JPH0561941B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a container for storing blood and blood products such as whole blood, concentrated red blood cells, and concentrated platelet fluid. [Prior Art] Conventionally, blood, particularly whole blood and red blood cells, has been stored by collecting blood in glass containers or polyvinyl chloride bags and storing the blood in a refrigerator at a low temperature of 4 to 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. It is also known that blood can be stored better than glass containers. However, even when stored in polyvinyl chloride bags like this, the function of red blood cells, especially the ability of red blood cells to carry oxygen, declines with the number of days of storage, so the current limit for storage in Japan is 21 days. However, after 2 weeks, the function deteriorates significantly.
In particular, the deterioration of concentrated red blood cells containing few plasma components is remarkable and 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. In particular, regarding adenine, Lee Wood et al., “Transfusion”, Vol. 11,
No. 3, p. 123 (1971), by using acidic citrate-glucose solution and adenine together.
They report that it can be stored for 35 days and that this method is the main storage method in Sweden. In addition, the large influence of PH indicates that “J.
Lab.and Clin.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 significant effect on the function of blood or blood products. In other words, in containers with poor carbon dioxide gas permeability, where carbon dioxide gas generated by glucose metabolism in stored blood accumulates inside the container, the pH of stored blood decreases, and the function of blood cell components decreases. Significant. Based on what has been said here, Dow
In Japanese Patent Application Laid-Open No. 53-20683, Corning
We proposed a blood storage bag that stores blood in contact with cured silicone rubber containing (OH) ₂ .
It is disclosed that the function of red blood cells can be maintained for more than 40 days. 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, it has a high pH buffering effect as an anticoagulant.
CPD liquid (Citrate-Phosphate-Dextrose)
It has been found to be superior to ACD solution (Acid-Citrate-Dextrose), and a preservation method using CPD solution has been put into practical use. Furthermore, Hamasaki et al.
PEP (Phospho-Enol-Pyruvate), ACD blood,
CPD blood (blood added with ACD liquid and CPD liquid, respectively)
2,3-DPG of red blood cells by adding
There have been reports that this method can maintain high levels, but it has not been put to 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℃, -80℃, and -198℃.For these purposes, bags made of films such as polyimide, fluorine resin, and stretched polyethylene are used. Proposed. Extending the shelf life of precious blood is
This is important for effective use of resources. 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. I haven't reached it yet. Regarding platelets, Murphy and Gardner
“Blood”, Vol. 46, p. 209-218 (1975) states that when storing platelet concentrates in containers made of vinyl chloride resin, the pH decreases and the lifespan of platelets is shortened. It is disclosed that when a container made of polyethylene is used, the pH decrease is small. 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 PH, and the rate of PH decline 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 within the container; (3) the material of the storage container. Although it is advantageous to use polyethylene, which has good gas permeability, it has been clarified that vinyl chloride resin can have the same effect if it is made thinner and more gas permeable. Based on these facts, Japanese Unexamined Patent Publication No. 58-29465
The publication discloses a platelet storage container made from a polymer of ethylene and α-olefin, an ionomer, and a laminate or coextrusion of an ionomer/polyester elastomer and a linear low-density polyethylene elastomer (hereinafter referred to as olefin resin). ing. Here, the amount of permeation of carbon dioxide gas is 3870 to about 7000ml/ ^m2・24hr・atm
And the oxygen permeability coefficient is approximately 1500ml/ ^m2・24hr・
We present containers that are atm or higher, 3870ml/
If the carbon dioxide gas permeability coefficient is less than ^m2・24hr・atm, carbon dioxide gas will not be able to escape sufficiently from the container.On the other hand, if the carbon dioxide gas permeability coefficient is significantly higher than 7000ml/ ^m2・24hr・atm, the liquid containing platelets will fail. It is said that if the pH of the product exceeds 7.5, its lifespan will be reduced. 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 consisting of a graft copolymer and a stabilizer. Here, the carbon dioxide gas permeability coefficient is 2.5 to 9.0×10 ³
ml/ ^m2・24hr・atm.
However, the permeability coefficient of carbon dioxide gas is 0.4
The thickness is 3000ml/ ^m2 /24hr/ATM.
In order to achieve high gas permeability, it is necessary to have a thickness of 0.2 mm or less, and with this alone there are concerns about strength. Furthermore, in order to prevent platelets from adhering to blood bags and to prevent a decrease in platelet aggregation ability caused by DOP plasticizers in polyvinyl chloride bags, JP 59-197256 discloses aminoalkylsiloxane-dimethylsiloxane-based A polyvinyl chloride bag covered with a silicone resin containing mainly alkylsiloxane units as thinly as possible without sacrificing thermal adhesive properties, JP-A-56-116466 and JP-A-56-
Publication No. 116469 proposes a blood bag made of a vinyl chloride resin that has a crosslinked layer on at least a portion of the surface layer of polyvinyl chloride, and a layer of organopolysiloxane with a linear structure formed on the crosslinked layer. has been done. However, the film strength of these silicone resins is low and may crack. As a result of studying the preservation 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. It was discovered that the cell components can be stored for a considerable period of time while retaining their functions sufficiently, that the partial pressure of carbon dioxide gas in the blood is kept low, and that there is little decrease in pH. Based on the well-known fact that platelets can be preserved well in containers with high carbon dioxide gas permeability, the present invention was completed after conducting studies on various storage containers. As a blood storage container that provides these 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 Nos. 59-145948 and 1987-145949. did. Japanese Patent Application No. 145948/1984 applies the fact that addition polymerization type silicone rubber, which has particularly excellent blood compatibility, strongly adheres to thermoplastic resin. This is a blood storage container consisting of: Furthermore, as a result of studying blood bags with high gas permeability and excellent blood compatibility, we found that the blood bag has a carbon dioxide gas permeability of 10,000 ml/ ^m2 /24 hr/atm or more, has practical strength, and can withstand autoclaving. It has been found that at least one layer of the film must be porous in order to provide heat resistance. 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. Furthermore, when a porous film is used, it has high water vapor permeability and a considerable amount of water evaporation cannot be avoided even during low temperature storage. [Object of the Invention] In order to improve the above-mentioned drawbacks of conventional blood storage containers, the present invention aims to improve the shelf life of blood and blood components while maintaining good functions of the blood components. The object of the present invention is to provide a plastic blood storage container that can be used for extended periods, has excellent permeability to gases, particularly carbon dioxide gas, can withstand 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, and the outer layer is a TPX resin film, the middle layer is a polyethylene film, For blood storage, comprising a polyurethane or polybutadiene resin film, an addition polymerization silicone rubber layer on the inner surface that comes into direct contact with blood, and an outer layer and an intermediate layer bonded with addition polymerization silicone rubber. It is a container. TPX resin (2-methylpentene polymer) is a highly transparent resin with a heat resistance of 130°C or higher, and its most important feature is its excellent gas permeability. While being relatively flexible, it can handle 50,000ml/ ^m2・24hr・with a thickness of 100μ.
Has carbon dioxide gas permeability higher than ATM. 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.
Furthermore, the present inventors also investigated the TPX-based resin.
TPX resin film surface corona discharge treatment, UV
It was discovered that strong adhesion can be achieved by treatment or glow discharge treatment such as low-temperature plasma.
TPX resin film has excellent mechanical strength, and although it has high gas permeability, it has a relatively low water vapor permeability, about three times that of polyethylene, and has sufficient performance as an outer layer material. It is something that you have. The middle layer is a material with heat sealing properties,
A material with high gas permeability and excellent tear strength is desirable, and examples of such materials include polyethylene, especially EVA, polyurethane, polybutadiene, and SEBS (styrene-ethylene-butadiene-styrene terpolymer).
All of them except SEBS have poor heat resistance, but in the structure 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 10,000ml/m ² ·24hr·atm or more, making them suitable materials for imparting high gas permeability. The addition-polymerizable silicone rubber constituting the inner surface that comes into direct contact with blood and the addition-polymerizable silicone layer that adheres the outer layer film and the intermediate layer film are the addition-polymerizable silicone compositions described in Japanese Patent Application No. 145948/1980, i.e. Addition polymerization containing an organohydrogenpolysiloxane having two or more hydrogen atoms per molecule in an amount sufficient to provide 1 to 6 hydrogen atoms directly bonded to silicon atoms per vinyl group in the composition. A mold silicone composition can be used.
In particular, it is preferable to use a composition containing less additives such as silicon oxide for the inner layer in order to impart 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 preferably at least 0.8, as stated in Japanese Patent Application No. 59-32609. is preferably 1.0 or higher. The innermost addition-polymerized silicone rubber layer provides blood compatibility, and the resin film in the middle layer remains at this temperature (approximately 120°C) during autoclaving.
It has the purpose of preventing welding and heat shrinkage of the intermediate layer film, and has a thickness of at least 1μ or more.
Preferably, it has a wall thickness of 5μ or more. Furthermore, the addition polymerized silicone rubber layer as an adhesive layer must have a thickness of 10μ or more, preferably 25μ or more.
A thickness of 100μ or less is economically effective. However, addition-polymerized silicone rubber has carbon dioxide gas permeability that is 50 times or more higher than that of the resin film described above, 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 the outermost layer film thickness should be 25μ or more.
Appropriate rigidity and strength can be imparted if the thickness is 150μ or less, preferably 50μ to 100μ. If it is 150μ or more, the rigidity will become high and the properties as a soft container will be lost, and if it is less than 25μ, there will be concerns about the strength. The thickness of the intermediate layer is preferably 30μ or more and 300μ or less. middle class
For 300 μ or more, reduce the amount of carbon dioxide gas permeation to 15,000 ml/
^m2・24hr・atm or more is difficult, and conversely
If the thickness is less than 30μ, the intermediate layer will not have sufficient strength when used as a heat-sealing layer, and will not be able to provide sufficient strength as a bag. Therefore,
It is desirable to set it to 50μ or more and 150μ or less. As an example of the present invention, in the case where 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, the method is not limited to this method, and laminating and coating may be reversed. Next, the surfaces not coated with the addition-polymerized silicone rubber of the middle layer are brought together, and ports for blood intake and extraction are set, using conventional methods such as heat sealing, ultrasonic sealing, and high frequency sealing. A bag (container) can be obtained by welding. If the port portion 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 bonded by coating with addition polymerized silicone rubber. By using the configuration according to the present invention, the water vapor transmission rate can be reduced.
Can be controlled to below 30g/ ^m2・24hr・atm,
In addition, even though a material with a low softening point is used for the intermediate layer, there is no problem such as adhesion or deformation of the films at the temperature during autoclaving, and the amount of carbon dioxide gas permeated is several thousand to tens of thousands of ml. / ^m2・24hr・
It can be freely changed within the ATM range and provides excellent performance as a blood storage container. Furthermore, it is possible to provide performance such as strength that sufficiently satisfies the disposable blood set standards set by the Ministry of Health and Welfare. [Effect of the invention] According to the invention, the amount of permeation of carbon dioxide gas is reduced.
It can be freely controlled within the range of 3,000 to 50,000ml/m ² / 24hr / atm, and has the strength necessary for a blood storage container. Furthermore, it uses a resin layer with poor heat resistance as an intermediate layer. It has heat resistance that can withstand autoclave treatment, making it suitable as a storage container for blood and blood products such as whole blood, concentrated red blood cell fluid, and concentrated platelet fluid. [Example] Hereinafter, the present invention will be explained in more detail with reference to Examples. TPX Film 220 (manufactured by Mitsui Petrochemicals) is dimethylpolysiloxane with a viscosity of 18000 cs at 25°C and dimethylvinylsilyl groups at both ends of the molecular chain, after corona treatment is applied to thicknesses of 50μ and 100μ in advance.
Trimethylsiloxane units per 100 parts
6 parts of polysiloxane consisting of 10 mol% dimethylsiloxane units, 40 mol% dimethylsiloxane units, 50 mol% methylhydrogen siloxane units, 20 parts silica, and 0.2 parts of an isopropyl alcohol solution of chloroplatinic acid (platinum content 1%).
Addition polymerization type silicone composition made by adding
Coated with a thickness of 100μ. To this, polyurethane (Takeda Pharmaceutical Company Limited - Takerakku 895),
50μ and 100μ films of EVA (Mitsui Petrochemical Co., Ltd. - 460, 660) and polybutadiene (Japan Synthetic Rubber Co., Ltd. - RB820) were laminated together and heated at 90°C for 2 hours to obtain a composite film. Next, the above-mentioned addition-polymerizable silicone rubber composition was coated to a thickness of 10 μm using a doctor blade method only on the portion of the composite film where the inner surface of the container on the polyurethane, EVA, and polybutadiene sides would be in direct contact with blood.
Crosslinking was carried out under the same conditions. The addition-polymerized silicone rubber sides of the composite film thus obtained were combined and made into a bag by heat sealing. The port and tube used at this time were made of soft vinyl chloride, and the port 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. The permeability of carbon dioxide gas was determined using the ASTM-D-1434 method, and water was placed in a heat-resistant bag and autoclaved at 121℃ for 20 minutes.
Deformation, adhesion, and other characteristics during high-pressure sterilization for 30 minutes are listed in Ministry of Health and Welfare Notification No. 448 (1966).
(September 28, 2016). The resin constituting the intermediate layer was measured for each single film. In addition, as a comparative example, we used 0.4 m/m of vinyl chloride resin (Sumilite), which is currently used in blood containers.
Table 1 shows gas permeability and water vapor permeability, Table 2 shows autoclave resistance, Table 3 shows tensile strength and tear strength. The test results for each bag are shown in Table 4.

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Claims (1)

[Scope of 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 contacts the blood or blood products is addition-polymerized. 1. A container for storing blood, comprising a type silicone rubber layer, and an outer layer and an intermediate layer bonded with addition polymerization type silicone rubber. 2 The permeation amount of carbon dioxide gas is 3000ml/ ^m2 .
The blood storage container according to claim 1, characterized in that the container has a capacity of 24 hours/atm or more.