JPS6157786B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION Technical Field The present invention relates to medical devices. More specifically, the present invention relates to a medical device made of vinyl chloride resin that has excellent functional maintenance during blood component storage. Prior Art As is well known, blood has a self-protective effect, and when blood comes into contact with a different interface other than the inner wall of a blood vessel, platelets adhere to the different interface, aggregation, and gelation of plasma, that is, formation of crosslinked fibrin. Formation occurs.
In conventional blood bags, platelets in the blood aggregate to the plastic interface that is the base material of the blood bag, and 6 hours after blood collection, the platelet aggregation function has decreased to approximately 60% at the time of blood collection.
%, and further drops to about 40% after 24 hours. On the other hand, from the point of view of the effective use of current platelet preparations, it is necessary to develop storage containers made of plastic that can store blood cells for longer periods of time, storage containers made of so-called blood-compatible plastic, or other medical devices. desired. Currently, blood bags made of soft vinyl chloride resin are widely used as such plastic containers or other medical devices due to their good processability, flexibility, transparency, low water vapor permeability, heat resistance, etc. has been done. These soft vinyl chloride resins are
Phthalate esters such as di-2-ethylhexyl phthalate (hereinafter referred to as DOP) are used as plasticizers.
Contains 30-60%. However, since phthalate esters have a high migration property, if a blood storage container is made from the above-mentioned soft vinyl chloride resin, for example,
It is known that the phthalate ester is eluted into plasma. For this reason, it has been reported that when phthalate esters dissolve into plasma containing concentrated platelets, it causes a decrease in the condensing ability, which is a function of platelets [Journal of the Japanese Society of Blood Transfusion 28282 (1982)]. On the other hand, polyester plasticizers are used as non-migratory plasticizers. Generally, this polyester plasticizer is mainly composed of fatty acid ester, so it has poor water resistance, hydrolyzability, etc.
It is well known that it is inferior to phthalate esters, which have a phenyl group as their backbone. OBJECTS OF THE INVENTION It is therefore an object of the present invention to provide a novel medical device. Another object of the present invention is to provide a medical device with good biocompatibility. Still another object of the present invention is to provide medical devices such as blood storage containers, catheters, and blood circuits that can prevent plasticizer migration and have good water resistance. These purposes are based on vinyl chloride resin and the general formula (However, in the formula, R is an aliphatic saturated hydrocarbon residue having 4 to 18 carbon atoms.) Ru. Further, the present invention is a medical device in which 20 to 120 parts by weight of biphenyltetracarboxylic acid tetraester represented by the general formula is blended with 100 parts by weight of vinyl chloride resin. Furthermore, the present invention
This medical device is made by blending 30 to 100 parts by weight of biphenyltetracarboxylic acid tetraester represented by the general formula with respect to 100 parts by weight of vinyl chloride resin. The present invention is a medical device in which R is an aliphatic hydrocarbon residue having 8 to 18 carbon atoms. Further, the present invention is a medical device in which R is an aliphatic hydrocarbon residue having 1 to 3 carbon atoms. Furthermore, the present invention
Biphenyltetracarboxylic acid tetraester has the general formula (However, in the formula, R is as described above.)
This medical device is a 3,3',4,4'-biphenyltetracarboxylic acid tetraester represented by:
Further, the present invention provides that biphenyltetracarboxylic acid tetraester has the general formula (However, in the formula, R is as described above.)
This medical device is a 2,3,3',4'-biphenyltetracarboxylic acid tetraester represented by:
Further, the present invention is a medical device that is a body fluid storage container. The present invention is a medical device in which the body fluid is blood. The present invention also provides catheters, blood transfusion sets,
A medical device that is an infusion set or blood circuit. DETAILED DESCRIPTION OF THE INVENTION The medical device according to the present invention includes a body fluid storage container such as a blood bag, a catheter, a blood transfusion set, an infusion set, and a blood circuit, preferably a body fluid storage container,
Especially blood bugs. The vinyl chloride resin used in the resin composition constituting the medical device according to the present invention includes polyvinylidene chloride, vinyl chloride in an amount of 50% by weight or more, preferably 60% by weight or more, in addition to a vinyl chloride homopolymer,
Most preferably, there are copolymers with other copolymerizable monomers containing 90% by weight or more, and the average degree of polymerization thereof is 700 to 3000, preferably 1000 to 2700. Comonomers for vinyl chloride include vinylidene chloride, ethylene, propylene, vinyl acetate, vinyl bromide, vinyl fluoride, styrene, vinyltoluene, vinylpyridine, acrylic acid, alkyl acrylates (for example, methyl acrylate, ethyl 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, etc. Furthermore, a styrene-acrylonitrile copolymer or a styrene-methacrylonitrile copolymer can be blended with the vinyl chloride resin. The biphenyltetracarboxylic acid tetraester used as a plasticizer is represented by the above general formula, and is used in an amount of 20 parts by weight per 100 parts by weight of vinyl chloride resin.
~120 parts by weight are used, preferably 30-100 parts by weight. R in the general formula is an aliphatic saturated hydrocarbon residue having 4 to 18 carbon atoms, preferably 4 to 12 carbon atoms, and most preferably 8 to 12 carbon atoms. This aliphatic saturated hydrocarbon residue may be a linear hydrocarbon group or a branched hydrocarbon group. The compound of the above general formula is a 3,3',4,4'-biphenyltetracarboxylic acid tetraester shown by the above general formula, or a 2,3,3',4-biphenyltetracarboxylic acid tetraester shown by the above general formula. There are carboxylic acid tetraesters. Examples of the 3,3',4,4'-biphenyltetracarboxylic acid tetraester represented by the general formula include 3,3',4,4'-buphenyltetracarboxylic acid tetra(n-octyl) ester. 3, 3′,
4,4′-biphenyltetracarboxylic acid tetra(2
-ethylhexyl) ester, 3,3',4,4'-
Biphenyltetracarboxylic acid tetra(2-methylheptyl) ester, 3,3',4,4'-biphenyltetracarboxylic acid tetra(n-nonyl) ester, 3,3',4,4'-biphenyltetra Carboxylic acid tetra(n-decyl) ester, 3,3',4,
4′-biphenyltetracarboxylic acid tetra(n-undecyl) ester, 3,3′,4,4′-biphenyltetracarboxylic acid tetra(n-dodecyl) ester, 3,3′,4,4′-biphenyltetracarboxylic acid tetra(n-dodecyl) ester enyltetracarboxylic acid tetra(n-tetradecyl) ester, 3,
3',4,4'-biphenyltetracarboxylic acid tetra(n-pentadecyl) ester, 3.3',4,4'-biphenyltetracarboxylic acid tetra(n-hexadecyl) ester, 3,3',4,4 '-biphenyltetracarboxylic acid tetra(n-heptadecyl) ester, 3,3',4,4'-biphenyltetracarboxylic acid tetra(n-octadecyl) ester, and the like. Examples of the 2,3,3',4'-biphenyltetracarboxylic acid tetraester represented by the general formula include 2,3,3',4'-biphenyltetracarboxylic acid tetra(n-octyl) ester, ,3,
3′,4′-biphenyltetracarboxylic acid tetra(2
-ethylhexyl) ester, 2,3,3',4'-
Biphenyltetracarboxylic acid tetra(2-methylheptyl) ester, 2,3,3',4'-biphenyltetracarboxylic acid tetra(n-nonyl) ester, 2,3,3',4'-biphenyltetra Carboxylic acid tetra(n-decyl) ester, 2,3,3',
4′-biphenyltetracarboxylic acid tetra(n-undecyl) ester, 2,3,3′,4′-biphenyltetracarboxylic acid tetra(n-dodecyl) ester, 2,3,3′,4′-biphenyltetracarboxylic acid tetra(n-dodecyl) ester enyltetracarboxylic acid tetra(n-tridecyl) ester, 2,
3,3',4'-biphenyltetracarboxylic acid tetra(n-tetradecyl) ester, 2,3,3',
4'-biphenyltetracarboxylic acid tetra(n-pentadecyl) ester, 2,3,3',4'-biphenyltetracarboxylic acid tetra(n-hexadecyl)
ester, 2,3,3',4-biphenyltetracarboxylic acid tetra(n-heptadecyl) ester,
Examples include 2,3,3',4'-biphenyltetracarboxylic acid tetra(n-octadecyl) ester. To produce the tetraesters represented by the above general formula, for example, biphenyltetracarboxylic acid or its dianhydride and the corresponding aliphatic alcohol are mixed in an organic solvent (e.g., p-xylene,
esterification catalysts, such as titanium tetrabutoxide, organic sulfonic acids such as p-toluenesulfonic acid, sulfuric acid, For the presence of phosphoric acid, phosphoric acid ester, etc., at a reaction temperature of 170 to 250℃
There is a method of reacting for 100 hours. The resin composition made of the vinyl chloride resin and a plasticizer is blended with metal soaps made of metals such as calcium and zinc and stearic acid, lauric acid, ricinoleic acid, naphthenic acid, and the like. Further, if necessary, epoxidized animal and vegetable oils such as epoxidized soybean oil and epoxidized linseed oil, lubricants, and other antioxidants are blended. Next, the medical device according to the present invention will be described using a blood collection bag as an example with reference to the drawings. In other words, the drawing shows a blood bag;
Outlet 1 and outlet 2 with multiple peel tabs
Blood collection bag 2 made of vinyl chloride resin composition with
The peripheral edge of the bag is heat-sealed by high frequency heating or other heating means, and a blood collection tube 6 made of a vinyl chloride resin composition is connected to the blood collection bag, which communicates with the internal space 5 of the blood collection bag. The internal space of this blood collection bag contains ACD as an anticoagulant.
- Solution A (e.g. 220 g of sodium citrate, 0.80 g of citric acid and glucose in 100 ml of aqueous solution)
2.20g), CPD liquid (e.g. 206mg of citric acid, 1.66mg of sodium citrate in 100ml of aqueous solution)
Contains 140mg of disodium phosphate, 1.46g of dextrose), etc. 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 7. In addition, when connecting a child bag in addition to the blood collection bag 3, the peripheral part 10 is similarly heat-sealed and is made of a vinyl chloride resin composition and equipped with a peel tab-equipped outlet 9, and communicates with the internal space 11. A first child bag 13 equipped with a connecting tube 12 made of a vinyl chloride resin composition is connected to the connecting outlet 2 of the blood collection bag 3 via a branch pipe 14, and connects the connecting needle 1 at the tip thereof.
It is connected to a connecting tube 16 connected by 5. Further, a connection tube 21 made of a vinyl chloride resin composition is provided with a discharge port 17 with a peel tab, has a sealed peripheral portion 18, and communicates with the internal space 19.
The connecting tube 21 is connected to the connecting tubes 12 and 16 via the branch pipe 14. The above was explained using blood bag as an example,
It can be similarly used for other blood storage containers, blood transfusion systems, infusion systems, catheters, blood circuits, dialysis tubes, etc. Next, the present invention will be explained in more detail by giving examples. Example 1 88.2 g (0.3 mol) of 3,3',4,4'-biphenyltetracarboxylic acid anhydride was placed in a 1 liter three-necked flask.
2-ethylhexanol 625g (4.8mol), aluminum oxide 1.98g and sodium hydroxide 0.2
g was supplied, and the reaction was carried out at a reaction temperature of 180 to 200°C for 4 hours. After the reaction was completed, excess 2-ethylhexanol was recovered by distillation under reduced pressure. Furthermore, it was washed with a dilute aqueous alkaline solution and water, and finally distilled under reduced pressure to obtain 3,3',4,4'-biphenyltetracarboxylic acid tetra(2-ethylhexyl) ester.
242.9g was obtained. This ester has a refractive index n
²⁵ _D was 1.493, specific gravity d ²⁰ was 0.988, and degree of esterification was 276. 50 parts by weight of the plasticizer synthesized in this way, polyvinyl chloride (degree of polymerization 1100), 3 parts of epoxidized soybean oil
A resin composition consisting of 1 part by weight of calcium stearate and 1 part by weight of calcium stearate and zinc stearate was thoroughly kneaded at a temperature of 150° C. using two rolls, and formed into a sheet having a thickness of 0.4 mm. The 100% modulus of this sheet is 78.5Kg/cm ²
It was hot. In addition, after immersing this sheet-like test piece in various liquids for a predetermined time,
The amount of weight change (amount of plasticizer eluted) of the specimen before and after immersion was investigated by drying for a period of time, and the results were as shown in Table 1. Furthermore, the test piece
After drying at 100℃ for 120 hours, the volatilization loss was 0.03.
It was in weight%. Next, the results of the elution test conducted in accordance with the Japanese Pharmacopoeia "Test Methods for Plastic Containers for Infusions" B-302 to 318 were as shown in Table 2. Furthermore, the results of the physical property test were as shown in Table 4. Example 2 3,3',4, produced in the same manner as in Example 1
A resin composition consisting of 50 parts by weight of 4'-biphenyltetracarboxylic acid tetra(n-dodecyl) ester, polyvinyl chloride (degree of polymerization 1700), 3 parts by weight of epoxidized soybean oil, 1 part by weight of calcium stearate and zinc stearate. to 150℃ using two rolls.
The mixture was thoroughly kneaded at a temperature of 0.4 mm and formed into a sheet with a thickness of 0.4 mm. When this sheet-like material was subjected to the same test as in Example 1, the weight change was as shown in Table 1, and the volatilization loss was 0.04% by weight. In addition, the results of the dissolution test, toxicity test, and physical property test are
It was as shown in Table 4. Example 3 2, 3, 3', produced in the same manner as in Example 1
50 parts by weight of 4'-biphenyltetracarboxylic acid tetra(2-ethylhexyl) ester, polyvinyl chloride (degree of polymerization 1300), 3 parts by weight of epoxidized soybean oil,
A resin composition consisting of calcium stearate and 1 part by weight of zinc stearate was prepared using two rolls.
The mixture was thoroughly kneaded at a temperature of 150°C and formed into a sheet with a thickness of 0.4 mm. When this sheet-like material was subjected to the same test as in Example 1, the weight change was as shown in Table 1, and the volatilization loss was 0.04%. Furthermore, the results of the dissolution test, toxicity test, and physical property test were as shown in Tables 2 to 4, respectively. Example 4 2, 3, 3′, produced in the same manner as Example 1
A resin composition consisting of 50 parts by weight of 4'-biphenyltetracarboxylic acid tetra(n-dodecyl) ester, pyrivinyl chloride (degree of polymerization 1100), 3 parts by weight of epoxidized soybean oil, calcium stearate, and 1 part by weight of zinc stearate. The mixture was thoroughly kneaded using two rolls at a temperature of 150°C and formed into a sheet with a thickness of 0.4 mm. When this sheet-like material was subjected to the same test as in Example 1, the weight change was as shown in Table 1, and the volatilization loss was 0.02% by weight. In addition, the results of the dissolution test, toxicity test, and physical property test are
It was as shown in Table 4. Comparative Example 1 The same method as Comparative Example 1 was carried out, except that di-2-ethylhexyl phthalate was used instead of tetraester, and a thickness of 0.4
It was molded into a sheet of mm. When this sheet-like material was subjected to the same test as in Example 1, the weight change was as shown in Table 1, and the volatilization loss was 3.7% by weight. In addition, the results of the dissolution test, toxicity test, and physical property test are
It was as shown in Table 4. Comparative Example 2 The same method as in Example 1 was carried out, except that 2,2'-biphenyldicarboxylic acid di(2-ethylhexyl) ester was used instead of the tetraester, and a thickness of 0.04 was obtained. It was molded into a sheet of mm. When this sheet-like material was subjected to the same test as in Example 1, the weight change was as shown in Table 1, and the volatilization loss was 2.5% by weight. In addition, the results of the dissolution test, toxicity test, and physical property test are
It was as shown in Table 4. Comparative Example 3 In the same manner as in Example 1, bicyclo[2,2,2]oct-7- was used instead of the tetraester.
A sheet having a thickness of 0.4 mm was formed using the same method except that ene-2,3,5,6-tetracarboxylic acid tetra(2-ethylhexyl) ester was used. When this sheet-like material was subjected to the same test as in Example 1, the weight change was as shown in Table 1, and the volatilization loss was 4.2% by weight. In addition, the results of the dissolution test, toxicity test, and physical property test are
It was as shown in Table 4. Example 5 Platelet-rich plasma (PRP) was obtained from 40 volumes of human venous blood collected using a plastic syringe containing 6 volumes of ACD-A solution by centrifugation (160G, 10 minutes). This PRP was aseptically dispensed in 2 ml portions into mini bags made from the sheet-like materials obtained in Examples 1 to 4 and Comparative Examples 1 to 3. Considering individual differences in blood, three blood samples were used for each test. this
Platelet aggregation test for PRP is carried out at room temperature for 2,6 minutes.
and an agglutination ability test of PRP stored in a bag for 24 hours. Equipment used: Aggregometer AUTORAM-11 (manufactured by Rika Denki Kogyo Co., Ltd.) Measurement temperature: 37°C Stirring speed: 1000 rpm Reagent: ADP final concentration 10 ^-5 M Reagent concentration: PRP/reagent = 10/1 Maximum aggregation rate of bag dispensing Let A ₁ be the maximum aggregation rate at each time, A ₂ , A ₆ , A ₂₄ , A ₂ /A ₁ , A ₆ /
Average value M of 3 samples for each value of A ₁ and A ₂₄ /A ₁
(A ₂ /A ₁ ), (A ₆ /A ₁ ) and M (A ₂₄ /A ₆ ) were compared. The measurement results were as shown in Table 5.

【table】

【table】

【table】

【table】

【table】

[Table] Specific effects of the invention As stated above, the medical device according to the present invention has
Since it is made from a resin composition consisting of vinyl chloride resin and biphenyltetracarboxylic acid tetraester represented by the general formula, the amount of plasticizer extracted is lower than that of conventionally used di-2-ethylhexyl phthalate. It is extremely low, about 1/20 of that, and the loss by volatilization is extremely low, and the migration to the surface is also low. Therefore, even if the medical device comes into contact with body fluids such as blood, the problem of decreased platelet aggregation ability due to elution of the plasticizer into plasma can be significantly improved. In particular, in platelet aggregation tests,
The rate of decline is significantly smaller than that of conventional products, so
Storage time can be significantly extended. In addition, the amount of biphenyltetracarboxylic acid tetraester represented by the general formula relative to 100 parts by weight of vinyl chloride resin was adjusted to 20 to 120 parts by weight, 30 to 100 parts by weight,
By using parts by weight, various physical properties can be exhibited without sacrificing the above-mentioned advantages. Therefore, medical devices such as body fluid storage containers such as plasma blood storage containers, catheters, blood transfusion sets, infusion sets, blood circuits, etc., especially medical devices that come into direct contact with body fluids or come into contact with medicinal fluids supplied into the body. It exhibits excellent effects when used. Also, when used in catheters or blood circuits,
Unlike conventional products, the elution of plasticizer is extremely small even after long-term use, so the soft vinyl chloride resin does not become hard, thereby eliminating the troubles that conventionally occurred when removing catheters from the body.

[Brief explanation of the drawing]

The drawing is a front view showing an example of a medical device according to the present invention. 3...Blood bug, 13,22...Child bug,
6, 16, 21...Tube.

Claims (1)

[Claims] 1. Vinyl chloride resin and general formula (However, in the formula, R is an aliphatic saturated hydrocarbon residue having 4 to 18 carbon atoms.) A medical device made of a resin composition consisting of biphenyltetracarboxylic acid tetraester represented by the formula. 2. The medical device according to claim 1, wherein the amount of biphenyltetracarboxylic acid tetraester represented by the general formula 1 is blended in an amount of 20 to 120 parts by weight based on 100 parts by weight of the vinyl chloride resin. 3. The medical device according to claim 2, wherein the amount of the biphenyltetracarboxylic acid tetraester represented by the general formula is 30 to 100 parts by weight based on 100 parts by weight of the vinyl chloride resin composition. 4. The medical device according to any one of claims 1 to 3, wherein R is an aliphatic saturated hydrocarbon residue having 4 to 12 carbon atoms. 5. The medical device according to any one of claims 1 to 4, wherein R is an aliphatic saturated hydrocarbon residue having 8 to 12 carbon atoms. 6 Biphenyltetracarboxylic acid tetraester has the general formula (However, in the formula, R is as described above.)
The medical device according to any one of claims 1 to 3, which is a 3,3',4,4'-biphenyltetracarboxylic acid tetraester represented by: 7 Biphenyltetracarboxylic acid tetraester has the general formula (However, in the formula, R is as described above.)
The medical device according to any one of claims 1 to 3, which is a 2,3,3',4'-biphenyltetracarboxylic acid tetraester represented by: 8. The medical device according to any one of claims 1 to 7, wherein the medical device is a body fluid storage container. 9. The medical device according to claim 8, wherein the body fluid is blood. 10. The medical device according to any one of claims 1 to 7, wherein the medical device is a catheter. 11. The medical device according to any one of claims 1 to 7, wherein the medical device is a blood transfusion set. 12. The medical device according to any one of claims 1 to 7, wherein the medical device is an infusion set. 13. The medical device according to any one of claims 1 to 7, wherein the medical device is a blood circuit.