JPS63120254A - Blood storage container - Google Patents

Abstract

PURPOSE:To improve the keeping quality of a platelet and to suppress the hemolysis of an erythrocyte, by constituting a soft container of a resin composition compounded with a plasticizer low in a migration property and filling said container with an anticoagulant solution compounded with reducing oligosaccharides or reducing sugar as an erythrocyte preservative. CONSTITUTION:A blood sampling bag 3 as a blood storage container is constituted of a sheet, which is made of a low migration plasticizer-containing vinyl chloride resin composition or an elastomer containing no plasticizer, equipped with a plurality of discharge port 1 each having a peel tab and a discharge port 2 and fused along the peripheral edge part thereof by a high frequency heating means. A blood sampling needle 7 is fitted to the leading end of a blood sampling tube 6 communicating with the internal space 5 of the blood sampling bag 3 and an anticoagulant solution such as an ACD-A solution or CPD solution containing reducing oligosaccharides or reducing sugar is received in the internal space of the blood sampling bag 3 as an erythrocyte preservative.

Description

[Detailed description of the invention] ■9 Prefectures with Inventions (Technical field) TECHNICAL FIELD The present invention relates to blood storage containers.

In detail, the present invention relates to a blood storage container that has good shelf life for platelets and less hemolysis.

(Prior art) Currently, as a plastic blood storage container, its processability,
Due to its good flexibility and heat resistance, materials made of soft vinyl chloride resin are widely used.

These soft vinyl chloride resins are used as plasticizers.
-Ethylhexyl phthalate (hereinafter referred to as DOP)
Contains 30-60% of phthalate esters such as. However, phthalate esters are highly migratory, so
It is known that when a blood storage container is made from the above-mentioned soft vinyl chloride resin, the Nisder phthalate is eluted. Thus, there are no reports that when phthalate esters dissolve into plasma containing concentrated platelets, it causes a decrease in the aggregation ability, which is a function of platelets [Journal of the Japanese Society of Blood Transfusion 28, 282 (1982) U. . Therefore, if possible, it is desired to use a material with less elution of plasticizer.

However, on the other hand, it is known that Nisdel phthalate, which is eluted from blood storage containers as mentioned above, has the effect of protecting red blood cells in stored blood [Bfood, 64.

6, 1270 (1984)], if blood is stored for a long period of time in a blood storage container made of a material that does not contain the plasticizer Nisdel tephthalate or a material that is extremely resistant to customer use (i.e., phthalate ester), hemolysis may occur. will occur.

II. OBJECTS OF THE INVENTION Accordingly, it is an object of the present invention to provide a novel blood storage container. Another object of the present invention is to provide a blood storage container with good platelet preservation and less hemolysis. A general object of the present invention is to provide a blood storage container made of vinyl chloride resin that does not contain di-2-ethylhexyl phthalate as a plasticizer.

The above objectives are to fill a soft container made of a resin composition containing a low migration plasticizer with an anticoagulant solution containing an oligosaccharide or reduced sugar as a red blood cell preservation agent. This is achieved by a blood storage container characterized by:

The present invention includes plasticizers such as trimellitic acid triester, pyromellitic acid tetraester, biphenyltetracarboxylic acid tetraester, phthalic acid diester whose ester group has 9 or more carbon atoms, polyester plasticizer, A soft container made of a vinyl chloride resin composition containing pentaerythritol ester, nitrile-based synthetic rubber, or a combination of two or more of these, containing mannitol, maltose, palatinose, or sucrose as a red blood cell preservative. This figure shows a blood storage container characterized by being filled with an anticoagulant solution. The present invention also provides an anticoagulant solution containing palatinose as a red blood cell preservation agent filled into a soft container made of a vinyl chloride resin composition containing biphenyltetracarboxylic acid tetraester as a plasticizer. 1 shows a blood storage container characterized by:

The above objects are also characterized in that an anticoagulant solution containing an oligosaccharide or reduced sugar as a red blood cell preservation agent is filled in a soft container made of 1 lastomer that does not contain a plasticizer. This is achieved by using a blood storage container that

The present invention provides a flexible container composed of an internally plasticized vinyl chloride resin, polyurethane, polyester elastomer, or a polymer blend of polyvinyl chloride and polyurethane, ethylene polymer, or caprolactone polymer, containing mannitol, maltose, and red blood cell preservatives.
This is a blood storage container characterized by being filled with an anticoagulant solution containing palatinose or saccharose. In the present invention, it is particularly preferable that the internally plasticized vinyl chloride resin is a vinyl chloride-ethylene vinyl acetate copolymer or a vinyl chloride-urethane copolymer.

IIl. Specific structure of the invention The present invention will be explained in more detail below.

The flexible container, which is the main body of the blood storage container of the present invention, is made of a resin composition such as a vinyl chloride resin composition containing a low-migration plasticizer.

The vinyl chloride resin is a copolymer of a vinyl chloride homopolymer with another monomer containing polyvinylidene chloride or vinyl chloride in an amount of 70% or more, preferably 85% or more. is included, and its average degree of polymerization is 500 to 3000
, preferably 1000 to 2000. Comonomers for vinyl chloride include vinylidene chloride, ethylene, propylene, vinyl acetate, vinyl bromide, vinyl fluoride, sulfuric acid, vinyl 1-toluene, vinylpyridine, acrylic acid, alkyl acrylate (e.g. Examples include methyl methacrylate, ethyl acrylate-1, isopropyl acrylate, n-butyl acrylate, 2-, I-thylhexyl methacrylate), acryloni-1 heliyl, methacryloni-1 heliyl, and the like.

Examples of low-migration plasticizers include tributyl trimellitate, trihexyl 1-limellitate, 1-ri-2-ethylhexyl 1-rimellitate, 1--n-octyl trimellitate, triisooctyl 1-limellitate, 1
-Lyzosyl 1-rimellitate, 1-liisodecyl 1-limeritate-1-, etc. 1..limellitate+= a i-diester, tetrabutyl biromellitate-1-, tetrahexyl biromellitate-1-, tel -ra 2-ethylhexylpyromeridate-1-. Pyromellitic acid monotraester such as tate, 3.3',
4.4'-biphenylte1-lacarvonetetra(
n-heptyl) ester, 3.3',4,4°-biphenyltetracarboxylic acid ester, 3.3',4.4'-biphenyltetracarboxylic acid tetra(2-ethylhexyl) ester, 3. 3',/1,4°-biphenylte]helacarboxylic acid tetra(2-methylheptyl) ester, 3,
3°,4,4゛-biphenylte1heracarboxylic acid 1
Hera(n-)nyl) Nisder, 3.3', 4.4'
-Biphenylte 1-lacarboxylic acid tetra(n-dodecyl) ester, 3.

3',4,4°-biphenyltetracarboxylic acid (n-te1~radecyl) such as nisnal, biphenyltetracarboxylic acid tetranisder, di-n-nonyl phthalate, di-n-decyl phthalate, di-n- undesired silk sauce
1, phthalic acid diesters having 9 or more carbon atoms in the ester group, such as seaport-dodecylphthale-1-, di-n-tridecyphthale-1-, n-decyl-n-1-lysosyl tsthalate, etc. Pentaerythri 1, a polyester plasticizer which is a viscous low degree of polymerization polyester with an average molecular weight of about 11,000 to aooo, in which several to several propylene glycol ester units of a dibasic acid such as adipic acid are connected in a linear chain. Pentaerythritol esters and nitrile synthetic rubbers such as Healte 1-1-la acetate and pentaerythritol 1-1-lutetraisobutyrate, and mixtures of two or more of these may be mentioned. These low migration plasticizers are usually used in an amount of 30-120 parts by weight, preferably 50-10 parts by weight, per 100 parts by weight of vinyl chloride resin.
0 tontsu part is blended.

Furthermore, this vinyl chloride resin composition contains calcium,
Metallic soaps containing metals such as zinc and stearic acid, lauric acid, ricinoleic acid, naphthenic acid, etc. may be blended.

Further, if necessary, epoxidized vegetable oils such as epoxidized soybean oil and epoxidized linseed oil, lubricants, and other antioxidants are blended.

The flexible container that is the main body of the blood storage container of the present invention may also be made of elastomers that do not contain plasticizers, such as internally plasticized polyvinyl chloride, polyurethane, polyester elastomers, and polyvinyl chloride and polyurethane, ethylene-based polymers (Elvaloy ■), It is possible to be composed of a polymer blend with a caprolactone-based polymer or the like.

In the blood storage container of the present invention, the soft container made of the above-mentioned material is filled with an anticoagulant solution containing an oligosaccharide or reduced sugar as a red blood cell preservation agent.

Examples of oligosaccharides used as red blood cell preservation agents include mannitol, maltose, palatinose, and saccharose, with palatinose being preferred. This palatinose-1, also known as isomaltulose, is two types of sugar in which glucose and fruc-1-hose are linked with α-1,6 bonds.It is the same as palatinose (isomaltase), which is found in the small intestine of many animals including humans. ), it can be hydrolyzed and absorbed into the body, and therefore, like mannitol, maltose, or sucrose, it has excellent biosafety.

As an anticoagulant solution containing these oligosaccharides or reduced sugars, ACD-A solution (
For example, in 100 d of aqueous solution, 1 sulfur citrate and 20 helium
0 g, citric acid o, aog and glucose 2.20 g), CPD solution (e.g. 0.327 g of citric acid, 2.63 g of sodium citrate, 0.2510 g of sodium dihydrogen phosphate, 2.0 g of dextrose in 100.d of aqueous solution). 3
(containing 2g) etc. are used.

Oligosaccharides or reduced forms of sugars as red blood cell preservatives are
These anticoagulant solutions are mixed in an amount that keeps the osmotic pressure of the bloodstream hypertonic, and the concentration is targeted to be 3mM to 100mM, preferably 10mM as the final concentration after mixing Tomotaka and the anticoagulant. )1 to 50+nH.

Next, a case in which a blood collection bag is manufactured as an example of the blood storage container of the present invention will be described with reference to the drawings. That is, FIG. 1 shows a blood bag made of the above-mentioned low-migration plasticizer-containing vinyl chloride resin composition or a plasticizer-free elastomer sheet, which is equipped with a plurality of peel-tab-equipped discharge ports 18 and discharge ports 2. The constructed blood collection bag 3 has its periphery fused by high frequency heating or other heating means, and is connected to a blood collection tube 6 made of a similar resin composition that communicates with the internal space 5 of the blood collection bag. There is. The internal space of this blood collection bag contains an anticoagulant solution such as ACD-A solution or CPD solution containing the above-mentioned oligosaccharide or reduced sugar as a red blood cell preservation agent.

Further, a blood sampling needle 7 is attached to the tip of the blood sampling tube 6 . A cap 8 is attached to this blood collection needle.

In addition, when connecting a child bag to the blood collection bag 3, the peripheral part 10 of a sheet made of a resin composition similar to that of the blood collection bag is fused, and the peripheral part 10 of a sheet made of the same resin composition as the blood collection bag is fused. A first child bag 13 equipped with a connecting tube 12 made of a variety of materials is connected to the connecting tube 16 via a branch pipe 14 to the connecting outlet 2 of the blood collection bag 3 by a connecting needle 15 at the tip.

It also has an outlet 17 with a peel tab, and a peripheral edge 18.
The connecting tube 21 of a similar second child bag 22, which is radio-frequency sealed and has a connecting tube 21 communicating with its internal space, is connected to the connecting tube 12 through a branch pipe 14.
16.

Although the above explanation has been made using blood collection bags as an example, the same applies to other blood storage containers such as blood transfusion bags, component fractionation bags, and storage bags. The blood is brought into contact with a blood storage container filled with an anticoagulant solution containing an oligosaccharide or reduced sugar as a red blood cell preservation agent in a soft container made of an oligomer that does not contain a plasticizer or a plasticizer. When stored, the amount of plasticizer eluted is extremely small compared to conventional blood storage containers made of vinyl chloride resin that contain highly migratory plasticizers such as di-2-ethylhexyl phthalate. Problems such as decreased platelet aggregation and toxicity caused by plasticizers have been resolved, and on the other hand, blood cell components in blood stored in blood storage containers remain in the anticoagulant solution even though plasticizers do not elute. It was revealed that hemolysis was not observed even over a long period of time due to the osmotic pressure regulating effect of oligosaccharides or reduced sugars blended into the product.

EXAMPLES Next, the present invention will be briefly and concretely explained with reference to Examples.

Examples 1 to 3 3,3°,4,4'-biphenyltetracarboxylic acid having the following structural formula (■) (hereinafter referred to as S-BTC I-1), 2,3, having the structural formula II 3°14′-biphenylte-1-lacarboxylic acid tetra(n-heptyl) ester (hereinafter referred to as α-8-CH), and a mixture of equal amounts of s-BTCH and α-BTCH (hereinafter referred to as m-BTCH)
Polyvinyl chloride resin (SIO03) with an average degree of polymerization of 1300
A plurality of mini bags each having an inner surface area of 46 CIIi were prepared from sheets of vinyl chloride resin compositions blended in the proportions shown in Table 1.

0 0 (R=-C7HI5
>0 C-0-RO! 1 0 (R=-07HI3
) Table 1 Mixing ratio (weight ratio) Example 1 Example 2 Example 3 PVC (31003) 100 100
100S-8 CM
5Q −-α-B-CH50- m-BTCH50 Epoxy soybean oil 10 10 10 ratio example 1 For comparison, di-2-ethylhexyl phthalate (DO
Vinyl chloride made by blending 10 parts by weight of epoxidized soybean oil and 1 part by weight of a higher fatty acid salt stabilizer as in the example with soft polyvinyl chloride made by blending 50 parts by weight of P> with 100 parts by weight of PVC. Inner surface area from sheet of resin composition 46
I made a cii mini bag.

Elution test 1) Extraction method The mini bags molded in Examples 1 to 35 and Comparative Example 1 were
After sterilization in an autoclave, 5 liters of CPD plasma was aliquoted and the tubes were closed with forceps. This was left in a 37°C oven for 24 hours to elute BTCH and DOP into plasma.

2) Measurement method To measure BTCH eluted into plasma, 4 to 8 μp of a plasma sample was directly introduced using a high performance liquid chromatograph under the following conditions.

BTCH measurement conditions Equipment: JASCO High Performance Liquid Chromatograph TRIROT
AR-III type column: Protesil 300 (Whatma
(manufactured by n company) 4.6mmφX 25cm Solvent: (A) 0.1% trifluoroacetic acid-aqueous solution (B)
0.1% trifluoroacetic acid-acetonitrile solution gradient: ioo% (A) → 5% (A), 95% (
B) 20 minutes detection: U monitor 280 nm Sample amount: 4 μΩ, 8 μp On the other hand, to measure DOP eluted in plasma, add 1 liter of 1N NaOH to 1 d of obtained plasma sample, stir, then add 2 ml of acetonitrile and stir roughly. 2500 r
The mixture was centrifuged for 10 minutes at 1) m, and the upper layer of 4 μΩ was introduced into a high-performance liquid chromatogram. The measurement conditions were as follows.

DOP measurement conditions equipment Nippon Bunko high performance liquid chromatograph B I P-
Type I column: NUC1eO3il 5C84, 6111mφ
X 25CIIl solvent Niacetonitrile: Water = 95:5 Flow rate: 'l, Qd/min Detection: Uv monitor 280nllll Sample amount: 4μp 3) Part of the resulting chromatograms are shown in Figures 3-5. Note that FIG. 2 shows a chromatogram of CPD plasma as a control. The measurement results of elution concentration in plasma are shown in Table 2. Example 1 5-BTCHO, 58 Example 2 α-BTCH'1.11 Example 3 m-BTCHo, 77〃
0.62 Comparative Example 1 DOP 336〃
328 Example 4 As in Examples 1 to 3, a mini bag with an inner surface area of 46 crft was made from a vinyl chloride resin sheet prepared using BPTE as a plasticizer at the blending ratio shown in Table 3.

Table 3 Mixing ratio (heavy ratio).

Example 4 PVC (S1003) 100BTC
H70 Epoxidized soybean oil 10 Highly treated fatty acid salt stabilizer 1 Elution test II After sterilizing the mini bags molded in Example 4 and Comparative Example 1 in an autoclave, 5 ml of serum was aseptically dispensed into Hibiscus I, and various The eluted BPTE and DOP concentrations were measured under the extraction conditions. The results are shown in Table 4.

(Left below) Table 4 BPTE DOP Extraction conditions Elution concentration Elution concentration 37°C
In the oven 1.51) Dm 400ppm
Leave for 24 hours in a 37℃ oven 5.01)l)m 75
01) pm 110 hours The elution concentration measurement was performed using the sample serum 1r! II! to 1NN
Add 11 ml of O(-1) and stir, add 3 ml of tetrahydrofuran to a colander, stir, and centrifuge at 200 Orpm for 5 minutes to separate the serum and tetrahydrofuran layers. The recovery rate in this method was 105% for both DOP and BPTE.

Todoroki Wandering Lost Dane Earth Craffy Condition Apparatus 2 Nippon Bunko High Performance Liquid Chromatograph RIRO CHO AR-III Type Column: Hitachi Gel # 3053 (ODS) 4.6 m
mφX 25cm melt 111. Niacetonitrile ioo%
, 1. Od/n+in detection: UV monitor 220nm
(D OP ) 280 nm (BPTE) Sample port; 4 μΩ 0.9% 307
! and autoclave extraction at 121°C for 150 minutes. When measured using 5 ml of the extract based on the "hemolysis test" of the 10th edition of the Japanese Pharmacopoeia "Test Methods for Plastic Containers for Infusions"), the d curvature was 0.2%, which was negative.

Place 1q of sample fragments of the sheets obtained in Examples 1 to 4 in 3d of Nissui Pharmaceutical Co., Ltd.'s extraction medium (MEM) culture medium, and
After extraction for 21 °Cl2O min, the extraction medium was diluted neat and in control medium to 67%, 33%, and the cells (HeL
a-S3) is administered, and the next day and the day after that, each medium is observed under a microscope, and the presence or absence of cell deformation, detachment, and growth inhibition is observed while comparing with the blank. When toxicity was determined on the second day, no difference from the blank was observed in any of the media, and no toxicity was observed.

The sheet obtained in Extractables Test Examples 1 to 4 has a surface area of 1
Cut it to a length of 200cm, and then cut it to a length of 5cm.
Cut into pieces with a width Q of 5 cm, put in a sterilized bottle, add 200 rni of distilled water, autoclave at 121°C for 60 minutes, and then pass the leachables test according to the Japanese Pharmacopoeia 10th edition ``Test Methods for Plastic Containers for Infusions.'' When measured based on
The sample met all test items.

Reference Experiment I: Intravenous Administration of Plasticizer to Mouse 1) Method A solution in which BPTE and DOP were dissolved in ethanol and emulsified in physiological saline was administered to the tail vein of a mouse, and the survival or death of the mouse was observed. The experimental conditions are as follows.

Solutions used: BPTE solution DOP solution Control solution Plasticizer 3% 3% 0% ethanol 6% 6% 6% EEN80
0.5% 0.5%
0.5% saline 90.5% 90.5
% 93.5% Test animal: ICR mouse (21-25
g), 10 males each Dose: 1 m/20 (l [15
00n*q (plasticizer)/kg (body weight)] Administration route: tail vein 2) Results The survival status of mice one day after administration was as follows.

BPTE solution 10/10 survivors DOP solution 7/10 survivors Control solution
10 animals/10 animals survival reference experiment I ■: Solubility of plasticizer in blood human serum 10rd! Transfer to a 100m separating funnel.

On top of this, 2 ml each of DOP or BPTE was added. This was left in a 37°C oven for about 66 hours. The lower serum portion was taken out and the DOP, ffi and BPTE'a levels in the serum were measured by high performance liquid chromatography.

2) Results The results obtained were as follows.

DOP Measured concentration 90.6-95.11)l)m
BPTE Measured concentration 0.2-0.251)[)I
II Examples 5 to 6 and Comparative Example 2 Forty-five blood samples were collected from a healthy male using a polypropylene syringe, and each anticoagulant solution 1 shown in Table 5 was immediately added to the sample.
．． 75th! 12. into the mini bag of Example 1 filled with.
After adding 5 d at a time and stirring gently, the mixture was stored at 4°C.

After 4 weeks, the plasma hemoglobin concentration was measured using the TMB method [Clinical Chemistry (CIin, Chem, > 23
．． 749 (1977)].

The results are shown in Table 6.

Table 5 Anticoagulant solution composition [g/100dl Example 5
Example 6 Comparative Example 2 Citric acid 0.327 0.327 0°327 Citric acid 2.63 2.63
2.63 Sodium Glucose 2.32 2.32 2.3
Dihydrogen phosphate 0.251 0.251 0.
251 Sodium Mannitol 4.5- Palatinose 13.5 - --6th
Table Plasma hemoglobin concentration (mo/dΩ) Example 5
65 Example 6 70 Comparative Example 2 112 Specific Effects of the Iv9 Invention As described above, the present invention provides a flexible container made of a resin composition containing a low migration plasticizer, which is used as a red blood cell preservative. A blood storage container is characterized in that it is filled with an anticoagulant solution containing an oligosaccharide or a reduced form of sugar. This blood storage container is characterized by being filled with an anticoagulant solution containing an oligosaccharide or a reduced form of sugar as a red blood cell preservation agent, so that when blood is stored in the blood storage container, In addition, the plasticizer hardly elutes from the blood storage container, and there is very little risk of reducing the aggregation ability of platelets in the stored blood, and the container contains 2-ethylhexysiphthale-1 or the like as a plasticizer. It has extremely good platelet storage properties compared to conventional blood storage containers made of vinyl chloride resin.

In addition, the blood storage container contains oligosaccharides or reduced sugars in the anticoagulant, and these oligosaccharides or reduced sugars work to prevent hemolysis of red blood cells. Even if it is not possible to suppress hemolysis due to the plasticizer that dissolves like a storage container, hemolysis is unlikely to occur when the stored blood is poured into the container.

These effects are due to the fact that plasticizers with low migration properties are effective for trimellitic acid mono-lyesters, pyromellitic acid tetraesters, biphenyltetracarboxylic acid tetraesters, and phthalic acid diesters with 9 carbon atoms in the ester group. , a polyester plasticizer, a pentaerythritol ester or a di-1-lyl synthetic rubber, or a combination of two or more of these, particularly preferably biphenyltetracarboxylic acid tetraester, or an ex-mer containing no plasticizer. Polymer blends of internally plasticized polyvinyl chloride, polyurethane, polyester elastomer or polyvinyl chloride with polyurethane, ethylene-based elastomer or caprolavone-based polymers, oligosaccharides or [J, the reduced form of sugar is mannitol,
If maltose, palatinose or sucrose, particularly palatinose is used, the resulting blood storage container will be better and the above effects will be even more pronounced.

[Brief explanation of the drawing]

FIG. 1 is a front view showing an example of the blood storage container of the present invention, FIG. 2 is a chromatogram of CPD plasma, and FIG.
Figures 5 to 5 are chromatograms of plasticizer-eluted CPD plasma. 3...Blood collection bag, 13.22...Child bag,
6.16.21...Tube. Patent Applicant: Chill Seven Co., Ltd. Figure 1, Figure 20, CPD Standing, No. 30

Claims (5)

[Claims] (1) A soft container made of a resin composition containing a low migration plasticizer is filled with an anticoagulant solution containing an oligosaccharide or reduced sugar as a red blood cell preservation agent. A blood storage container characterized by: (2) As a plasticizer, trimellitic acid triester, pyromellitic acid tetraester, biphenyltetracarboxylic acid tetraester, phthalic acid diester whose ester group has 9 or more carbon atoms, polyester plasticizer, pentaerythritol ester, or An anticoagulant made by blending mannitol, maltose, palatinose, or sucrose as a red blood cell preservation agent in a soft container made of a vinyl chloride resin composition blended with nitrile synthetic rubber or a combination of two or more of these. The blood storage container according to claim 1, characterized in that it is filled with a solution. (3) A soft container made of a vinyl chloride resin composition containing biphenyltetracarboxylic acid tetraester as a plasticizer is filled with an anticoagulant solution containing palatinose as a red blood cell preservative. The blood storage container according to claim 2, characterized in that: (4) A blood storage container characterized in that a soft container made of an elastomer that does not contain a plasticizer is filled with an anticoagulant solution containing an oligosaccharide or reduced sugar as a red blood cell preservation agent. . (5) A soft container made of internally plasticized vinyl chloride resin, polyurethane, polyester elastomer, or a polymer blend of polyvinyl chloride and polyurethane, ethylene polymer, or caprolactone polymer as red blood cell preservatives such as mannitol, maltose, and palatinose. Claim 4, characterized in that it is filled with an anticoagulant solution containing saccharose or saccharose.
Blood storage container as described in Section.