JPH0790038B2 - Manufacturing method of plastic container containing chemical liquid for preventing deterioration of chemical liquid due to oxygen - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to a method for manufacturing a drug solution-filled plastic <br/> container. In particular, a method of manufacturing it without chemical loaded plastic container that alteration of the chemical solution over the high-pressure steam sterilization and long-term.

[0002]

2. Description of the Related Art In recent years, in medical treatment such as infusion, a closed system has been used in order to prevent the content liquid from coming into contact with the outside world. The medical fluid container used for this closed system is required to discharge the content liquid due to gravity and the structure of the container and the flexibility of the material of the container. Further, this type of medical liquid container is required to have heat resistance to withstand high-pressure steam sterilization in order to sterilize the content liquid. Further, it is preferably made of a transparent material so that the content liquid can be monitored from the outside. Conventional containers containing chemicals have mainly been glass bottles and glass ampoules, but plastic containers containing chemicals are on the market so that they can be used in closed systems.

[0003]

A plastic container containing a chemical solution of this kind is usually subjected to high-pressure steam sterilization to sterilize the content solution. At room temperature, even plastic materials with low gas permeability, such as polyvinyl chloride, have high gas permeability during high-pressure steam sterilization, and oxygen existing in the atmosphere penetrates into the container through the container wall formed of the plastic material. It will be easier. Also, even at room temperature, plastic containers have higher gas permeability than glass bottles and glass ampoules, so plastic containers are packed with a packaging material with a high gas barrier property, but even if they are stored for a long period of time, the atmosphere will change. Oxygen present inside gradually penetrates the container wall and enters the container. The drug solution in the container contains high-concentration amino acid infusion containing tryptophan, fat emulsion for infusion, and infusions containing antibiotics that are easily oxidized or hydrolyzed by the presence of oxygen. In many cases, there is a risk of deterioration and discoloration.

[0004]

[MEANS FOR SOLVING THE PROBLEMS] A container having at least one discharge port formed of a flexible plastic material having heat resistance contains a component which is easily deteriorated by oxygen.
Both the one containing the chemical solution and the oxygen scavenger have high oxygen
Wrapped in a transparent transparent packaging material and sealed,
A small amount of oxygen passing through the material is removed by the oxygen scavenger, and the container is removed.
Chemical-filled plastic that prevents oxygen from entering the interior for a long time
A method for manufacturing a flexible container, which is a flexible plastic having heat resistance.
At least one or more outlets made of stick material
Containing a component that is easily altered by oxygen in a container with
Replace the oxygen in the container and the chemical liquid with an inert gas.
State where there is virtually no oxygen in the container and in the chemical solution
And then in a water vapor atmosphere free of oxygen.
Perform pressure steam sterilization until the pressure for autoclaving is maintained.
In addition, cool the container containing the sterilized drug solution in an inert gas atmosphere.
Then remove the sterilized container with oxygen scavenger
High so that there is a space around the oxygen absorber even if not
Wrapped in a transparent flexible packaging material that is impermeable to oxygen gas
It is characterized in that the oxygen-containing chemical liquid
A method of manufacturing a plastic container containing a chemical solution that prevents alteration
By adopting it , the above problems were solved.

[0005]

[0006] The present inventors have found that after high-pressure steam sterilization and sterilization even long-term chemical solution various studies to develop a method for producing it is not chemical-filled plastic container that alteration, flexible having heat resistance sealing a drug solution in a container having at least one or more exhaust ports formed in a plastic material
When entering, there is substantially no oxygen in the container and in the chemical solution.
Avoid, and on top of, an oxygen-free steam atmosphere
Subjected to high-pressure steam sterilization in air, and the high-pressure steam sterilization completed
By encapsulating both the chemical solution-containing container and the oxygen scavenger in a packaging material having heat resistance and high oxygen gas impermeability so that a space exists at least around the oxygen scavenger, the packaging material during high-pressure steam sterilization becomes The chemical solution does not deteriorate even when it becomes permeable to oxygen, and after sterilization
Is a space provided in the packaging material and containing the oxygen scavenger.
To remove even the slight amount of oxygen that permeates the packaging material
The present invention has been completed by finding out that the chemical solution is not deteriorated for a longer period of time.

[0007]

[0008]

[0009]

[0010]

[0011]

[0012]

[0013]

[0014]

[0015]

[0016]

[0017]

[0018]

[0019]

[0020] Then, high above the chemical-filled plastic container
Sterilize under pressure steam . As a sterile way, Oh Tokure <br/> Bed, Tower autoclave and funnel mat or the like is used. In the case of an autoclave, the pressure during autoclave sterilization and cooling after sterilization is maintained by introducing an inert gas into the atmosphere. In the case of tower autoclave and funnel mat, replace the water with inert gas to prevent oxygen from entering the plastic container containing the chemical solution. The inert gas used is preferably nitrogen gas. High pressure steam
During sterilization, the container easily permeates oxygen gas, and the chemical solution
Even if it is easy to deteriorate, the high pressure steam sterilization atmosphere is
Qualitatively anoxic, and the drug solution is substantially acid free
Since it is filled in the original state, the drug in the plastic container
The liquid is not altered by oxygen. Also, high pressure steam
After germs, actively moisten the moisture absorbed by the container in the dryer.
It is preferable to disperse. Furthermore, the drying is performed with an inert gas.
It is more preferable to carry out in an atmosphere.

[0021] After sterilization, together with a deoxygenating agent the drug solution filled plastic container, such space around at least the oxygen scavenger is present, packaged in a packaging material having a high oxygen gas-impermeable. When space deoxidizer around it packaged in packaging material so as not to exist, the oxygen removal removal effect of the oxygen absorber is deteriorated and alteration drug solution in a plastic container at the time of storage after sterilization by oxidation or the like in the oxygen It is easy to happen.
In addition, a method for allowing a space to exist around the oxygen absorber ,
When put on SL liquid medicine filled plastic container and an oxygen scavenger in the packaging material, a method of simultaneously and how to put the air or inert gas, covered with a structure having a hole communicating with the other surface of the oxygen scavenger from one side, A method of putting a plastic container containing an oxygen absorber and a chemical solution on a plate with unevenness and putting it in the packaging material,
There are a method of providing a convex portion on the packaging material, a method of using a packaging material composed of a tray portion and a sheet-shaped lid, and the like. Well
In addition, the amount of oxygen absorber used should be
Acid that does not deteriorate due to the oxidation of chemicals with oxygen.
An amount that can maintain the elementary concentration is necessary. That is, the packaging
Deoxygenates the space between the material and the container containing the oxygen scavenger
Form a substantially oxygen-free layer and protect packaging material during storage
A small amount of oxygen that permeates and penetrates is removed by the anoxic layer, and inside the container
To prevent oxygen from entering the
It is the amount to be removed through the vessel wall.
In the case of a plastic container containing a concentrated amino acid infusion
Requires an oxygen absorption of 10 ml or more.
It is preferable to use an oxygen absorber with a volume of 100 ml or more.
Yes. Examples of the oxygen scavenger include metals such as iron and halogens
Powders made of metal fluoride, ascorbic acid and catechol
It is known to use an organic compound whose main ingredient is alcohol. these
The oxygen scavenger of Mitsubishi Gas Chemical Co., Ltd. [Product name: Agere
S] and several other manufacturers. this
Some oxygen scavengers include those that only absorb oxygen and some
Some emit carbon dioxide at the same time as elementary absorption. tray
When using a packaging material composed of a cover and a sheet-shaped lid
Is an oxygen absorber that releases carbon dioxide at the same time as absorbing oxygen.
It is preferably used. In other words, packaging material with oxygen absorber
When the oxygen in the material is removed, the pressure in the packaging material decreases and the pin
Since there is a risk of problems such as the generation of holes, oxygen
If carbon dioxide is released at the same time as absorption, the pressure inside the packaging material
This is because it can be kept constant.

Examples of the packaging material having high impermeability to oxygen gas include a three-layer laminated film having layers of an ethylene-vinyl alcohol copolymer film and a polyvinylidene chloride film, and a laminated film having an aluminum layer. In the three-layer laminated film having transparency, it is preferable to laminate an unstretched polypropylene film or an unstretched polyethylene film on the inner layer of the ethylene-vinyl alcohol copolymer film, and the heat fusion property becomes good. Further, it is preferable to laminate a biaxially oriented polypropylene film, a polyester film or the like on the outer layer of the ethylene-vinyl alcohol copolymer film in order to reduce the influence of moisture in the external atmosphere. In addition, an olefin resin such as polyethylene or polypropylene, a packaging material having a large thickness such as polyester, polyurethane or polyamide can also be used. According to this method, a cross-linked ethylene-vinyl acetate copolymer, which easily causes blocking with the packaging material, can be used as the raw material of the plastic container. Well
When using the above-mentioned transparent three-layer laminate film,
In some cases, some chemicals are susceptible to deterioration by ultraviolet rays.
Therefore, at least one layer of the three-layer laminated film
Is an ultraviolet light such as benzophenone type or phenyl salicylate type
To contain a line absorber or to transmit ultraviolet rays
It is preferably colored in order to reduce the color.

The plastic container containing a chemical solution according to the present invention manufactured as described above hardly deteriorates due to the oxidation of the internal chemical solution by oxygen even during long-term storage.

[0024]

The present invention will be described in detail with reference to the drawings. As shown in FIG. 1, a plastic container 11 containing a chemical solution of the present invention includes a plastic container 12, a packaging material 13,
It is composed of an oxygen absorber 14 and a chemical solution 15. The plastic container 12 is made of the above-mentioned flexible plastic material, but linear low-density polyethylene having low water vapor permeability is suitable. The plastic container 12 is manufactured by various methods. For example, one open end of a tubular sheet obtained by inflation molding of linear low-density polyethylene is heat-welded, and a suspension port for suspending a plastic container is provided, and a discharge port is inserted at the other open end. Method of heat welding, two sheets obtained by extrusion molding of linear low-density polyethylene are overlapped, and the peripheral portion thereof is heat-welded, a linear low-density polyethylene with a small diameter outlet at the upper end There is a method in which a blow molded product having a subsequent container portion is molded, and the vicinity of the side peripheral edge portion and / or the lower peripheral edge portion of the blow molded product is heat-welded. Of these methods, the method using a blow-molded product is most suitable because the discharge port is not heat-welded and there is no risk of leakage, and this method was used in this example. The above-mentioned chemical solution 15 is injected from the discharge port 16.
At this time, the chemical liquid 15 to be injected is made substantially oxygen-free, and the plastic container 1 is injected immediately before the injection.
The inside of 2 is replaced with nitrogen, and immediately thereafter, a chemical solution and nitrogen gas are simultaneously injected. After the injection, the opening of the outlet 16 is sealed with a plastic material and a rubber stopper is attached, and in order to keep the outer surface of the rubber stopper aseptic, a plastic film is sealed so that it can be easily peeled off during use.

[0025]

Next, the plastic container 12 containing the chemical solution
Is sterilized by autoclaving in an atmosphere consisting of steam substantially free of oxygen. This sterilization is performed by, for example, an autoclave. A plurality of plastic containers 12 containing a chemical solution are housed in an autoclave. Then, steam is introduced into the autoclave from the boiler for a predetermined time, and the air in the autoclave is discharged. After discharging, steam at a predetermined temperature is introduced into the autoclave and sterilized.
An inert gas is appropriately introduced to secure the pressure in the autoclave during sterilization. After sterilization, a predetermined amount of cooling water is introduced into the autoclave to sufficiently cool the drug solution and then taken out.
Next, the plastic container 12 and the oxygen absorber 14 are
Put in the packaging material 13 described above. At this time, the oxygen absorber 14
Cover with a structure 17 having holes that communicate from one side to the other
Put together and enclose. In addition, the amount of gas in the packaging material 13 is small.
At least 50% humidity was applied.

FIG. 2 shows another plastic container 21 containing a chemical solution of the present invention. Plastic container 21 containing chemical liquid
Is a plastic container 22, packaging material 23, oxygen absorber 2
4 and the chemical solution 25. Plastic container 22
Was manufactured using a blow molded product as in the case of FIG. Further, the method of injecting the chemical solution 25 from the discharge port 26 was performed in the same manner as in FIG.

Next, the plastic container 22 containing the chemical solution 25 is subjected to high-pressure steam sterilization in an atmosphere of steam substantially free of oxygen. This sterilization is performed by, for example, an autoclave. A plastic container containing a chemical solution is housed in multiple units in an autoclave. Then,
Steam is introduced into the autoclave from the boiler for a predetermined time, and the air in the autoclave is discharged. After discharging, steam at a predetermined temperature is introduced into the autoclave and sterilized. An inert gas is appropriately introduced to secure the pressure in the autoclave during sterilization. After sterilization, a predetermined amount of cooling water is introduced into the autoclave to cool the drug solution sufficiently.

After cooling, the oxygen absorber 2 is added to the packaging material 23 described above.
A plastic container 22 containing a drug solution is put together with 4 . At this time, nitrogen gas is filled and sealed.

As shown in FIGS. 3 (a) and 3 (b),
The oxygen removing effect of the oxygen absorber 34 can be enhanced by placing the oxygen absorber 34 and the plastic container containing the chemical solution on the plate 37 having the unevenness and putting the oxygen absorber 34 in the packaging material 33.

[0031]

[0032]

Example 1 A 12% amino acid infusion solution containing an essential amino acid as a main component
Was filled in a bag made of linear low-density polyethylene.
Substitute nitrogen in the amino acid transfusion and in the bag to substantially oxygenate
Of the linear low-density polyethylene
Seal with a len film, attach a rubber stopper, and
Laminate the resin blended with propylene and polyethylene
It was sealed with a coated polyester film. This bag containing the chemical solution was subjected to high-pressure steam sterilization at 115 ° C. for 40 minutes. A predetermined amount of nitrogen gas was introduced into the autoclave in order to maintain the pressure during sterilization and cooling. After cooling, the bag containing the chemical solution was put into a biaxially oriented polypropylene film (thickness 2
(0 μm) as an outer layer and a polyvinylidene chloride-coated polyamide film (20 μm) as an intermediate layer and an unstretched polypropylene film as an inner layer were wrapped in a three-layer laminate film. At this time, an oxygen scavenger (trade name: manufactured by AGELESS Mitsubishi Gas Chemical Co., Inc.) was enclosed together with air having a humidity of 60% to obtain a desired plastic container containing a chemical solution.

COMPARATIVE EXAMPLE 1 High-pressure steam sterilization was performed using a bag containing a chemical solution without using an oxygen scavenger.
A plastic container containing a chemical liquid was obtained in the same manner as in Example 1 except that the packaging was performed after packaging with the packaging material (using an oxygen absorber).
Instead, when the bag containing the chemical solution before packaging is sterilized with high pressure steam,
It can be regarded as almost equal) .

[0035]

Comparative Example 2 A plastic container containing a drug solution was obtained in the same manner as in Example 1 except that the oxygen absorber was enclosed in a bag containing the drug solution so as to be in close contact with the packaging material.

[0037]

The transmittance of visible light (420 nm) was measured in order to examine the degree of alteration of the chemical liquid in the plastic container containing the chemical liquid obtained as described above, and the results are shown in Table 1.

[0039]

[Table 1]

[0040]

EFFECTS OF THE INVENTION It is possible to prevent deterioration of a drug solution in a container due to oxygen during sterilization and during storage after sterilization, and to store the drug solution in a stable state. As it is made of plastic, it is light and convenient to carry. Flexible plastic containers can be used in closed systems to prevent airborne infections. Since the packaging material is transparent, it is easy to perform foreign matter inspection and observation of the storage state.

[Brief description of drawings]

FIG. 1 is a schematic front view showing an example of a plastic container containing a chemical liquid for preventing the chemical liquid from being deteriorated by oxygen obtained by the present invention.

FIG. 2 is a schematic front view showing another example of a plastic container containing a chemical liquid for preventing the chemical liquid from being deteriorated by oxygen obtained by the present invention.

FIG. 3 (a) is a schematic front view showing another example of a plastic container containing a chemical liquid for preventing the chemical liquid from being deteriorated by oxygen obtained by the present invention, and FIG. 3 (b) is a III-III schematic cross section of the same example. It is a side view.

[Explanation of symbols]

 11, 21, 31 ... Plastic container containing chemical liquid 12, 22, 32 ... Plastic container 13, 23, 33 ... Packaging material 14, 24, 34 ... Deoxidizer 15, 25, 35 ... Chemical liquid 16, 26, 36 ... Discharge port 17 ......... Structure having holes communicating with each other 37 ....

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location A61J 1/00 390 S

Claims (7)

[Claims] 1. A high oxygen content of both an oxygen scavenger and a container containing a chemical solution containing a component easily changed by oxygen in a container having at least one discharge port formed of a flexible plastic material having heat resistance. A plastic container containing a chemical liquid, which is packaged and hermetically sealed with a transparent packaging material having gas impermeable property, and a small amount of oxygen that permeates the packaging material is removed by the oxygen scavenger to prevent oxygen from entering the container for a long time. A method of manufacturing, wherein a container having at least one or more discharge ports formed of a heat-resistant flexible plastic material is provided with a chemical solution containing a component that is easily deteriorated by oxygen, and oxygen in the container and the chemical solution are inactive. Substituting with gas and sealing in a container and chemical liquid in a state where oxygen does not substantially exist, and then high-pressure steam sterilization is performed in a steam atmosphere in which oxygen does not exist, and the high-pressure steam sterilization is performed. The container containing the sterilized drug solution is cooled in an inert gas atmosphere while maintaining the pressure of 1, and then the sterilized container is high together with the oxygen scavenger so that a space exists at least around the oxygen scavenger. A method for producing a plastic container containing a chemical liquid, which is characterized in that it is packaged and sealed with a transparent flexible packaging material having oxygen gas impermeable property, which prevents the chemical liquid from being deteriorated by oxygen. 2. A method of making oxygen substantially absent in the container and in the chemical solution is to inject a chemical solution containing a component which is easily deteriorated by oxygen into the container and then bubble an inert gas into the chemical solution. The method for producing a plastic container containing a chemical liquid according to claim 1, which prevents deterioration of the chemical liquid due to oxygen. 3. A method of making oxygen substantially absent in the container and the chemical liquid is to replace oxygen in the chemical liquid with an inert gas in advance and inject the chemical liquid into the container together with the inert gas. The method for producing a plastic container containing a chemical liquid according to claim 1, which prevents deterioration of the chemical liquid due to oxygen. 4. The oxygen absorber according to claim 1, wherein the oxygen absorber used is covered with a structure having a hole communicating from one side to the other side. A method for manufacturing a plastic container containing a chemical liquid, which prevents deterioration of the chemical liquid due to oxygen. 5. The method according to claim 1, wherein when the oxygen absorber is enclosed in the packaging material, the oxygen absorber is placed on a plate having irregularities and enclosed in the packaging material. Item 8. A method for producing a plastic container containing a chemical liquid, which prevents the chemical liquid from being deteriorated by oxygen. 6. The oxygen-containing chemical liquid according to claim 1, wherein an inert gas is simultaneously enclosed in the packaging material when the sterilized container containing the chemical liquid is enclosed in the packaging material. Manufacturing method of a plastic container containing a chemical liquid for preventing deterioration of the container. 7. The method according to claim 1, wherein when the sterilized drug solution-containing container is sealed in the packaging material, the gas in the packaging material has a humidity of at least 50% or more. A method for producing a plastic container containing a chemical liquid, which prevents the chemical liquid from being deteriorated by the described oxygen.