to any one of claims 1 to 7, wherein the first packaging material is polypropylene, high-density polyethylene, or polyester. (→ The first packaging material is a laminate film with an unstretched polypropylene film as an inner layer and a biaxially oriented polypropylene film as an outer layer, or a laminate film with an unstretched polypropylene film as its inner layer and a nylon film as an intermediate layer and a biaxially oriented polypropylene film as an outer layer. The container according to any one of claims 1 to 7, wherein the outer layer is a laminate film. (10) The second packaging material is 0.1 ((COcm /
cnisee, cmHg) x 10'2 (35℃
The container according to any one of claims 1 to 9, having an oxygen permeability coefficient of 1 or less (dry). 11. The container according to claim 10, wherein the packaging material for the qTJ brush 2 is a three-layer laminate film having a polyvinyl alcohol film as an intermediate layer. 02. The container according to claim 10, wherein the second packaging material has an aluminum layer on the surface of a polyvinyl chloride, polyester, polypropylene, or high-density polyethylene film. α3 Claims characterized in that packaging with the first and second packaging materials is performed by heat fusion, and the second packaging material is heat fused to the first packaging material at a predetermined portion. The container according to any one of Items 1 to 12. (141 A first notch is provided in the heat-sealed portion of the first packaging material, and a second notch is provided at a position corresponding to the first notch in the heat-sealed portion of the second packaging material. 14. The manufacturing method according to claim 13, wherein the first and second packaging materials are opened along the first and second notches.