JPS62144660A - Blood preserving container - 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] [Industrial Field of Application] The present invention is applicable to whole blood, red blood cells, t! A Container for storing blood and blood products such as thick liquid and platelet concentrate.

[Prior art]

Traditionally, blood, especially whole blood and red blood cells, is stored by collecting blood in glass containers or PVC hangers and storing them in the refrigerator for 4 hours.
It has been stored at a low temperature of ~6°C.

In particular, vinyl chloride bags are flexible and transparent, have heat resistance that can withstand high-pressure steam sterilization, cold resistance that can withstand low temperatures during blood storage, and mechanical strength that can withstand various operations for separating blood components. Furthermore, it has been widely used all over the world because of its excellent processability and hygienic properties. Preservability of blood
It is known to be superior to glass containers.

However, even when stored in such polyvinyl chloride bangs, the function of red blood cells, especially the oxygen carrying capacity of red blood cells, decreases with the number of days of storage, so the storage period is currently set at 21 days in Japan. However, after 2 weeks, the function deteriorates significantly, and the deterioration is particularly noticeable in concentrated red blood cells containing few plasma components, which has become a clinical problem.

On the other hand, the demand for platelet preparations has increased significantly in recent years for the purpose of imparting blood clotting functions, but platelets lose their adhesive and aggregating abilities within a short period of time after storage begins, so their shelf life is limited. In Japan, blood is collected for 48 hours at room temperature after blood collection, but in fact more than half of the blood loses its function within that period.

Maintaining the blood oxygen carrying ability of red blood cells and the coagulation ability of platelets for a long time not only helps in the effective use of precious human blood resources, but also is a fundamentally important issue that affects the effectiveness of blood transfusion itself. More and more research is being carried out.

Much of the research into preserving the oxygen-carrying ability of stored red blood cells for a long period of time concerns preservation solutions, and methods of adding inosine, adenine, adenosine, etc. to the preservation solution have been proposed. Especially regarding adenine, Lee Wood et al., “Transfusion”, Vol. IL No.
, 3, p, 123 (1971), Acid Citrate-Grape IJ! It is reported that by using the solution and adenine together, it can be stored for 35 days, and that this method is the main storage method in Sweden. In addition, the large influence of pi means “J,
Cab, and Cl1n, Medicine”
, Vol. 80. No.

5, p. 723-728 (1972), and it has also been reported that the gas permeability of synthetic resins used in blood storage containers has a large impact on the function of blood or blood products. There is. In other words, in a container with poor carbon dioxide gas permeability, where carbon dioxide gas generated by the glucose metabolism of stored blood accumulates inside the container, the p■ of stored blood will decrease, and the function of blood cell components will be significantly reduced. .

Based on what has been said here, Ilow Corn
In Japanese Patent Application Laid-open No. 53-20683, ing company has disclosed Ca (
A blood storage bag is proposed in which blood is stored in contact with cured silicone rubber containing 0■) 2, and it is disclosed that the function of red blood cells can be maintained for 40 days or more. Furthermore, although the effect of shaking is presented here, the gas permeability of the material is not mentioned in a strict sense. In addition, since it is advantageous to maintain a high pH, CPD liquid (Citrate-Phosph), which has a high pH buffering effect, is used as an anticoagulant.
ate-Dextrose) is ACD liquid (＾cid-
It has been found that CPD liquid is superior to Citrate-Dextrose (Citrate-Dextrose), and a preservation method using CPD liquid has been put into practical use. Furthermore, Hamasaki et al.
It has been reported that the 2.3-DPG level in red blood cells can be maintained high by adding pho Enol Pyruvate to ACD blood and CPD blood (blood to which ACD fluid and CPD fluid have been added, respectively). However, it has not been put into practical use because it is complicated to operate and cannot be sterilized by heat.

In addition, there are frozen blood bags that are used in a frozen state at extremely low temperatures such as -30°C, -80°C, and -198°C, and bags made of films such as polyimide, fluororesin, and stretched polyethylene have been proposed for these purposes. has been done. Extending the shelf life of precious blood is important for effective resource utilization. In a frozen state, it is possible to preserve red blood cells for at least six months or more, and the preservation of blood of rare blood types and blood fraction components has already been put into practical use. However, it is known that it takes a lot of effort to remove cryoprotectants such as glycerol that are added when freezing blood, and the recovery efficiency is low, so it has not been widely used except for fresh frozen plasma. Not yet reached.

Regarding platelets, Murphy and Gardn
er “Blood”, Vol. 46. p, 2
09-21B (1975), when storing a platelet concentrate, using a container made of vinyl chloride resin causes a decrease in PL+, which shortens the lifespan of platelets, but when a container made of polyethylene is used, It is disclosed that there is little decrease in pi. Furthermore, as a result of research into the conditions necessary to maintain the lifespan of platelets, we found that (1) lactic acid generated by platelet glycolysis lowers p)I, and the rate of decrease in pl+ is approximately inversely proportional to the number of platelets. (2) Glycolysis is suppressed by allowing carbon dioxide gas generated by platelet metabolism to escape outside the storage container and increasing the oxygen partial pressure inside the container. (3) Gas can be used as a material for storage containers. It is advantageous to use polyethylene, which has good permeability, but it has been clarified that vinyl chloride resin can have the same effect if it is made thinner to allow gases to pass through it more easily.

Based on these facts, JP-A-58-29465 discloses polymers of ethylene and α-olefins, ionomers, and laminates or coextrudates of ionomer/polyester elastomers and linear low-density polyethylene elastomers (hereinafter referred to as olefins). Discloses a platelet storage container made from a polymer based resin. here,
The permeation amount of carbon dioxide gas is 3870 to about 7000 m1/
m・24hr・atm, and the oxygen permeability coefficient is about 1500mj/, 1・24hr・atm or more, and 3870rn! / m・24
If the carbon dioxide gas permeability coefficient is less than hr/atm, carbon dioxide gas cannot escape sufficiently from the container, and on the other hand, if it is significantly higher than 7000 mf/nf/24 hr-atm, the pH of the liquid containing platelets will be 7. It is said that if the value exceeds .5, the lifespan will be shortened.

However, this container is unsuitable for storing red blood cells because it tends to cause hemolysis.

Furthermore, in JP-A-59-189154, a vinyl chloride monomer is reacted with a styrene-butadiene copolymer and/or its derivative in the presence of a polymer plasticizer such as a linear polyester or an ethylene copolymer. We have proposed a resin composition comprising the graft copolymer obtained by this method and a stabilizer.

Here, the carbon dioxide gas permeability coefficient is 2.5 to 9.
．． Q X IQ3+++j / rd ・24hr-a
tm. However, the permeability coefficient of carbon dioxide gas is 3000ml/r at 0.4mm thickness.
d・24 hr-atm is barely enough, and in order to achieve high gas permeability, it is necessary to make the thickness 0.21 .mu. or less, and with this alone, there is concern in terms of strength.

Furthermore, prevention of platelet adhesion to blood bags and platelet a by DOP plasticizer in polyvinyl chloride bags.
For the purpose of preventing a decline in collective ability,
No. 6 discloses a bag made of polyvinyl chloride covered with a silicone resin mainly composed of an alkylsiloxane unit based on aminoalkylsiloxane-dimethylsiloxane, as thinly as possible without sacrificing thermal adhesive properties, disclosed in JP-A No. 56-116466 and JP-A No. 116-116-466. Publication No. 56-116469 discloses a blood made of a vinyl chloride resin having a crosslinked layer on at least a part of the surface layer of polyvinyl chloride, and a layer of organopolysiloxane having a linear structure formed on the crosslinked layer. A bag is suggested. However, the film strength of these silicone resins is low and may crack.

As a result of studying the storage of blood, particularly whole blood and concentrated red blood cells, the present inventors found that blood and concentrated red blood cells packed in thin polyvinyl chloride or polyethylene resin containers can be stored at 4 to 6°C. , that the cell components can be stored for a considerable period of time while retaining their functions sufficiently, and that the partial pressure of carbon dioxide gas in the blood is kept low at that time, p.
), and based on the fact that, as is known, platelets have excellent preservation in containers with high carbon dioxide gas permeability, we investigated various storage containers. As a result, the present invention was completed.

As a blood storage container that provides high gas permeability,
The present inventors previously proposed a blood storage container made of a single film or a composite film in Japanese Patent Application No. 59-145948 and No. 59-145949. Special application 1984-1
No. 45948 applies the fact that addition polymer silicone rubber, which has particularly excellent blood compatibility, firmly adheres to thermoplastic resin. It is a container for

Furthermore, as a result of studying blood bags with high gas permeability and excellent blood compatibility, we found that the amount of carbon dioxide gas permeation was 10.0.
It has been found that at least one layer of the film needs to be porous in order to provide the film with a practical strength of 00 m1/cd ・24 hr ・atm or more, as well as heat resistance that can withstand autoclaving. If autoclave resistance is excluded, EVA, polyurethane, polybutadiene, etc. satisfy this condition, but these resins have the disadvantage of softening and deforming at temperatures below 100°C. Further, when a porous film is used, water vapor permeability is high and a considerable amount of water evaporation cannot be avoided even during low temperature storage.

[Purpose of the invention]

In order to improve the above-mentioned drawbacks of conventional blood storage containers, the present invention aims to extend the shelf life of blood and blood components while maintaining good functionality of the blood components. The object of the present invention is to provide a blood storage container made of plastic, which has excellent gas permeability, particularly carbon dioxide gas, is resistant to autoclave treatment, and has relatively low water vapor permeability.

[Structure of the invention]

That is, the present invention is a container for storing blood and blood components, which includes a container for easily removing carbon dioxide gas from the blood.
The outer layer is a TPX resin film, the middle layer is a polyethylene, polyurethane, or polybutadiene resin film, and the inner surface that comes into direct contact with blood is an addition polymerization silicone rubber layer, and the outer layer and the intermediate layer are addition polymerization silicone rubber. This blood storage container is characterized by being glued with

TPX resin (2-methylpentene polymer) is a highly transparent resin with heat resistance of 130°C or higher, and its most important feature is its excellent gas permeability. 50.5mm at 100μ thickness while being relatively flexible. OOOmf / m ・24hr-atm
It has a carbon dioxide gas permeability of

However, the adhesion properties of this material are known to be poor. As shown in Japanese Patent Application No. 59-145948, it has been found that certain addition-polymerized silicones adhere well not only to soft vinyl chloride resins but also to PE, EVA, polybutadiene, and polyurethane. They have also found that TPX-based resin can be firmly bonded by subjecting the surface of the TPX-based resin film to corona discharge treatment, UV treatment, or glow discharge treatment using low-temperature plasma or the like. Although TPX resin film has excellent mechanical strength and high gas permeability, it has relatively low water vapor permeability, about three times that of polyethylene, and has sufficient performance required as an outer layer material. It is something that you have.

The intermediate layer is preferably made of a material that has heat-sealing properties, high gas permeability, and excellent tear strength. Such materials include polyethylene, especially EVA, polyurethane, polybutadiene, and 5EBS (styrene-ethylene). -butadiene-styrene terpolymer), etc. All have inferior heat resistance except for 5EBS, but
With the configuration according to the present invention, this is not a particular problem because the shape can be maintained as long as it does not melt at 120° C. or lower. These resins have a thickness of 100μ and a carbon dioxide gas permeation rate of 1.
0. OOOmZ/nr ・24 hr-atm or more, and is a material suitable for imparting high gas permeability.

The addition polymerization type silicone rubber constituting the inner surface that comes into direct contact with blood and the addition polymerization type silicone layer bonding the outer layer film and the intermediate layer film are disclosed in Japanese Patent Application No. 59-145948.
The addition-polymerizable silicone composition described in the above-mentioned No. 1, i.e., contains 2 hydrogen atoms per molecule in an amount sufficient to provide 1 to 6 hydrogen atoms directly bonded to a silicon atom per vinyl group in the composition. Addition-polymerizable silicone compositions containing organohydrogenpolysiloxanes having at least 100% polysiloxane can be used. In particular, for the inner layer, it is preferable to use a composition containing less additives such as silicon oxide in order to provide compatibility with blood. However, in addition-polymerizable silicone compositions, the ratio of hydrogen atoms directly bonded to silicon, which is the point of adhesion with these thermoplastic resin films, to vinyl bonds is disclosed in Japanese Patent Application No. 59-3260.
As stated in No. 9, at least 0.8 or more, preferably 1
．． It is desirable that it be 0 or more.

The innermost addition-polymerized silicone rubber layer provides blood compatibility, prevents the interlayer resin films from welding together at this temperature (approximately 120°C) during autoclaving, and prevents heat shrinkage of the interlayer film. It is desirable to have a wall thickness of at least 1μ or more, preferably 5μ or more.

Furthermore, the addition polymerization type silicone rubber layer as an adhesive layer is 1
0μ or more is required, preferably 25μ or more and 100μ or less, which is economically effective! However, the addition polymerization type silicone rubber has carbon dioxide gas permeability that is 50 times or more higher than that of the above-mentioned resin film, and has almost no effect on gas permeability.

The thickness of the outermost layer and intermediate layer film is determined by the required gas permeability and is not particularly limited, but if the outermost layer film thickness is 25μ to 150μ, preferably 50μ to 100μ, it will have appropriate rigidity. It can add strength.

If it is 150μ or more, the rigidity becomes high and the properties as a soft container are lost, and if it is less than 25μ, the strength becomes unstable. The thickness of the intermediate layer is preferably 30 μm or more and 300 μm or less. If the intermediate layer is 300μ or more, the carbon dioxide gas permeation rate is 15.0
It is difficult to make it more than 00m1/rrr・24hr-atm, and conversely, if it is less than 30μ, the strength is insufficient when the intermediate layer is used as a heat-sealing layer, and it is not possible to provide sufficient strength as a bag. Therefore,
It is desirable that the thickness be 50μ or more and 150μ or less.

As an example of the present invention, when the intermediate layer is used as an adhesive layer during bag making, an addition polymerizable silicone rubber composition is attached to one side of two thermoplastic resin films that have been previously treated to improve adhesion such as corona discharge treatment. After coating, laminating, and applying heat to bond and integrate the addition-polymerized silicone rubber composition, the addition-polymerized silicone rubber composition is applied to the surface of the film that forms the intermediate layer, leaving the peripheral area that will become the seal of the container. A silicone rubber composition can be coated and crosslinked by heating. Of course, it is not limited to the original nature, and lamination and coating may be reversed. Next, the sides that are not coated with the addition polymerized silicone rubber of the middle layer are placed together, the boat part for taking in and taking out the blood is set, and conventional methods such as heat sealing, ultrasonic sealing, high frequency sealing, etc. are used. A bag (container) can be obtained by welding. If the boat part is made of the same material as the material forming the intermediate layer, it may be bonded by the method described above, or if it is made of another material, it may be coated with addition polymerized silicone rubber and bonded.

With the configuration according to the invention, the water vapor transmission rate can be reduced to 30 g
/ rrr ・It can be controlled to 24 hr-atm or less, and even though a material with a low softening point is used for the intermediate layer, there are no problems such as adhesion or deformation of the films at the temperature during autoclaving, and carbon dioxide The amount of gas permeation can also be freely changed within the range of several thousand to tens of thousands -/nf/24 hr-at-, and can provide excellent performance as a blood storage container.

Furthermore, it is possible to impart performance such as strength that sufficiently satisfies the disposable blood cent standards set by the Ministry of Health and Welfare.

〔Effect of the invention〕

According to the present invention, the permeation amount of carbon dioxide gas is 3000~
50. It can be freely controlled within the range of OOOmf / rd ・24hr ・atm, and has the strength necessary for a blood storage container, even though it uses a resin layer with poor heat resistance as an intermediate layer. It has heat resistance that can withstand autoclave treatment, and can be used with whole blood,
Suitable as a storage container for blood and blood products such as concentrated red blood cell fluid and platelet concentrate.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples.

TPX film 220 (manufactured by Mitsui Petrochemicals) having a thickness of 50 μm and 100 μm was subjected to corona treatment in advance, and then treated with 100 parts of dimethylpolysiloxane, which has a viscosity of 18,000 cs at 25°C and has dimethylvinylsilyl groups at both ends of the molecular chain. On the other hand, polysiloxane 6 consisting of 10 mo1% of trimethylsiloxane units, 40 mo1% of dimethylsiloxane units, and 50 mo1% of methylhydrogen siloxane units
20 parts of silica and 0.2 parts of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 1%) were coated to a thickness of 100 μm. To this, polyurethane (manufactured by Takeda Pharmaceutical - Takerakku 895), EVA (manufactured by Mitsui Petrochemical - 460,6)
60), Polybutadiene (Japan Synthetic Rubber - RB820)
) 50μ and 100μ films were pasted together,
A composite film was obtained by heating at 90° C. for 2 hours. Then,
The above-mentioned addition-polymerizable silicone rubber composition was coated to a thickness of 10μ by the doctor blade method only on the inner surface of the container on the polyurethane, EVA, and polybutadiene sides of this composite film, which was in direct contact with the ff1L liquid, and then subjected to the same conditions. and cross-linked.

The addition-polymerized silicone rubber sides of the composite film thus obtained were combined to form a bag by heat sealing. The boat part and tube used at this time were made of soft vinyl chloride, and the port part was attached by adhesion using addition polymerized silicone rubber.

In addition, a part of the obtained composite film was used for physical property tests such as tensile strength, tear strength, carbon dioxide gas permeability, and water vapor permeability. Carbon dioxide gas permeability is ASTM-I
)-1434 method, and during high-pressure sterilization in an autoclave at 121°C for 20 minutes with water in a heat-resistant bag,
Deformation, adhesion state, and other characteristics were determined according to Ministry of Health and Welfare Notification No. 448 (September 28, 1966). The resin constituting the intermediate layer was measured for each single film. In addition, as a comparative example, vinyl chloride resin 0.4 m/m (Sumilite VMB 7170B-manufactured by Sumitomo Bakelite) currently used in IflL liquid containers
, gas permeability and water vapor permeability are shown in Table 1, autoclave resistance is shown in Table 2, tensile strength and tear strength are shown in Table 3 and 2. Autoclave resistance is shown in Table 3. Strength and tear strength Table 4 Blood bag test results (Note) In Tables 1 to 4 TPX...TPX resin PVC...Vinyl chloride resin PUR...Polyurethane P
B...Polybutadiene Si...Silicone rubber PP...Polypropylene EVA...Ethylene-vinyl acetate copolymer Internal value in parentheses after the symbol:
The thickness is μ).

Claims (2)

[Claims] (1) A storage container for blood or blood products, in which the outer layer is a TPX resin film, the middle layer is a polyethylene, polyurethane, or polybutadiene resin film, and the inner surface that comes into contact with blood or blood products has an addition-polymerized silicone rubber layer. What is claimed is: 1. A container for storing blood, characterized in that the outer layer and the middle layer are bonded with addition polymerization type silicone rubber. (2) Carbon dioxide gas permeation amount is 3000ml/m^2
- The blood storage container according to claim 1, which is configured to have a capacity of 24 hours/atm or more.