JPH074406B2 - Bag-shaped container having low temperature resistance, blood bag, and method for manufacturing laminated material - Google Patents

Description

TECHNICAL FIELD The present invention relates to a bag-like container used as a package that can be used at an extremely low temperature of liquid nitrogen temperature of about −196 ° C., and particularly blood such as red blood cells, platelets and plasma. The present invention relates to a bag-shaped container suitable for components, sterilization, enzymes, other physiological or foods, drugs, etc. for frozen storage, a blood bag, and a method for producing a laminated material used for these.

<Conventional technology> Conventionally, as a blood storage method, a blood storage method using an ACD anticoagulant (a method of storing in a glass bottle containing an ACD container or a soft vinyl chloride container), a slow freezing method (-80 to
It is known to store in a soft vinyl chloride container at -85 ° C), etc., but in the former method, metabolism of blood progresses during storage and the usable period of blood is as short as 21 days after blood collection, In the latter method, a frost damage inhibitor such as high-concentration glycerin is added.
There are drawbacks such as the quality of red blood cells also decreasing in a few years,
Neither method is suitable as a long-term blood preservation method.

Therefore, a rapid cryopreservation method has been developed in which a physiological solution such as a blood component is instantly frozen in a liquid substance and stored at an extremely low temperature of about -150 to -200 ° C. However, in this case, a storage container that can withstand such an extremely low temperature, can be sterilized, and is simple to use is required. For example, a soft vinyl chloride container used for conventional blood storage is
It does not have resistance at cryogenic temperatures of -196 ° C, and cracks will occur even when subjected to a slight impact during freezing. In addition, due to the processing of metal containers such as aluminum and stainless steel, it is difficult to seal and open the container inlet and outlet,
Liquid nitrogen may flow into the container, and because it is opaque, the state of the storage solution cannot be seen from the outside, and there is a problem that the quality of the storage solution cannot be confirmed before taking it out, and the manufacturing cost is high. It becomes expensive.

Fluorine-based resins and polyimides are known as high-temperature and high-temperature-resistant polymer materials, and a bag-shaped container composed of an inner layer of tetrafluoroethylene-6-fluorene propylene copolymer and an outer layer of polypyromellitimide laminate is blood. In some cases, it is used for frozen storage. In particular, polyimide has excellent heat resistance with almost no melting point and flexibility even at liquid helium temperature (4 ° K) and resistance to cryogenic temperatures. Because it is colored, it cannot be seen through from the outside depending on the contents. Polyimide has one of the lowest thermal conductivity among polymer materials, and slows the freezing speed, which affects the recovery rate and performance of the stored liquid, and conditions such as heat sealing. Further, polyimide is very expensive in terms of price.

In addition, as described in US Pat. No. 3,576,650, it has been proposed to apply polyethylene such as a container used at a cryogenic temperature using a biaxially oriented polyolefin film. The heat sealing operation can stretch the sealing portion and its periphery. However, it has a drawback that it is necessary to protect it with a metal net or the like so as not to receive an impact on the seal portion in actual use. Ordinary high-density polyethylene (molecular weight, up to about 500,000) is at most -100 ° C
However, it could not withstand a low temperature of -196 ° C.

Proposed is a cryogenic temperature-resistant container in which an inner layer made of unstretched polyethylene having a very high molecular weight by the low-pressure polymerization method and an outer layer such as biaxially-stretched polyethylene terephthalate are laminated as disclosed in Japanese Patent Publication No. 64-49429 which solves the above problems. did.

In the above invention, the inner layer and the outer layer are laminated with an adhesive, and polyester, polyurethane, and epoxy-based reaction-curable adhesives have a small amount of unreacted low-molecular-weight substance, which is hygienic. , I was worried when storing for a long time.

<Problems to be solved> The present invention has been made in view of completely solving the above problems, and autoclave sterilization is possible.
To provide a bag-like container made of an inert material which can withstand use at an extremely low temperature of about 0 ° C. and which has no fear of adversely affecting a physiological solution to be contained, and a manufacturing method thereof. To aim.

<Means for Solving the Problems> In the present invention, when laminating an inner layer made of unstretched polyethylene having an extremely high molecular weight by an low pressure polymerization method and an outer layer such as biaxially stretched polyethylene terephthalate, a metal or metal compound is laminated on the outer layer. Is a bag-shaped container obtained by heat-sealing the inner layers of a laminated material in which the thin film of (1) is provided and the intermediate layer is laminated via polyethylene that has been acid-modified.

The unstretched polyethylene of extremely high molecular weight by the low-pressure polymerization method of the inner layer used in the present invention has a molecular weight of 1 million or more by the viscosity method and 3 million or more by the light scattering method, and such a value of the molecular weight is extremely low. Gives endurance physical properties. Since it has an extremely high melt viscosity, it is usually used as a desired film having a thickness of 0.025 to 0.125 mm by subjecting a powder product to a block-shaped product by press molding, ram extrusion or the like and then planing.

This film has high impact strength due to its extremely high molecular weight, and retains a certain flexibility and good physical properties even at -196 ° C. In addition, since the melt viscosity is extremely high, the inner surface does not fuse even in autoclave sterilization at 121 ° C for 30 minutes, and the fusion seal is made at a temperature 30 to 50 degrees higher than ordinary high-density polyethylene. In addition to polyethylene's inactivity, there are few low-molecular substances and good hygiene, and it is chemically stable, and even if erythrocytes etc. are stored for a long period of time, the adverse effects such as alteration of the contents hardly poses a problem. . Further, since it is unstretched polyethylene in the present invention, there is no difference between the container body and the seal part which is stretched by heat like low molecular weight polyethylene which has been highly stretched to have low temperature resistance. No cracks and no worries.

The outer layer must have a higher heat-melting temperature and heat-bonding temperature than the polyethylene of the inner layer, and at extremely low temperatures such as -196 ° C, those that do not deteriorate substantially the same as physical properties at room temperature can be used. Biaxially stretched polyethylene terephthalate, stretched or non-stretched polyethylene terephthalate, polyparabanic acid resin, perfluoroalkoxy resin, polytetrafluoroethylene, ethylene-tetrafluoroethylene alternating copolymer, tetrafluoroethylene-
0.003 to 0.075 of hexafluoropropylene copolymer, chlorotrifluoroethylene resin, or aromatic polyimide resin
It is a mm-thick film. The method for laminating the inner layer and the outer layer is such that aluminum, zinc, copper, or another metal such as aluminum oxide, iron oxide, ITO, or silicon oxide is used on the laminating surface of the outer layer film.
Providing a thin film layer of a metal compound such as a metal oxide such as silicon dioxide, aluminum nitride, a metal nitride such as silicon nitride,
The middle layer is made of acid-modified polyethylene, and the inner layer and outer layer are heat-pressed. As the method, a method of laminating acid-modified polyethylene by extrusion, a heat treatment for further improving the adhesive strength, and a method of heat-pressing the acid-modified polyethylene, which has been previously formed into a film, by a sand laminating method, or an acid For example, a method of coating a water-based emulsion paint of modified polyethylene fine particles, drying (and further heating and melting), and then heat-pressing and sandwiching is used.

Examples of the acid-modified polyethylene used for the intermediate layer include ethylene-methyl tacrylate copolymer, ethylene-ethyl (metal) acrylate copolymer, ethylene-acrylic acid copolymer, ethylene-metal acid copolymer, ethylene anhydride. A polyethylene-based adhesive resin having adhesiveness to a metal or a metal compound such as a maleic acid-grafted acid copolymer and an ionomer resin is used.

The metal or metal compound thin film layer formed on the laminated surface of the outer layer acts as an anchor for heat-bonding the outer layer and the intermediate layer made of acid-modified polyethylene,
Its thickness is about 1Å and it has its performance.

The forming method may be any one of a vacuum vapor deposition method, a sputtering method and an ion plating method.

In particular, when it is necessary to check the blood bag and the contents, attention must be paid to the film thickness of metal and metal compound. IT
Some of O and the like are relatively transparent, but generally used metals such as aluminum influence the light transmittance depending on the film thickness. For aluminum, 50 Å or less,
It shows a light transmittance of 90% or more, but is almost 0 at 300 Å or more.
%. In the case of blood bags, when the light transmittance is 30% or less, it is very difficult to see through foreign substances and modified substances, so the light transmittance of the laminated product is 30% or more (preferably 50%).
The film thickness of the metal or the metal compound must be controlled so that the above is satisfied.

The acid-modified polyethylene used for the intermediate layer generally has an embrittlement temperature of −50 ° C. to −80 ° C. and does not have strength resistance at −196 ° C., but is not suitable for materials having strength resistance at −196 ° C. Since it is sandwiched, it has strength resistance at -196 ° C as a laminate.

However, it is desirable that the thickness of the acid-modified polyethylene is as thin as possible so long as it has adhesive strength, and it should be thinner than the thickness of the inner layer polyethylene that is 2 μm or more that can be formed into a film.

In the case of the bag-shaped container of the package of the present invention, it can be used as a bag-shaped container by stacking the inner layers so that they are in contact with each other and heat-sealing the periphery.

When used as a blood bag, it can be used as a convenient container if it is heat-sealed under the condition that a liquid injection port and an injection port made of an ultra-high molecular weight polyethylene molded product are interposed as shown in Fig. 1. In this case, EOG sterilization, steam sterilization, or radiation sterilization is performed beforehand.

Example 1 An aluminum thin film 2 (thickness 20 to 30 Å) was formed on one surface of an outer layer 1 made of a biaxially stretched polyethylene naphthalate film having a thickness of 12 μm by a high frequency pattering method.
Then, an ethylene-maleic anhydride graft copolymer (with an outer layer provided with a thin film and an inner layer 4 consisting of an 80 μm-thick ultra high molecular weight polyethylene cutting film (Mitsui Petrochemical, average molecular weight of about 5.4 million by light dispersion method) ( Admer NF-550
(Manufactured by Mitsui Petrochemical Co., Ltd.) was sandwiched by a roll press through the extruded intermediate layer 3 to obtain a laminate shown in FIG. 2, which was further heat treated with a hot roll at 135 ° C. at a speed of 10 m / min.

The laminated body was superposed so that the inner layer surfaces thereof were in contact with each other, and the surrounding three sides were heated and fused to obtain a bag-shaped container, and 400 ml of physiological saline was filled therein, and the remaining one was heat-sealed and sealed. A package was obtained. This package was subjected to high-pressure steam sterilization at 121 ° C. for 60 minutes, then once returned to room temperature, then placed vertically in a liquid nitrogen tank and rapidly frozen. Freezing was completed in about 2 minutes. Further, this package was thawed in warm water at 40 ° C. This freeze-thawing was repeated three times, but there was no peeling of the seal portion, damage to the container, and no outflow of the content liquid. Also,
The light transmittance of this container was 80%, which was sufficient to see through the state of the contents.

In addition, there is no specific standard for blood storage containers at present, but it is desirable that the standard of the plastic container testing method for infusions of the 11th revision of the Japanese Pharmacopoeia should be cleared at least. In particular, in the item of this test method, the ultraviolet absorption spectrum of the eluate test is a severe check for the monomers and oligomers that are dissolved from the material. As a result of performing the above-mentioned test method on the container obtained in this Example, the criteria of all items such as the eluate test and the acute toxicity test were cleared. Regarding UV absorption spectrum, the absorbance is 220nm or more and less than 241nm, 241n
Both m and 350 nm were 0.05 or less, and it was confirmed that the container was excellent in hygiene with few monomers and oligomers dissolved from the material.

Comparative Example 1 A polyethylene-naphthalate film and an ultra-high molecular weight polyethylene film used in Examples were coated with a polyester-isocyanate adhesive at 4.0 g / m ² to obtain a laminate. This laminate was also evaluated according to the criteria of the infusion plastic container test method in the same manner as in the example.) Except for the UV absorption spectrum of the eluate test, the criteria for other items were cleared, but the UV absorption Regarding the spectrum, the absorbance was 0.06 above the reference value of 0.05 at wavelengths of 220 nm or more and less than 241 nm and at 0.08,241 nm or more, which was the limit, and the standard could not be cleared due to the large elution of monomers and oligomers from the material.

<Effects of the Invention> As described above, the bag-shaped container of the present invention has a good heat-sealing property and is easy to manufacture, and moreover, can withstand high-pressure steam sterilization and is flexible even at an extremely low temperature of −196 ° C. In addition, it has a sufficient mechanical strength, and also in terms of toxicity and hygiene, it uses a laminate in which hygienic films are laminated without using a reactive adhesive that uses monomers or oligomers. Very few substances elute in the material,
It is an excellent container for cryopreservation of physiological solutions such as blood.

The light transmittance of the laminated material is 30% or more, preferably 50%.
When it is more than%, it can be used in blood bags,
It greatly contributes to long-term stable storage of blood.

[Brief description of drawings]

FIG. 1 is a sectional view showing the structure of a blood bag, and FIG. 2 is a sectional view of a laminated material. 1 ... Outer layer, 2 ... Thin film 3 ... Intermediate layer, 4 ... Inner layer

Claims (4)

[Claims] 1. An inner layer made of unstretched polyethylene having an extremely high molecular weight by a low-pressure polymerization method and an outer layer made of a plastic film having a melting point higher than that of the inner layer and not deteriorating in physical properties even at -196 ° C. Alternatively, a bag-shaped container having a low temperature resistance, which is obtained by providing a thin film of a metal compound and heat-sealing the inner layers of the laminated material with an intermediate layer made of acid-modified polyethylene interposed between the thin film and the inner layer. 2. A blood bag according to claim 1, wherein the laminated material has a light transmittance of 30% or more, preferably 50% or more. 3. A bag-shaped container or blood bag having low temperature resistance according to claim 1 or 2, which uses a laminated material in which the thickness of the intermediate layer is thinner than that of the inner layer. 4. A metal or metal compound thin film is provided on the laminated surface of an outer layer made of a plastic film which does not deteriorate in physical properties even at -196 ° C., and an extremely thin film is formed by a low pressure polymerization method through an intermediate layer made of acid-modified polyethylene. A method for producing a laminated material, which comprises laminating an inner layer made of unstretched polyethylene having a high molecular weight and then heat-pressing it.