JP2001305131A - Vessel for blood test - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a vessel for blood test which can quickly coagulate blood even when the blood contains added heparin, can use a conventionally used ordinary blood coagulation accelerator, and can be manufactured with high productivity. SOLUTION: In this vessel for blood test, a heparin neutralizer (for example, polyamine sulfone) and a blood coagulation accelerator (for example, silica, kaoline, cerite, or bentonite) are separately contained.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a blood test container used for a clinical test such as a serum biochemical test, and more particularly to a blood test suitably used for collecting and testing blood of a patient receiving heparin administration. For containers.

[0002]

2. Description of the Related Art In recent years, in order to collect and test blood for serum tests such as serum biochemical tests, serum immunological tests, and blood cell tests, it has been necessary to shorten the blood clotting time and obtain serum quickly. Enabled blood test containers are being actively used. In such a blood test container, a blood coagulation accelerator is stored in the container in advance, and blood coagulation is promoted by the action of the agent, so that a rapid blood test can be performed.

[0003] By the way, there is a blood to be subjected to a blood test to which various drugs are added. For example, in blood of a dialysis patient, heparin which is a blood anticoagulant is added to the blood. With respect to such heparin-added blood, in a conventional blood test container containing only a blood coagulation accelerator, the effect of the blood coagulation accelerator is not exhibited due to the presence of heparin, and the purpose is to shorten the blood coagulation time. Could not be fulfilled.

A blood test container for such heparin-added blood is disclosed in Japanese Patent Application Laid-Open No. 58-1460.
As described in Japanese Patent Application Publication, a blood test container in which a heparin neutralizing agent and a blood coagulation accelerator are contained in a container is known.

In the manufacture of such a blood test container,
Due to its convenience, a method has been adopted in which a heparin neutralizing agent and a blood coagulation promoter are dissolved or dispersed in a solvent or a dispersion medium, and this solution or dispersion is spray-coated on the inner surface of the container.

However, in this method, the heparin neutralizing agent and the blood coagulation promoter come into contact in a solvent or a dispersion medium, and the coagulation activity is reduced depending on the type of the blood coagulation promoter. Therefore, this method is applied to this method. There are only very limited blood coagulation promoters that can be used.

[0007] Examples of the blood coagulation accelerator applicable to such a production method include ellagic acid-based substances.
However, when this drug is used, there is a problem that only a special solvent can be used due to the low stability of the drug, a problem that the application operation on the inner surface of the container is complicated due to a high viscosity, and furthermore, a problem that the drug is There was a problem that the coated surface became opaque and the collected blood could not be visually observed from outside.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems, and it is possible to rapidly coagulate even heparin-added blood, It is an object of the present invention to provide a blood test container that can use a conventionally used general blood coagulation accelerator and that is excellent in productivity.

[0009]

According to the first aspect of the present invention,
A blood test container, wherein a heparin neutralizing agent and a blood coagulation promoter are stored in a separated state.

According to a second aspect of the present invention, there is provided a blood test container comprising a tubular member having one end closed and the other end opened, wherein a serum separating agent is stored in the closed end of the tubular member. The blood test container according to claim 1, wherein a heparin neutralizing agent is held on the surface of the agent, and a blood coagulation promoter is held on the inner surface of the tubular member.

The invention according to claim 3 is the blood test container according to claim 1 or 2, wherein the heparin neutralizing agent is an amine salt and / or a quaternary nitrogen-containing substance.

The invention according to claim 4 is the blood test container according to claim 3, wherein the quaternary nitrogen-containing substance is polyamine sulfone.

The invention according to claim 5 is the invention wherein the blood coagulation promoter is at least one selected from the group consisting of silica, kaolin, celite and bentonite.
A blood test container according to any one of the above.

Hereinafter, the present invention will be described in detail.

The container constituting the blood test container of the present invention is not particularly limited as long as it has a shape capable of containing blood and reacting with a drug, but is preferably a general blood collection tube. One example is a tubular member having one end closed and the other end opened.

The content of the container is not particularly limited, and is about 1 to 20 mL, more preferably 2 to 10 m.
A container having an inner capacity of about L can be used.

In the blood test container of the present invention, the container contains a heparin neutralizing agent and a blood coagulation promoter, and the heparin neutralizer and the blood coagulation promoter are separated from each other in the container. It is stored in.

That is, the heparin neutralizing agent and the blood coagulation promoter are contained in a container so as not to contact each other. This is because when the heparin neutralizing agent and the blood coagulation promoting agent come into contact with each other, they interfere with each other and reduce the blood coagulation promoting effect. However, the term "separated state" in the present invention does not necessarily mean that the two drugs are completely separated without any contact, and there is some contact at the boundary between the two drugs. However, it also means that most of the medicines are not in contact with each other.

The storage form of the heparin neutralizing agent and the blood coagulation promoter is not particularly limited.
There is a method in which a blood coagulation promoter is held on the side surface in the container, and a heparin neutralizing agent is held on the bottom surface in the container. In addition, by providing a part that does not hold the medicine at the boundary between the holding part of the blood coagulation accelerator and the holding part of the heparin neutralizing agent, the two kinds of medicines are stored more securely so as not to come into contact with each other. Is preferred.

Here, that the drug is "held" means
Before blood collection, it is immobilized on the inner surface of the container, but it comes into contact with blood after blood collection, so that it can be eluted into blood.

However, if the two drugs are stored separately, it is not always necessary to hold them on the inner wall surface of the container as described above, and a heparin neutralizer and a blood coagulation promoter are placed on a carrier. The carrier may be held in a non-contact state, and the carrier may be stored in a container.

When a serum separating agent is stored in the closed end of the tubular member as described below, the heparin neutralizing agent is held on the surface of the serum separating agent, that is, the surface constituting the space inside the container. It is preferable that the blood coagulation promoter is held on the inner surface of the container closer to the opening end than the storage site of the serum separating agent.

The heparin neutralizing agent is not particularly limited, and examples thereof include amine salts and quaternary nitrogen-containing substances. These amine salts and quaternary nitrogen-containing substances have a function of adsorbing and neutralizing heparin in blood and inactivating heparin.

The amine salt may be any of primary, secondary or tertiary amine salts. The amine constituting the amine salt may be linear or cyclic, and may be a low molecular compound or a high molecular substance having a low molecular repeating structure. Further, examples of the halogen radical or acid radical constituting the amine salt include halogen radicals such as chloride ion and bromide ion, and acid radicals of inorganic acids and organic acids. Examples of the inorganic acid include hydrohalic acids such as hydrochloric acid, sulfuric acid, and sulfurous acid, and examples of the organic acid include formic acid and acetic acid.

Specific examples of the above amine salt include, for example,
Hexadecyldimethylamine hydrochloride represented by the formula (I) and tetradecyldi (aminoethyl) represented by the formula (II)
Glycine.

[0026]

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[0027]

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The quaternary nitrogen-containing substance may be linear or cyclic as long as it is a substance having a quaternary nitrogen, and even if it is a low molecular compound, it has a low molecular repeating structure. It may be a high molecular substance having. Examples of the low molecular weight compound among the quaternary nitrogen-containing substances include dodecyltrimethylammonium chloride represented by the formula (III).

[0029]

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Among the quaternary nitrogen-containing substances, examples of the polymer substance include a polycation having a repeating unit represented by the general formula (IV).

[0031]

Embedded image (Where R ¹ · R ² is an alkyl group, R ³ · R ⁴ is hydrogen or an alkyl group, X is a halogen radical or an acid radical, Y is an alkylene group or -alkylene group -SO _2- , and the above units are repeated. The number is 5-2000, provided that R ¹ · R ²
With regard to, if most of the repeating structure has an alkyl group, a part substituted with hydrogen may be included in a part of the repeating structure. )

Among the polymer substances represented by (IV), it is preferable to use a quaternary nitrogen-containing substance having a repeating unit represented by the formula (V), and particularly a repeating substance represented by the formula (VI). A quaternary nitrogen-containing substance having a unit (generic name: polyamine sulfone) can be suitably used. In formulas (V) and (VI), as for the methyl group bonded to nitrogen, if most of the methyl group in the repeating structure is a methyl group, a part of the methyl group bonded to hydrogen or another alkyl group may be partially substituted. May be included.

[0033]

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[0034]

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The amount of the amine salt and / or the quaternary nitrogen-containing substance contained in the blood test container is appropriately adjusted depending on the type of the amine salt and the like, the amount of blood collected in the container and the concentration of heparin in the blood. However, it is preferably stored in an amount of about 0.1 × 10 ^{−3 to} 10 mg / mL of collected blood, and particularly preferably 5 × 10 ^{−3 to} 0.1 m.
g.

The method for storing the heparin neutralizing agent in the container is not particularly limited, but a method of preparing a solution of water or an appropriate organic solvent and spraying the solution on the inner wall surface of the container may be used. And a method in which a substance supported on a carrier is dispersed in water, and the dispersion is spray-coated on a tube wall. In addition, when the solution is retained on the serum separating agent, a method of dropping the aqueous solution or the like onto the separating agent with a dropper may be used.

After spraying or dripping the above solution of the heparin neutralizing agent, it is preferable to dry it in order to enhance the storage stability. This drying may be performed immediately after the heparin neutralizing agent is applied, or both may be dried at the same time after the blood coagulation promoter described later is also applied.

The blood coagulation accelerator contained in the blood test container of the present invention may be any one which promotes the activation of blood coagulation factors when it comes into contact with blood and has the function of promoting platelet aggregation. There is no particular limitation.

Examples of the blood coagulation accelerator include fine powders such as glass, silica, kaolin, celite and bentonite. In particular, porous silica containing at least 20% by weight of an amorphous component is preferably used. it can.

The particle size of the fine powder is preferably 50 μm or less, and more preferably the average particle size is 10 μm or less.

The above fine powder has a linseed oil absorption of 20
~ 40ml / 100g, BET specific surface area 5000 ~ 3
Those having a surface area in the range of 0000 cm ² / g are more preferred. Linseed oil absorption is JIS K-5
10 shows a value measured in accordance with No. 101. The above BET
The specific surface area is the amount of gas adsorbed on the surface of the inorganic substance,
The amount of gas that covers the surface as a monolayer from the equilibrium pressure at that time and the saturated vapor pressure of the adsorbed gas is obtained, and the value is obtained by multiplying this by the average cross-sectional area of the adsorbed gas molecules.
As the adsorption gas, nitrogen gas, oxygen gas, argon gas, methane gas, or the like is used. According to this method, a surface area value including pores that cannot be measured by measuring the linseed oil absorption amount is measured.

When the amount of the blood coagulation accelerator is small, the blood coagulation time may be long or coagulation may be incomplete. When the amount is large, the test value may be adversely affected. 10 ^-6 to 1 × 10 ^-2 g is preferred, and 5 × 10 ^-5 to 1 × 10 ^-3 g is more preferred.

As a method for storing the blood coagulation accelerator,
A method of spray-coating the aqueous dispersion directly on the tube wall, a method of dispersing a substance supported on a carrier in water, and spray-coating the dispersion on the tube wall can be used. The order of storing the blood coagulation promoter and the heparin neutralizing agent in the container, if both are stored so that they do not contact,
It does not matter which order is stored first.

After the aqueous solution of the blood promoting agent or the like is applied by spraying, it is preferable to dry it in order to enhance the storage stability.

In the blood test container of the present invention, a serum separating agent may be stored at the closed end of the tubular member. The serum separating agent moves between the clot and the serum by centrifugation after blood collection,
Separate the serum by forming a septum.

The serum separating agent is a gel having a thixotropic property. For example, additives such as a thixotropic agent, a specific gravity adjusting agent, and a viscosity adjusting agent are added to a synthetic resin having fluidity at room temperature. And obtained by mixing.

Examples of the synthetic resin include dicyclopentadiene oligomers and the like, and examples of the thixotropic agent include condensates of sorbitol and aromatic aldehydes, polyoxyethylene polyoxyalkylene block copolymers and the like. As the specific gravity adjuster, for example, silica or the like, and as the viscosity adjuster, for example,
And phthalic acid esters.

The blood test container of the present invention may further contain a blood clot adhesion preventing component. This can prevent blood clot components from adhering to the inner surface of the container after coagulation of blood, and can effectively separate blood clots and serum without restricting the movement of blood clots during centrifugation.

As the blood clot adhesion preventing component, a hydrophilic substance which is hardly soluble or insoluble in water can be used, for example, an aliphatic modified silicone oil (for example, dimethylpolysiloxane, etc.), an aromatic modified silicone oil (E.g., methylphenylpolysiloxane), partially saponified polyvinyl alcohol, and vinylpyrrolidone-vinyl acetate copolymer. When a modified silicone oil is used, it is preferable to further add a water-soluble substance in order to prevent a decrease in the coagulation promoting performance due to the fact that the modified silicone oil covers the surface of the blood coagulation promoter. Examples of the water-soluble substance include polyvinyl alcohol and polyvinyl pyrrolidone.

The anticoagulant component can be stored in a container at the same time as the coagulation promoter by adding it to the blood coagulation promoter dispersion.

Examples of the material of the container constituting the blood test container of the present invention include thermoplastic resins such as polyethylene, polypropylene, polystyrene, polyethylene terephthalate, polymethyl methacrylate, and polyacrylonitrile; unsaturated polyester resins, epoxy resins, Thermosetting resins such as epoxy-acrylate resins; cellulose acetate, cellulose propionate, ethyl cellulose,
Modified natural resins such as ethyl chitin; silicate glasses such as soda-lime glass, phosphosilicate glass, and borosilicate glass; glasses such as quartz glass;

Further, a sealing member can be attached to the opening of the blood test container of the present invention in order to improve the storage stability of the medicine contained therein. As the sealing member, a sheet-shaped sealing member may be used in addition to the rubber plug having a shape fitted into the opening. Examples of the material forming the plug include a material having excellent sealing properties such as butyl rubber, and the material forming the sealing member include aluminum foil.

Further, in the blood test container of the present invention, a tubular member having one end closed and the other end opened and a member for hermetically sealing the opening are used in accordance with the amount of blood to be collected. By setting the inside to a reduced pressure state, it is also possible to adopt a configuration generally called a vacuum blood collection tube.

[0054]

Next, an embodiment of the present invention will be described. However, the present invention is not limited to only these examples.

In the examples and comparative examples, the following were used as reagents and containers. -Heparin neutralizing agent Polyamine sulfone (Nitto Boseki Co., Ltd.)-Blood coagulation accelerator Fine powder silica (trade name: Imsil A)
25, manufactured by Illinois Chemical Co., Ltd.) ・ Serum separating agent: thixotropic separating agent (trade name: Esrect, manufactured by Sekisui Chemical Co., Ltd.) ・ Clot adhesion inhibitor vinylpyrrolidone-vinyl acetate copolymer (molar ratio: 6: 4) ( Product name: Rubiscol 64,
・ Container polyethylene terephthalate inner volume 10m
l (14.5φ × 100 mm) (Sekisui Chemical Co., Ltd.) ・ Seal material Butyl rubber stopper

Example 1 Thixotropic Separating Agent
5 g was stored in the bottom (closed end) of a polyethylene terephthalate container. Next, 1 L of a 2% by weight aqueous solution of a vinylpyrrolidone-vinyl acetate copolymer was added to finely divided silica
g was added and dispersed uniformly. 20 μL of this dispersion was spray-applied only to the inner surface of the container while being careful not to apply it on the separating agent in the container, and dried at room temperature. Next, after adding and dissolving 50 mL of purified water (water for injection in the Japanese Pharmacopoeia) to 0.203 g of the purified polyamine sulfone and completely dissolving it, pay attention so as not to come into contact with the finely powdered silica on the inner surface of the container. 100 μL was dispensed on the separating agent. This container was dried at 55 ° C. for 12 hours to obtain a blood test container of the present invention.

Comparative Example 1 Thixotropic Separating Agent
5 g was stored in the bottom (closed end) of a polyethylene terephthalate container. Next, 1 L of a 2% by weight aqueous solution of a vinylpyrrolidone-vinyl acetate copolymer was added to finely divided silica
g was added and dispersed uniformly. Next, 50 mL of purified water (water for injection in the Japanese Pharmacopoeia) was added to 0.203 g of the purified polyamine sulfone to completely dissolve it, and then added to the above dispersion and mixed thoroughly. 20 μL of this mixture was dispensed into the above-mentioned container and dried at 55 ° C. for 12 hours to obtain a blood test container of a comparative example.

[Evaluation of Performance] Five ml of three types of blood (heparin concentration: 0, 1, 3 U / mL) to which heparin was added were respectively collected in the blood test container, stoppered, and then gently mixed by inverting 5 times. The blood was allowed to stand and the time required for the blood to clot was measured. The determination of coagulation was made at the time when the upper surface of the blood did not move even when the blood test container was tilted, and the blood did not flow even when the blood test container was kept upside down.

In the blood test containers of the examples, blood coagulation was completed within 30 minutes after blood collection at any concentration of heparin. On the other hand, in the blood test container of the comparative example, it took 2 hours from collection of blood to completion of blood coagulation at any concentration of heparin.

Incidentally, the case where blood coagulation was promoted using the blood test container of the example and the case where blood coagulation was spontaneously performed in a container containing no drug were common biochemical test items. Were compared, but no significant difference was observed.

[0061]

The blood test container of the present invention is as described above, and contains the heparin neutralizing agent and the blood coagulation promoter in a separated state, so that the blood coagulation activity does not decrease. In addition, even blood containing heparin can be rapidly coagulated.

Claims (5)

[Claims] 1. A blood test container wherein a heparin neutralizing agent and a blood coagulation promoter are stored in a separated state. 2. A blood test container comprising a tubular member one end of which is closed and the other end of which is opened, wherein a serum separating agent is stored at the closed end of the tubular member, and heparin neutralizing is carried on the surface of the serum separating agent. Agent is held,
The blood test container according to claim 1, wherein a blood coagulation accelerator is held on the inner surface of the tubular member. 3. The blood test container according to claim 1, wherein the heparin neutralizing agent is an amine salt and / or a quaternary nitrogen-containing substance. 4. The blood test container according to claim 3, wherein the quaternary nitrogen-containing substance is polyamine sulfone. 5. The blood test container according to claim 1, wherein the blood coagulation promoter is at least one selected from the group consisting of silica, kaolin, celite, and bentonite.