JPH08299413A - Blood component preserving container - Google Patents

Abstract

PURPOSE: To provide a blood component preserving container being made of non-polyvinyl chloride resin and with excellent preservating properties for erythrocyte. CONSTITUTION: A blood component preserving container with an inner wall layer prepd. of a polymer compsn. consisting of at least one copolymer selected from a group of ethylene-vinyl acetate copolymers, ethylene-acrylate copolymers and ethylene-methacrylate copolymers and a low MW org. ester plasticizer is provided.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a substantially chlorine-free blood component storage container suitable for storing and storing blood components, particularly erythrocyte-containing liquid.

[0002]

2. Description of the Related Art Properties required for a blood component storage container (blood bag) include transparency for observing the state of a content liquid (blood component) and flexibility for facilitating operations such as blood collection, transfusion, and blood component separation. Properties, strength that can withstand these operations, hygiene and safety, etc. Since soft polyvinyl chloride containing a plasticizer (hereinafter referred to as soft PVC) almost satisfies the above-mentioned required performance, even though disposal after use is regarded as a problem, it is still a material for blood bags. Occupies the mainstream of. In particular, in the storage of red blood cell components, the plasticizer contained in soft PVC is eluted, and it is observed that the effect of suppressing morphological changes and hemolysis of red blood cells is observed, whereas other polymers such as ordinary polyethylene and polypropylene may be used. Soft PVC is used exclusively as a container material because it has no significant effect. However, PVC
The treatment of waste will continue to be a major problem, and there is a great need for "non-PVC" storage containers for blood components. Various proposals have been made along this direction, but the actual situation is that they have not reached the stage where they are fully satisfactory. For example, special table flat 3
In JP-A-502298, a composition of non-PVC plastic (a specific example is a composition composed of styrene elastomer, polypropylene, etc.) and citrate ester has a function of suppressing the hemolysis phenomenon of red blood cells. However, in the range that the present inventors have tried, it is inferior to the hemolytic suppression effect of the plasticizer in soft PVC and is not practical.

[0003]

SUMMARY OF THE INVENTION In view of the above situation, the present invention has been made to provide a blood component storage container which is a non-PVC system and which is excellent in the preservability of red blood cells.

[0004]

These problems are achieved by the present invention described in (1) to (8) below.

(1) A polymer composition comprising at least one copolymer selected from the group consisting of ethylene-vinyl acetate copolymer, ethylene-acrylic acid ester copolymer and ethylene-methacrylic acid ester copolymer and a low molecular weight organic ester plasticizer. Blood component storage container for inner wall layer.

(2) The blood component storage container according to (1) above, wherein the content of vinyl acetate component in the ethylene-vinyl acetate copolymer is 15 to 40% by weight.

(3) The content of acrylic ester component in the ethylene-acrylic ester copolymer is 15
The blood component storage container according to (1) above, which is ˜40% by weight.

(4) The content of methacrylic acid ester in the ethylene-methacrylic acid ester copolymer is 15
The blood component storage container according to (1) above, which is ˜40% by weight.

(5) The blood component storage container according to the above (1) or (3), wherein the ethylene-acrylic acid ester copolymer is an ethylene-methyl acrylate copolymer or an ethylene-ethyl acrylate copolymer.

(6) The blood component storage container according to the above (1) or (4), wherein the ethylene-methacrylic acid ester copolymer is an ethylene-methyl methacrylate copolymer.

(7) The blood component storage container according to any one of (1) to (6) above, wherein the content of the plasticizer is 3 to 35% by weight.

(8) The plasticizer is one selected from the group consisting of phthalic acid ester, trimellitic acid ester, adipic acid ester, sebacic acid ester, azelaic acid ester, tartaric acid ester, citric acid ester and malic acid ester. The blood component storage container according to any one of (1) to (7) above, which comprises two or more types.

The essence of the present invention is that at least one copolymer selected from the group of ethylene-vinyl acetate copolymer, ethylene-acrylic acid ester copolymer and ethylene-methacrylic acid ester copolymer (hereinafter referred to as copolymer (A)), A blood component storage container having a polymer composition with a molecular organic ester plasticizer (hereinafter referred to as a plasticizer (B)) as an inner wall layer, which comprises an ester portion of a copolymer (A) and a plasticizer (B). It is considered that the moderate affinity controls the amount of the plasticizer (B) eluted in the blood component (that is, acts as an inhibitor against the hemolytic phenomenon) and exerts an excellent effect.

First, the copolymer (A) will be described. The ethylene-vinyl acetate copolymer (hereinafter referred to as EVA) is a polymer produced by a generally known method.
Considering the interaction (affinity / compatibility) with the plasticizer (B), flexibility and transparency, the vinyl acetate component content is preferably 15 to 40% by weight, more preferably 18 to 35%.
It is preferably in weight%. Also, due to moldability, processability, mechanical properties of the molded product, etc., temperature 190 ° C, load 2160g
The MFR (melt flow rate) is preferably 0.2 to 20, and more preferably 0.5 to 10.

As the ethylene-acrylic acid ester copolymer, ethylene-methyl acrylate copolymer (E
MA) and ethylene-ethyl acrylate copolymer (EEA) are typical examples, and as ethylene-methacrylic acid ester copolymers, ethylene-methyl methacrylate copolymer (EMMA) and ethylene-ethyl methacrylate copolymer (EEMA) are typical examples. Is.
For the same reason as EVA, these copolymers have an acrylic acid ester or methacrylic acid ester component content of preferably 15 to 40% by weight, more preferably 1% by weight.
It is 8 to 35% by weight, and the MFR (measured under the same conditions as EVA) is preferably 0.2 to 20, and more preferably 0.5 to 10 is suitable.

Next, the plasticizer (B) in the present invention refers to a low molecular weight organic ester compound used for plasticizing ordinary polyvinyl chloride materials, and includes phthalic acid ester, trimellitic acid ester, adipic acid ester and sebacine. Acid esters, azelaic acid esters, tartaric acid esters, citric acid esters, malic acid esters and the like are preferable. The molecular weight of these is preferably 200 to 800, more preferably about 250 to 600. If the molecular weight is too low, there is a problem of volatility, and if the molecular weight is too high, it is difficult to bleed out because the copolymer (A) does not easily move between molecules, and as a result, the inhibitory effect on the hemolysis of red blood cells may be reduced. Because. Considering bleed-out properties and effects on the human body comprehensively, specific examples of desirable plasticizers include di-2-ethylhexyl phthalate, di-n-decyl phthalate, di-n-hexyl adipate, and adipine. Acid di-2-ethylhexyl, acetyl citrate tri-n-butyl, acetyl citrate tri-n
-Hexyl, butyryl citrate tri-n-butyl, butyryl citrate tri-n-hexyl, acetylmalate di-n-hexyl, acetylmalate di-n-octyl,
Di-n-hexyl butyrylmalate, di-n-butyl diacetyl tartrate, di-n-hexyl diacetyl tartrate,
Examples thereof include di-n-butyl dibutyryl tartrate and di-n-hexyl dibutyryl tartrate. Of course, the invention is not limited to these compounds.

Then, the copolymer (A) and the plasticizer (B)
The polymer composition with is a copolymer (A) or a plasticizer (B)
The amount of the plasticizer (B) is preferably 3 to 35% by weight, more preferably 5 to 35% by weight in the polymer composition.
It should be 30% by weight. This is because if the amount of the plasticizer (B) is too small, a good erythrocyte-protecting effect will not be exhibited, and if it is too large, moldability / workability and mechanical properties of the molded product will often deteriorate. The polymer composition may contain other polymers and additives for improving gas permeability, flexibility, transparency, mechanical properties, etc. within the range not impairing the gist of the present invention. In particular, ethylene-propylene copolymer (EP), ethylene-butene-1-copolymer (E
B), block (polystyrene-ethylene butylene copolymer-polystyrene) (SEBS), block (polyethylene-ethylene propylene copolymer-polystyrene) (SEPS), block (polystyrene-ethylene butylene copolymer-polyethylene) (SEBE), block (polystyrene-ethylene) Propylene copolymer-polyethylene) (SEPE), block (polyethylene-ethylene butylene copolymer-polyethylene) (E
When the so-called thermoplastic elastomer such as EBE) or block (polyethylene-ethylene propylene copolymer-polyethylene) (EEPE) is introduced into the polymer composition in an amount of about 5 to 30% by weight, the above properties may be improved.

The polymer composition of the present invention can sufficiently withstand low temperature sterilization such as ethylene oxide gas sterilization, but lacks heat resistance against high-pressure steam sterilization usually performed at 100 to 130 ° C. In this case, heat resistance improving treatment such as radiation (electron beam, γ-ray) crosslinking or chemical crosslinking is preferably performed.

Further, in the present invention, "the polymer composition is used as the inner wall layer" means that, in the container sheet of the present invention, a layer of the polymer composition of the copolymer (A) and the plasticizer (B) is used alone. And a multi-layered body having at least one polymer (or other polymer composition) layer as a layer having the polymer composition as an inner wall surface (a surface in direct contact with a blood component-containing liquid) Means there is.

In the case of, it is used to control the mechanical properties (flexibility, strength, etc.), moldability, gas permeability, etc. of the container. Here, as the other polymer (or other polymer composition), the following are suitable.

(A) Ethylene-based polymer High-pressure low-density polyethylene (LDPE), linear low-density polyethylene (LLDPE: propylene, butene-1, pentene-1, hexene-1, octene-1,4-methylpentene-1) 2 to 20 mol% of α-olefins such as
Copolymerization is preferable), EVA (vinyl acetate content is preferably about 2 to 20% by weight), EMA (methyl acrylate content is about 2 to 20% by weight), EEA ( The ethyl acrylate content is preferably about 2 to 20% by weight), EMMA (the methyl methacrylate content is preferably about 2 to 20% by weight), and the like, and the moldability and mechanical properties of the molded product. Considering the above, the MFR at a temperature of 190 ° C. and a load of 2160 g is preferably 0.1 to 20, and more preferably 0.3 to 15.

(B) Polymer containing propylene as a main component: Isotactic polypropylene (isot-PP), syndiotactic polypropylene (synd-PP) or a copolymer containing them as a main component. The block copolymer may be either a block type or a random type (a random copolymer is preferable from the viewpoint of flexibility),
As comonomers, ethylene, butene-1, hexene-
1, etc., the comonomer content is 2 to 30 mol%
The degree is good. In addition, due to the moldability and mechanical properties of the molded product, the MFR at a temperature of 230 ° C. and a load of 2160 g is
Preferably 0.2-40, more preferably 0.3-30
The ones are good.

(C) Polymer composition of ethylene-based polymer or propylene-based polymer and flexible polymer (a) or (b) and the above-mentioned EP, EB, SEBS,
It is a polymer composition with a flexible polymer such as SEPS, SEBE, SEPE, EEBE, EEPE, and these flexible polymers may occupy 5 to 40% by weight. Amorphous atactic polypropylene may be used as the flexible polymer, in which case 10 to 30% by weight is suitable.

The thickness of the sheet forming the container is
In the case of a single layer of, preferably 0.05 to 0.70 m
m, more preferably 0.08 to 0.50 mm,
In the case of the multi-layer, the polymer composition layer (inner wall layer) of the copolymer (A) and the plasticizer (B) is preferably 0.02 to
0.20 mm, more preferably 0.03 to 0.15 m
m, the total thickness is preferably 0.05 to 0.80 m
m, more preferably 0.08-0.60 mm is recommended.

In the present invention, a blood bag means a soft plastic container for storing a liquid containing blood components, particularly red blood cells, and such a product can be manufactured by a generally known method. That is, the above-mentioned polymer composition is extruded through a T die or a circular die alone or simultaneously with other polymers, and the obtained flat sheet, tubular sheet, parison, etc. are subjected to thermoforming, blowing, stretching and cutting. It may be processed into a predetermined shape and form by appropriately utilizing a technique such as fusion (heat sealing). A laminating method may be applied to produce the multilayer sheet. Needless to say, in order to prevent blocking between the sheets, the inner surface or outer surface of the container may be roughened (embossed), an antiblocking agent, a slip agent or the like may be added.

[0026]

The present invention will be described in more detail with reference to the following examples.

After preparing the pellets of the polymer composition, sheets and blood component storage containers (minibags) according to Examples and Comparative Examples were prepared, and their water permeability was measured, tensile elastic modulus was measured, heavy metals and eluates were tested. I went. (1) Examples 1 to 12, Comparative Examples 1 to 3 [Materials and Method] Preparation of Raw Polymer and Plasticizer: The polymers and plasticizers shown in Table 1 were prepared.

[Table 1] Preparation of polymer composition: Polymers and plasticizers shown in Table 1 are appropriately selected and fed to a twin-screw melt-mixing extruder for 150 to 19
The extruded strands kneaded at 0 ° C. were water-cooled, cut and dried to obtain a pelletized polymer composition. Table 2 shows the composition (weight ratio) of the polymer composition.

[Table 2] Production of sheet: T or for single layer or for multiple layers, appropriately selected from the polymers or polymer compositions of Table 1 and Table 2
Extrude the sheet from the die at 160-180 ° C.,
After cooling with a casting roller kept at ℃, trimming the sheet with a thickness of 0.35 mm and a width of 200 mm into 6
It was wound at a speed of m / min.

Evaluation of Physical Properties of Sheet: The double-beam type self-recording spectrophotometer (Shimadzu Corporation, UV-3
00) and used as a measure of transparency. Further, the sheet was cut into a dumbbell shape, and the tensile modulus was measured according to JIS K7113, and used as a measure of flexibility.

Heavy metal and eluate test: The sheet obtained in (1) was tested according to the general test method “Plastic container test method for infusion” of the Japanese Pharmacopoeia.

Evaluation of hemolysis level: Using the sheet obtained in the above, a rectangular mini bag (having an effective surface area of about 80 cm ² with an inside surface area of about 80 cm ² ) having an internal dimension of 50 mm × 80 mm was prepared by the heat sealing method. Ethylene oxide gas sterilization (60 ° C., 8 hours).

Separately, a red blood cell concentrate (C
RC) was prepared.

Each 50 ml of this CRC was aseptically dispensed into the above mini bag in a clean bench and stored at 4 ° C. for 3 weeks.

On the other hand, diethylhexyl phthalate was added to 55P.
With respect to the polyvinyl chloride sheet containing HR (Comparative Example 2) and the sheet made of polypropylene, SEBS and a plasticizer (Comparative Example 3), a mini bag having the same shape was prepared and subjected to the test.

[Test Results] All of the sheets of Examples 1 to 12 and Comparative Examples 1 to 3 were successfully prepared, and as shown in Table 3, the transparency and flexibility of the sheets were within a practically sufficient range. there were. It has also been confirmed that heavy metals and eluates clear the standards.

Comparing the hemolysis levels in Table 3, the blood component storage container of the present invention (mini bags of Examples 1 to 12)
Is comparable to the commonly used plasticizer-containing polyvinyl chloride minibag (Comparative Example 2). On the other hand, when the composition does not contain a plasticizer (Comparative Example 1) or when it contains a plasticizer and has a composition different from that of the present invention (Comparative Example 3), the hemolysis level is high and it is not suitable for storing red blood cells. is there.

[Table 3] (2) Examples 13 and 14 [Material and Method] Production of electron beam irradiation bag: Example 1 and Example 4
The mini-bag consisting of the sheet used in 1. was irradiated with an electron beam (about 8 Mrad) by an electron beam irradiation device (EPS-750, Nisshin High Voltage Co., Ltd.).

Evaluation of electron beam irradiation sheet: Separately from the mini bag of 100 mm width × 3000 mm length, the sheet was irradiated with an electron beam under the same conditions as described above, and the transmittance in water was measured by the above-mentioned method, and the tensile elastic modulus was measured. And a heavy metal and eluate test.

The mini bag obtained in (1) was subjected to high-pressure steam sterilization (115 ° C., 30 minutes), dried, and then
The hemolysis level was evaluated by the method described above.

[Test Results] As shown in Table 4 which shows the properties of the sheet and the mini bag which were cross-linked by electron beam irradiation, the blood component storage container of the present invention (the mini bag of Examples 13 and 14) contained red blood cells. It has been shown to be good to store.

It was confirmed to pass the heavy metal and eluate tests.

Shape of mini bag after high-pressure steam sterilization
Almost no change was seen in the appearance.

[Table 4]

The container for storing blood components of the present invention comprises at least one copolymer (A) selected from the group consisting of ethylene-vinyl acetate copolymer, ethylene-acrylic acid ester copolymer and ethylene-methacrylic acid ester copolymer, and a low molecular weight organic compound. Since the polymer composition with the ester plasticizer (B) is used as the inner wall layer, it is eluted in the blood component due to the appropriate affinity between the ester portion of the copolymer (A) and the plasticizer (B) (that is, hemolysis). The amount of the plasticizer (B) that acts as an inhibitor against the phenomenon) is controlled, and the preservability of red blood cells is excellent.

Since the content of the vinyl acetate component in the ethylene-vinyl acetate copolymer is 15 to 40% by weight, the interaction (affinity / compatibility) with the plasticizer (B), the flexibility and the transparency are good, The plasticizer (B) can be eluted appropriately and is flexible and easy to use, and the content liquid can be easily confirmed.

Since the content of the acrylic acid ester component in the ethylene-acrylic acid ester copolymer is 15 to 40% by weight, the interaction with the plasticizer (B) (affinity
Compatibility, flexibility and transparency are good, the plasticizer (B) can be eluted appropriately, and it is flexible and easy to use, and it is easy to confirm the content liquid.

Since the methacrylic acid ester content in the ethylene-methacrylic acid ester copolymer is 15 to 40% by weight, the interaction with the plasticizer (B) (affinity
Compatibility, flexibility and transparency are good, the plasticizer (B) can be eluted appropriately, and it is flexible and easy to use, and it is easy to confirm the content liquid.

Since the ethylene-acrylic acid ester copolymer is an ethylene-methyl acrylate copolymer or an ethylene-ethyl acrylate copolymer,
The amount of the plasticizer (B) eluted in the blood component (that is, acting as an inhibitor against the hemolysis phenomenon) is controlled,
Excellent preservation of red blood cells.

Since the ethylene-methacrylic acid ester copolymer is an ethylene-methyl methacrylate copolymer, the amount of the plasticizer (B) eluted in the blood component (that is, acting as an inhibitor against the hemolysis phenomenon) is controlled. , Has excellent preservation of red blood cells.

Since the content of the plasticizer (B) is 3 to 35% by weight, a good effect of protecting red blood cells can be obtained, moldability and processability are good, and it is an excellent material for a blood component storage container.

The plasticizer (B) is a phthalic acid ester, trimellitic acid ester, adipic acid ester, sebacic acid ester, azelaic acid ester, tartaric acid ester,
Since it is one or more selected from the group of citrate esters and malate esters, it can bleed out appropriately, is highly safe, and has excellent erythrocyte preservability.

Claims (8)

[Claims] 1. An ethylene-vinyl acetate copolymer, an ethylene-acrylic acid ester copolymer and an ethylene-
A blood component storage container comprising a polymer composition of at least one copolymer selected from the group of methacrylic acid ester copolymers and a low molecular weight organic ester plasticizer as an inner wall layer. 2. The blood component storage container according to claim 1, wherein the content of vinyl acetate component in the ethylene-vinyl acetate copolymer is 15 to 40% by weight. 3. The content of acrylic acid ester component in the ethylene-acrylic acid ester copolymer is 15 to 40.
The blood component storage container according to claim 1, wherein the blood component storage container is wt%. 4. The content of methacrylic acid ester in the ethylene-methacrylic acid ester copolymer is 15 to 40.
The blood component storage container according to claim 1, wherein the blood component storage container is wt%. 5. The blood component storage container according to claim 1, wherein the ethylene-acrylic acid ester copolymer is an ethylene-methyl acrylate copolymer or an ethylene-ethyl acrylate copolymer. 6. The blood component storage container according to claim 1, wherein the ethylene-methacrylic acid ester copolymer is an ethylene-methyl methacrylate copolymer. 7. The blood component storage container according to claim 1, wherein the content of the plasticizer is 3 to 35% by weight. 8. The plasticizer is one or two selected from the group consisting of phthalic acid ester, trimellitic acid ester, adipic acid ester, sebacic acid ester, azelaic acid ester, tartaric acid ester, citric acid ester and malic acid ester. It is more than one kind, The claim 1 characterized by the above-mentioned.
7. The blood component storage container according to any one of 1 to 7.