JPH06209980A - Medical instrument - Google Patents

Abstract

PURPOSE:To improve the blood preservation performance and stability by forming the clothes medical instrument such as blood bag from the resin composition which is formed by compounding the malic acid dialkyl ester having special general formula and stabilizing agent having each special ratio, into a vinyl chloride group resin. CONSTITUTION:As for a medical instrument e.g. blood bag, a blood taking-out tube 6 made of a resin composition is connected to a blood taking-out bag 3 made of the resin composition. With the blood taking-out bag 3, a plurality of subsidiary bags 13 and 22 made of the resin composition are connected by the respective connecting tubes 12 and 21 made of the resin composition. In this case, the resin composition is formed by compounding 5-100 pts.wt. of malic acid dialkyl ester having the general formula shown separatedly and 1-20 pts.wt of a stabilizing agent into 100 pts.wt of the vinyl chloride group resin. In the general formula shown separatedly, each of (a) and (b) is 2-12, and R is a hydrogen atom, acetyl group, propionyl, or butylyl group.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical device, and more particularly to a highly safe medical device. More specifically, the present invention relates to a blood bag which is highly safe while maintaining the preservation performance of blood and blood components.

[0002]

2. Description of the Related Art Recently, as a blood storage container for transfusion,
Mainly in order to reduce the damage of red blood cells, it has been changed from a hard glass container to a soft polyvinyl chloride soft bag. The flexible soft polyvinyl chloride blood bag is used more and more due to its good processability, flexibility, transparency, low water vapor permeability, heat resistance and the like. These soft polyvinyl chlorides contain 30 to 60 parts by weight of phthalic acid ester as a plasticizer. It is known that the phthalic acid ester elutes into the blood over time during blood storage, and protects the cell membrane of various cells, which are blood components, particularly the surface of red blood cells. It is also true that some people worry about the safety of phthalates when they are fed into the body by blood transfusion.

[0003]

DISCLOSURE OF THE INVENTION As described above, a plasticizer having a plasticizing efficiency equal to or higher than that of a phthalic acid ester of a plasticizer conventionally used for soft polyvinyl chloride for medical use is maintained, and By selecting a plasticizer that has an equal or higher level of protection against red blood cell membranes and a higher level of safety than phthalate esters, a soft polyvinyl chloride resin composition that has a level of blood preservation performance equal to or higher than conventional and is highly safe. The purpose is to obtain a medical device molded from.

[0004]

The present invention is based on the general formula (I) based on 100 parts by weight of a vinyl chloride resin.

[0005]

[Chemical 2]

(Where a and b are 2 to 2 respectively)
12 and R is hydrogen atom, acetyl group, propionyl group or butyryl group) 5 to 100 parts by weight of malic acid dialkyl ester, and stabilizers 1 to 2
A medical device made of a resin composition containing 0 part by weight. In addition, the present invention provides that the general formulas a and b are 4, 6,
8 is a medical device. Further, the malic acid dialkyl ester of the present invention is malic acid dihexyl ester, malic acid dioctyl ester, malic acid monohexyl monooctyl ester, acetylmalic acid di-hexyl ester, acetylmalic acid di-octyl ester, acetylapple. The medical device is characterized by being acid monohexyl-monooctyl ester, butyrylmalic acid di-hexyl ester, butyrylmalic acid di-octyl ester, butyrylmalic acid monohexyl-monooctyl ester. Further, the stabilizer of the present invention is a medical device characterized by comprising an epoxidized vegetable oil, a barium-zinc type stabilizer and a calcium-zinc type stabilizer as main components. The molded article of the present invention is a blood bag and a tube, which is a medical device.

The vinyl chloride resin used in the resin composition for medical devices according to the present invention contains, in addition to a vinyl chloride homopolymer, 70% by weight or more, preferably 85% by weight or more of vinyl chloride. It is also possible to use a copolymer with another monomer such as vinylidene chloride. The average degree of polymerization is 700 to 3000, preferably 1000 to 240.
It is 0. Further, as a comonomer for vinyl chloride, vinylidene chloride, ethylene, propylene, vinyl acetate, vinyl bromide, vinyl fluoride, styrene, vinyltoluene, vinylpyridine, acrylic acid, alkyl acrylate (for example, methyl acrylate, ethyl acrylate). Acrylate, isopropyl acrylate, n-butyl acrylate, 2-ethylhexyl acrylate, etc.), methacrylic acid, alkyl methacrylate (eg, methyl methacrylate, ethyl methacrylate, 2-ethylhexyl methacrylate, etc.), acrylonitrile, methacrylonitrile and the like. Further, the vinyl chloride resin may be blended with a styrene-acrylonitrile copolymer or a styrene-methacrylonitrile copolymer.

The malic ester used as a plasticizer is represented by the general formula (I), and is 5 to 100 parts by weight, preferably 4 parts by weight based on 100 parts by weight of the vinyl chloride resin.
It is used in an amount of 0 to 80 parts by weight, more preferably 50 to 70 parts by weight. A and b in the general formula (I) are 2, 4, 6, 8, 10, and 12, respectively. More preferably, 4, 6 and 8. That is, when a or b is 1 or less, the elution amount of the plasticizer is high, while when a or b is 13 or more, the plasticization efficiency is low. Therefore, an excessive amount of the compounding amount is required to obtain sufficient flexibility. Inferior in compatibility with resin. Further, a and b may be linear or side chains, and those expressed as malic acid dioctyl ester include structural isomers such as malic acid di-2-ethylhexyl ester having a side chain alkyl group.

The method for synthesizing these malic acid diesters is not a special method, and malic acid and an alcohol having a molar amount of more than 2 times are heated and reacted in the presence of sulfuric acid. The reaction product was neutralized with caustic soda, washed with water, and then purified by distillation. Furthermore, when proceeding to the reaction with the hydroxyl group of malic acid, acid anhydride was reacted in the presence of sulfuric acid. The reaction product was neutralized with caustic soda, washed with water, and then purified by distillation.

As the stabilizer, an epoxy compound,
For example, epoxidized soybean oil, epoxidized vegetable oil such as epoxidized linseed oil, di-2-ethylhexyl epoxy hexahydrophthalate, vinylcyclohexanedioxide 3,4-epoxy-6-methylcyclohexylmethyl-3,4-epoxy-6-methylcyclohexanecarbonate, Cyclohexene oxide derivatives such as dicyclopentadiene dioxide and metal soaps such as calcium, zinc, barium, magnesium and tin with stearic acid, lauric acid, ricinoleic acid, naphthenic acid and 2-ethylhexoic acid, for example calcium stearate. , Zinc stearate, calcium laurate, zinc laurate, barium stearate, magnesium stearate, tin stearate, etc. or the above epoxy compound and metal N mixture of class is blended. In addition to these, there are organic stabilizers such as phosphites such as didecylphenyl phosphite, and mixtures of stearoylbenzomethane and palmitoylbenzoylmethane. The amount thereof is usually 1 to 20 parts by weight, preferably 2 to 15 parts by weight, based on 100 parts by weight of the vinyl chloride resin. Each of the stabilizers can be used alone, but it is preferable to use the epoxy compound in combination with a metallic soap, a phosphite ester, or an organic stabilizer.
The amount of the epoxy compound is usually 1 to 15 parts by weight, preferably 5 to 10 parts by weight, based on 100 parts by weight of the vinyl chloride resin, and epoxidized soybean oil is most preferable. The metal soap, phosphite or organic stabilizer is 0.01 to 8 parts by weight, preferably 0.05 to 5 parts by weight, based on 100 parts by weight of the vinyl chloride resin, and Ca-Zn.
Based or Ba—Zn based metallic soaps are preferred.

Although no toxicity data are shown when malic acid dialkyl ester is administered into blood by blood transfusion or the like, malic acid itself is a substance present in the living body, and phthalate having a phthalic acid structure not present in the living body is present. It can be easily estimated that the toxicity is lower than that of acid ester.

Next, a case where a blood bag is manufactured as an example of the medical device of the present invention will be described with reference to the drawings. That is, FIG. 1 shows a blood bag. A blood sampling bag 3 made of the resin composition of the present invention having a plurality of outlets 1 with peel tabs and outlets 2 has its peripheral portion subjected to high frequency heating or other heating. A blood collection tube 6 made of the resin composition of the present invention, which is fused by means and communicates with the internal space 5 of the blood collection bag, is connected. A CPD solution or the like is stored as an anticoagulant in the internal space of the blood collection bag. A blood collection needle 7 is attached to the tip of the blood collection tube 6.

When the child bag made of the resin composition of the present invention is connected in addition to the blood collection bag 3, the peripheral portion 1 made of the resin composition of the present invention provided with a discharge port 9 with a peel tab.
The first child bag 13 provided with the connecting tube 12 made of the resin composition of the present invention, which is fused with 0 and communicates with the internal space 11 thereof, has the outlet port 2 for connecting the blood collecting bag 3 via the branch pipe 14. To the connecting tube 1 connected by the connecting portion 15.
6 is connected. In addition, the beer tab-equipped discharge port 17 is provided, and the peripheral edge portion 18 is high-frequency-sealed.
A connecting tube 21 made of the resin composition of the present invention, which is connected to 9
The connecting tube 21 of the child bag 22 made of the resin composition of the present invention including the connecting tube 1 via the branch pipe 14
2, 16 are connected.

Although the blood bag has been described above as an example, other blood storage containers, blood transfusion system containers, blood circuit containers, infusion bags, various medical tubes such as catheters and dialysis tubes, and artificial kidneys, The same can be applied to artificial organs such as artificial lungs and artificial livers, and breathing circuit device-related equipment such as breathing circuit tubes. Since the use as the medical device of the present invention has particularly excellent cold resistance, it is suitable as a cryopreservation container or blood bag for blood or the like, and further has an effect when used for a blood bag and a tube connected thereto. Remarkably, the point is that it is suitable when a fluid such as a liquid or gas such as a body fluid or a drug solution is injected into, discharged from, or stored in or brought into contact with the medical device, and is suitable for the purpose of the present invention. If it is a thing, it will not be specifically limited.

[0015]

EXAMPLES Next, the present invention will be described in more detail with reference to examples.

(Examples 1 to 7 and Comparative Example 1) Polyvinyl chloride (S-1003, manufactured by Kanegafuchi Chemical Co., Ltd .; average degree of polymerization: 13)
00) 100 parts by weight of the plasticizer and stabilizer shown in Table 1 were mixed in the ratio shown in the same table, and a sheet having a thickness of about 0.4 mm was obtained by an ordinary method, that is, extrusion molding. The results of the tensile properties, eluate test and safety test (cytotoxicity test) of the sheet are shown in the same table. Also, after cutting the sheet into a predetermined shape, two sheets are stacked and the inner surface area is about 5
A high-frequency seal was made so as to have a size of 0 cm 2, and a blood bag for testing was prepared. When this bag was fusion-sealed and then subjected to high-pressure steam sterilization, no remarkable deformation was observed in any of the Examples and Comparative Examples, and there was no practical problem.

A test piece having a total of 6 square centimeters on the front and back of the sheet was put in a glass test tube and then subjected to high-pressure steam sterilization (121 ° C. for 20 minutes). 5 ml of whole blood with CPD
Was aseptically dispensed, then the container was sealed, and the mixture was allowed to stand at 4 ° C for 28 days for storage. After storage, the mixture was centrifuged at 1500 rpm for 10 minutes at room temperature, and the concentration of hemoglobin contained in the supernatant plasma was measured by the cyanmethemoglobin method, which was used as an index of hemolysis that occurred during storage. The results are shown in Table 1.

[0018]

[Table 1]

DBM: malic acid dibutyl ester DHM: malic acid dihexyl ester DOM: malic acid dioctyl ester DDM: malic acid didecyl ester ADOM: acetylmalic acid dioctyl ester, PDOM: propionyl malic acid dioctyl ester phthalic acid ester: di-n -Decyl phthalate

The tensile properties were measured according to Japanese Industrial Standard JISK-6301 using a strograph manufactured by Toyo Seiki Seisakusho, and a rubber No. 3 dumbbell was pulled at a speed of 200 per minute.
mm, measured at 23 ° C. The eluate test was carried out in accordance with the Ministry of Health and Welfare Public Notice No. 448 “Vinyl Chloride Resin Blood Set Standard” to determine whether the test was acceptable or not. 18 cytotoxicity tests
Place a square centimeter sample sheet and 3 ml of MEM medium (Nippon Pharmaceutical Co., Ltd.) in a screw vial,
An extract is obtained by autoclaving at 1 ° C. for 60 minutes.
The solution was administered to Hela-S3 cells, cultured at 37 ° C for 2 days, and then observed under a microscope. No difference was found in comparison with a blank test in which no extract was administered, and cell growth was inhibited. Those that were killed or those whose cells were dead were defined as positive.

(Examples 8 to 10 and Comparative Examples 2 to 4) Each plasticizer shown in Table 2 was dissolved in ethanol to obtain 50,000 p.
As a pm solution, two glass test tubes were prepared for each plasticizer. 4.90 ml of 10 mM phosphate buffered saline (PBS, pH 7.4) was added to each, and 50 μl of an ethanol solution of a plasticizer was added (final concentration of the plasticizer was 500 p.
pm) Stir well. 50 μl of CPD-added human plasma was added to one of the two tubes, and PBS 50 μl was added to the other test tube.
Both tubes were incubated at 37 ° C, with the addition of 1 as a control.

After a predetermined time has passed (0 minutes, 15 minutes, 30 minutes,
After 60 minutes, 120 minutes, and 240 minutes), 500 μl was sampled, 5 ml of isopropanol was added thereto and well stirred, 5 ml of diethyl ether was further added, and the mixture was well stirred again, followed by centrifugation (2500 rpm, 10 mi).
n) The upper layer was taken, the solvent was distilled off under nitrogen gas at 30 ° C., the residue was dissolved in 500 μl of ethyl acetate, and the residual amount of the plasticizer was quantified by gas chromatography. The results are shown in Table 2 and FIG. 2 as the plasticizer residual rate.

<Gas chromatography conditions> ・ Column: Silicone SE-30, Chromosorb WAW DMCS
5%, 1.1m ・ Helium gas flow rate: 60 ml / min ・ Detector: FID ・ Sample addition amount: 5 μl ・ Column temperature: 200 ° C

[0024]

[Table 2]

From Table 2 and FIG. 2 showing the plasticizer residual ratio,
In the control to which plasma was not added, almost no plasticizer was decomposed by incubation at 37 ° C. for 4 hours. On the other hand, when plasma is added,
Phthalate ester (Comparative Example 2) and citric acid ester (Comparative Examples 3 and 4) were hardly decomposed by incubation at 37 ° C. for 4 hours, whereas malate ester (Examples 8 to 10) 30-60% was decomposed. This result indicates that malate ester is easily decomposed by the enzyme in plasma. Therefore, it is considered that it is easily decomposed into malic acid and alcohol even in the living body, and is expected to have higher safety than phthalic acid ester and citric acid ester.

[0026]

INDUSTRIAL APPLICABILITY The medical device according to the present invention contains 5 to 100 parts by weight of a malic acid dialkyl ester represented by the general formula and 100 to 1 parts by weight of a vinyl chloride resin, and stabilizers 1 to 2.
Molded with a resin composition containing 0 parts by weight, it has the same physical properties (tensile elasticity) as the conventional plasticizer phthalate ester, and has the same processing (extrusion molding,
High-frequency sealing, adhesion, sterilization, etc.) were possible, and there was an effect that the safety was high. Further, when used as a material for a blood bag, the blood component, especially the red blood cells, has good preservation performance and high safety.

[Brief description of drawings]

FIG. 1 is a plan view showing an example of a blood bag according to the present invention.

FIG. 2 is a diagram showing the decomposition rate of the plasticizer used in the present invention in plasma.

[Explanation of symbols]

1, 2, 9, 17 ... Ejection port, 3 ... Blood collection bag, 6, 16, 21 ... Tube, 7 ... Blood collection needle, 13, 22 ... Child bag.

Claims (1)

[Claims] 1. To 100 parts by weight of vinyl chloride resin,
General formula (I) (However, in the formula, a and b are 2 to 12, respectively,
R represents a hydrogen atom, an acetyl group, a propionyl group or a butyryl group) and is made of a resin composition containing 5 to 100 parts by weight of a malic acid di-alkyl ester and 1 to 20 parts by weight of a stabilizer. A medical device comprising a molded product.