JP3243348B2 - Medical equipment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art In recent years, as a blood storage container for transfusion,
It has been changed from hard glass containers to soft polyvinyl chloride soft bags, mainly to reduce red blood cell damage. Blood bags made of flexible soft polyvinyl chloride are increasingly used due to their good workability, flexibility, transparency, low water vapor permeability, heat resistance and the like. These soft polyvinyl chlorides contain 30 to 60 parts by weight of a phthalate ester as a plasticizer. It is known that the phthalate ester elutes into the blood over time during preservation of blood, and has a positive effect of protecting various cells as blood components, particularly the cell membrane on the surface of red blood cells. It is also true that some phthalates are concerned about their safety when introduced into the body by blood transfusion.

[0003]

As described above, a plasticizing efficiency equal to or higher than that of a phthalate ester of a plasticizer conventionally used for medical soft polyvinyl chloride is maintained. By selecting a plasticizer that has an equivalent or better protective effect on erythrocyte membranes and that is safer than phthalate, it has a blood preservation performance equal to or higher than that of the conventional, highly safe soft polyvinyl chloride resin composition The purpose is to obtain a medical device molded from.

[0004]

According to the present invention, a compound represented by the general formula (I) is used per 100 parts by weight of a vinyl chloride resin

[0005]

Embedded image

(Where a and b each represent 2 to 2)
12, 5 to 100 parts by weight of a dialkyl malate having a hydrogen atom, an acetyl group, a propionyl group or a butyryl group);
It is a medical device made of a resin composition containing 0 parts by weight. Further, the present invention provides that the general formulas a and b are 4, 6,
8 is a medical device. Further, the dialkyl malate of the present invention is dihexyl malate, dioctyl malate, monohexyl monooctyl malate, di-hexyl acetylmalate, di-octyl acetylmalate, acetyl apple. A medical device characterized by being monohexyl acid monooctyl ester, butyryl malate di-hexyl ester, butyryl malate di-octyl ester, and butyryl malate monohexyl monooctyl ester. Further, the present invention provides a medical device characterized in that the stabilizer of the present invention contains an epoxidized vegetable oil, a barium-zinc-based stabilizer and a calcium-zinc-based stabilizer as main components. Further, the medical device is characterized in that the molded article of the present invention is a blood bag and a tube.

The vinyl chloride resin used in the resin composition for medical devices according to the present invention contains 70% by weight or more, preferably 85% by weight or more of vinyl chloride, in addition to the homopolymer 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.
0. Further, comonomer for vinyl chloride includes vinylidene chloride, ethylene, propylene, vinyl acetate, vinyl bromide, vinyl fluoride, styrene, vinyltoluene, vinylpyridine, acrylic acid, alkyl acrylate (for example, methyl acrylate, ethyl acrylate) Examples include acrylate, isopropyl acrylate, n-butyl acrylate, 2-ethylhexyl acrylate, and the like, methacrylic acid, alkyl methacrylate (for example, methyl methacrylate, ethyl methacrylate, 2-ethylhexyl methacrylate, and the like), acrylonitrile, and methacrylonitrile. Further, a styrene-acrylonitrile copolymer or a styrene-methacrylonitrile copolymer can be blended with the vinyl chloride resin.

The malic acid ester used as the plasticizer is represented by the general formula (I), and is 5 to 100 parts by weight, preferably 4 parts by weight, per 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, they are 4, 6, and 8. That is, when a or b is 1 or less, the amount of the plasticizer eluted increases, while when a or b is 13 or more, the plasticizing efficiency is low, so that an excessive amount of compounding is required to obtain sufficient flexibility. Poor in compatibility with resin. Further, a and b may be linear or side chains, and those expressed as dioctyl malate include structural isomers such as di-2-ethylhexyl malate having an alkyl group in the side chain.

The method for synthesizing these malic acid diesters is not particularly special, and malic acid and alcohol having a molar concentration twice or more are reacted by heating in the presence of sulfuric acid. The reaction product was neutralized with sodium hydroxide, washed with water, and purified by distillation. Further, when proceeding the reaction to the hydroxyl group of malic acid, the acid anhydride was reacted in the presence of sulfuric acid. The reaction product was neutralized with sodium hydroxide, washed with water, and purified by distillation.

As the stabilizer, epoxy compounds,
For example, epoxidized vegetable oils such as epoxidized soybean oil and epoxidized linseed oil, di-2-ethylhexyl epoxy hexahydrophthalate, vinylcyclohexanedioxide, 3,4-epoxy-6-methylcyclohexylmethyl-3,4-epoxy-6-methylcyclohexane carbonate, Metal soaps such as cyclohexene oxide derivatives such as dicyclopentadienedioxide or calcium, zinc, barium, magnesium, tin and stearic acid, lauric acid, ricinoleic acid, naphthenic acid, 2-ethylhexoic acid, etc., for example, calcium stearate , Zinc stearate, calcium laurate, zinc laurate, barium stearate, magnesium stearate, tin stearate, etc. N mixture of class is blended. In addition, there are phosphites such as didecylphenyl phosphite and organic stabilizers such as a mixture of stearoylbenzomethane and palmitoylbenzoylmethane. The amount 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 together with a metal soap, a phosphite or an organic stabilizer.
The epoxy compound is used in an amount of 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 preferred. Metal soaps, phosphites or organic stabilizers are used in an amount of 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.
-Based or Ba-Zn-based metal soap is preferred.

Although no toxicity data is shown when dialkyl malate is administered to blood by transfusion or the like, malic acid itself is a substance in the living body and has a phthalic acid structure not found in the living body. It can be easily estimated that the toxicity is lower than that of the 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 collection bag 3 made of the resin composition of the present invention having a plurality of discharge ports 1 with peel tabs and a plurality of discharge ports 2 has a peripheral portion heated by high frequency 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. In the internal space of this blood collection bag, a CPD liquid or the like is stored as an anticoagulant. A blood collection needle 7 is attached to the tip of the blood collection tube 6.

When a child bag made of the resin composition of the present invention is connected in addition to the blood collection bag 3, a peripheral portion 1 made of the resin composition of the present invention having an outlet 9 with a peel tab is provided.
A first child bag 13 provided with a connection tube 12 made of the resin composition of the present invention, which is fused to the inner space 11 and is connected to the internal space 11, is connected via a branch pipe 14 to a connection outlet 2 of the blood collection bag 3. And the connecting tube 1 connected by the connecting portion 15
6 is connected. In addition, a discharge port 17 with a beer tab is provided, and the peripheral portion 18 is sealed with a high frequency, so that the internal space 1 is provided.
Connecting tube 21 made of the resin composition of the present invention which communicates with connecting tube 9
The connecting tube 21 of the child bag 22 made of the resin composition of the present invention provided with the connecting tube 1
2, 16 are connected.

The above description has been made with reference to a blood bag as an example, but other blood storage containers, blood transfusion system containers, blood circuit containers, infusion bags, medical tubes such as catheters and dialysis tubes, artificial kidneys, etc. The present invention can be similarly used for artificial organs such as an artificial lung and an artificial liver, respiratory circuit device-related instruments such as a tube for a respiratory circuit, and the like. The use as a medical device of the present invention is particularly excellent in cold resistance, so it is suitable as a cryopreservation container for blood or the like or a blood bag, and is more effective when used in a blood bag and a tube connected thereto. It is remarkable, but the point is that when a fluid such as a liquid such as a bodily fluid or a medicinal solution or a gas is injected into, discharged from, or stored in or comes into contact with the medical device, it is suitable and meets the purpose of the present invention. It is not particularly limited as long as it is one.

[0015]

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 plasticizers and stabilizers shown in Table 1 were mixed in the proportions shown in the table, and a sheet having a thickness of about 0.4 mm was obtained by a conventional method, ie, extrusion molding. The results of tensile properties, dissolution test and safety test (cytotoxicity test) of the sheet are shown in the same table. After the sheet is cut into a predetermined shape, two sheets are overlapped, and the inner surface area is about 5
A high-frequency sealing was performed so as to be 0 square centimeter to prepare a blood bag for testing. After the bag was sealed and subjected to high-pressure steam sterilization, no remarkable deformation was observed in any of Examples and Comparative Examples, and there was no practical problem.

A test piece having a total of 6 square centimeters on both sides of the sheet was placed in a glass test tube, and then subjected to high-pressure steam sterilization (121 ° C. for 20 minutes). Add 5ml of CPD added whole blood to this
Was aseptically dispensed, sealed and stored at 4 ° C. for 28 days. After storage, the suspension 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, and this was used as an index of hemolysis generated during storage. The results are shown in Table 1.

[0018]

[Table 1]

DBM: dibutyl malate DHM: dihexyl malate DOM: dioctyl malate DDM: didecyl malate ADOM: dioctyl acetyl malate, PDOM: dioctyl propionyl malate phthalate: di-n -Decyl phthalate

The tensile properties were measured using a strograph manufactured by Toyo Seiki Seisakusho in accordance with Japanese Industrial Standard JISK-6301, and the rubber No. 3 dumbbell was pulled at a pulling 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's Public Notice No. 448, "Standards for Blood Sets Made of Vinyl Chloride Resin", and pass / fail was determined. The cytotoxicity test is 18
A square centimeter sample sheet and 3 ml of MEM medium (manufactured by Nippon Pharmaceutical Co., Ltd.) were placed in a screw vial, and 12
An autoclave treatment is performed at 1 ° C. for 60 minutes to obtain an extract.
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 to which no extract was administered, and the cell growth was hindered. , Or those in which the cells were killed were regarded as positive.

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

After a lapse of a predetermined time (0 minute, 15 minutes, 30 minutes,
After 60 minutes, 120 minutes and 240 minutes), sample 500 μl, add 5 ml of isopropanol and stir well, further add 5 ml of diethyl ether, stir well again, and then centrifuge (2500 rpm, 10 mi).
n). The upper layer was removed, the solvent was distilled off at 30 ° C. under nitrogen gas, 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 residual ratio of the plasticizer.

<Gas chromatography conditions> Column: Silicone SE-30, Chromosorb WAW DMCS
5%, 1.1m ・ He gas flow rate: 60 ml / min ・ Detector: FID ・ Amount of sample added: 5μl ・ Column temperature: 200 ℃

[0024]

[Table 2]

From Table 2 and FIG. 2 showing the residual ratio of the plasticizer,
In the control without added plasma, incubation at 37 ° C. for 4 hours showed little degradation of any plasticizer. In contrast, when plasma is added,
Phthalates (Comparative Example 2) and citrates (Comparative Examples 3 and 4) were hardly decomposed by incubation at 37 ° C. for 4 hours, while malate (Examples 8 to 10) 30-60% had been degraded. This result indicates that malate ester is easily degraded by enzymes in plasma. Therefore, it is considered that it is easily decomposed into malic acid and alcohol even in a living body, and higher safety than phthalate and citrate is expected.

[0026]

The medical device according to the present invention comprises 5 to 100 parts by weight of a dialkyl malate represented by the general formula and 100 to 100 parts by weight of a vinyl chloride resin, and 1 to 2 parts of a stabilizer.
Since it was molded with a resin composition containing 0 parts by weight, it has the same physical properties (tensile elasticity) and the same processing (extrusion molding,
High-frequency sealing, adhesion, sterilization, etc.), and high safety. Further, when used as a material for a blood bag, there is an effect that storage performance of blood components, particularly red blood cells, is good and safety is high.

[Brief description of the drawings]

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

FIG. 2 is a graph showing the degradation rate of a plasticizer used in the present invention in plasma.

[Explanation of symbols]

1, 2, 9, 17 ... outlet, 3 ... blood collection bag, 6, 16, 21 ... tube, 7 ... blood collection needle, 13, 22 ... child bag.

Continuation of the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) A61J 1/10 C08K 5/11 C08L 27/06 C08J 9/04

Claims (5)

(57) [Claims] 1. A compound of the general formula (I) wherein a and b are each 2 to 12 and R is a hydrogen atom, an acetyl group, a propionyl group or a butyryl group with respect to 100 parts by weight of a vinyl chloride resin. 5 to 100 parts by weight of a dialkyl malate having
A medical device comprising a molded product made of a resin composition containing up to 20 parts by weight. Embedded image (2) A and b in the general formula (I) are
The medical treatment according to claim 1, which is any one of 4, 6, and 8.
Appliances. (3) The dialkyl malate is
Dihexyl malate is dihexyl malate
Esters, dioctyl malate, malic acid
Nohexyl monooctyl ester, acetylmalic acid
Di-hexyl ester, di-octyl acetylmalate
Ester, monohexyl acetylmalate-monooctyl
Ester, butyryl malate di-hexyl ester,
Butyryl malate di-octyl ester and butyryl
Any of monohexyl malate-monooctyl ester
The medical device according to claim 1 or 2, wherein (4) Said stabilizers include epoxidized vegetable oils, burr
Any of Umu-zinc and calcium-zinc stabilizers
4. The method according to claim 1, wherein
A medical device according to any of the claims. (5) The molding may be a blood bag and / or
Is a tube The method according to any one of claims 1 to 4,
Medical instruments.