WO2000045162A1

WO2000045162A1 - Blood coagulation preventing agents and blood collection containers containing the same

Info

Publication number: WO2000045162A1
Application number: PCT/JP1999/007159
Authority: WO
Inventors: Noriyuki Tatsumi
Original assignee: Nagase & Co., Ltd.
Priority date: 1999-01-26
Filing date: 1999-12-20
Publication date: 2000-08-03
Also published as: AU1690400A; JP2000210380A

Abstract

Blood coagulation preventing agents containing as the active ingredient an inorganic acid salt of magnesium; and blood collection containers containing an inorganic acid salt of magnesium. Because of being capable of effectively preventing blood coagulation, these agents and containers are appropriately usable, in particular, in preventing blood specimens collected for various diagnostic examinations from coagulation.

Description

TECHNICAL FIELD A blood coagulation inhibitor and a blood collection container containing the same

The present invention relates to a novel anticoagulant and a blood collection container containing the same. More specifically, the present invention relates to a blood coagulation inhibitor which effectively prevents blood coagulation, and is particularly preferably used to prevent blood coagulation collected for a blood test used for various diagnoses, and The present invention relates to a blood collection container in which is stored. Background art

In recent years, clinical tests have become an indispensable element in diagnosing disease states and determining the effects of treatment. The purpose of this clinical test is to test biological functions. (1) A test (physiological test) that examines direct biological information in the living body, and (2) Biological components such as blood, urine, and tissues. Can be broadly divided into tests for examining biotransformations (specimen tests). In the latter sample test, the blood test plays a particularly important role.

This blood test includes (1) chemical tests to check electrolytes and pH, (2) measurement of chemical components in blood, measurement of infectious diseases, blood types, cancer-related antigens, etc. Furthermore, they can be broadly divided into biochemical tests for examining bacteria, viruses and pathological cells, and (3) blood tests for examining the morphology and number of blood cells and coagulation function.

In order to perform such a blood test, first, the blood of the subject is collected in a blood test container, and in this case, measures are taken so that the collected blood does not coagulate before being subjected to the test. It is important.

Blood is fluid while circulating in blood vessels, but once removed outside the blood vessels, it loses fluidity, for example, once it is transferred into a test tube. This is because fibrinogen in plasma is converted into fibrin fibrin, forming a fibrin web, This is because the whole liquid becomes a gel and solidifies.

Such coagulation is initiated when blood coagulation factor XII in plasma comes into contact with a surface (eg, glass) of a negatively charged solid phase or the like. That is,

Factor XII would when adsorbed on the surface activated factor XII (XII _a), which is interposed calcium ions, acts on each coagulation factor, ultimately to produce a thrombin, the thrombin Fuiburino one Gen Limited digestion to fipurin, and fibrin is converted to blood coagulation factor XIII (XI

It is crosslinked by Il a) to form a fibrin web and the blood clots.

Various types of blood have been developed and used to prevent such coagulation of collected blood. For example, metal salts of ethylenediaminetetraacetic acid, sodium citrate, sodium heparin, synthetic hirudin, and a sulfonated gen-based polymer having a weight-average molecular weight of 300 or more or a salt thereof (JP-A-8-43337) No. 7) is known as a blood coagulation inhibitor for blood collection.

However, these anticoagulants can be applied to testing of some of the above three items (chemical items, biochemical items, and blood items), but cannot be applied to tests of other items. However, it was not always satisfactory because of problems such as high price, high price, unstable performance and insufficient performance. Under such circumstances, the present invention can be applied to blood tests of all chemical, biochemical and blood items, is versatile, has an excellent effect of preventing blood coagulation, and An object of the present invention is to provide a blood coagulation inhibitor which is stable in effect and is inexpensive, and a blood collection container containing the same. Disclosure of the invention

The present inventor has conducted intensive studies to develop a blood coagulation inhibitor having the above preferred properties and a blood collection container containing the same, and as a result, the inorganic acid salt of magnesium has an unexpectedly excellent blood coagulation prevention effect, The present inventors have found that the agent can be used as a universal anticoagulant, and based on this finding, have completed the present invention.

That is, the present invention (1) an anticoagulant comprising an inorganic salt of magnesium as an active ingredient,

(2) The anticoagulant according to (1), wherein the inorganic acid salt of magnesium is magnesium sulfate or a hydrate thereof.

(3) The anticoagulant according to (1) or (2), which is used for a blood test,

(4) A blood collection container containing a magnesium salt of inorganic acid in the container, and

(5) The blood collection container according to (4), wherein the inorganic acid salt of magnesium is magnesium sulfate or a hydrate thereof.

Is provided. BEST MODE FOR CARRYING OUT THE INVENTION

The anticoagulant of the present invention contains magnesium as an active ingredient and is particularly effective in preventing coagulation of blood collected for a blood test.

Examples of the inorganic acid salts of magnesium include magnesium sulfate, magnesium ammonium sulfate, magnesium potassium sulfate, magnesium sodium sulfate, magnesium calcium sulfate, magnesium calcium potassium sulfate, magnesium chloride, magnesium chloride, magnesium potassium chloride, and magnesium chloride. Magnesium sodium, magnesium nitrate, magnesium phosphate, magnesium phosphate ammonium, magnesium hydrogen phosphate, magnesium orthoborate, magnesium metaborate, magnesium carbonate, magnesium carbonate ammonium, magnesium calcium carbonate and their hydrated salts And the like. These may be used alone or in combination of two or more. Magnesium sulfate and its hydrous salts are particularly preferred in terms of performance and cost.

Although the mechanism of the anticoagulant effect of the inorganic salts of magnesium is not always clear, it has been shown that thrombin has a function of converting fibrinogen into fibrin by limited degradation and fibrin network formation by fibrin crosslinking. It is presumed that calcium ions in the blood involved are replaced by magnesium ions.

In the blood coagulation inhibitor of the present invention, together with the inorganic acid salt of magnesium, As far as the object of the invention is not impaired, conventionally known substances having an anticoagulant action, for example, metal salts of ethylenediamine tetrafate, sodium citrate, sodium heparin, synthetic hirudin, sulfonated gen-based polymers, if desired Alternatively, a salt thereof, or another thrombin inhibitor or the like can be appropriately used. Here, other thrombin inhibitors include, for example, gabexate methylate, nafamostat mesylate, (2R, 4R) —4-methyl-1- 1— [N ² — (3-methyl-1,2,3, 4-tetrahydro-18-quinolinesulfonyl) -1-L-arginyl] -12-piperidinecarboxylic acid monohydrate.

The amount of the blood coagulation inhibitor of the present invention added to blood is appropriately selected depending on the type of the inorganic acid salt of magnesium and the desired anticoagulation time, but is usually 1 to 50 ragZml, preferably 2 to 4 Omg. / ml range. If the added amount is less than 1 mgZml, the effect of preventing blood coagulation may not be sufficiently exerted, and if it exceeds 5 OmgZinl, the effect is not improved for the amount, but rather adversely affects the blood test. May be given.

The form of the anticoagulant of the present invention is not particularly limited, and may be in the form of a powder, an aqueous solution or an aqueous suspension contained in an aqueous medium. As the aqueous medium, an aqueous medium that does not disturb the blood test, preferably, physiological saline can be used.

Next, the blood collection container of the present invention will be described.

The blood collection container of the present invention contains the inorganic salt of magnesium in a container, and the inorganic salt of magnesium is used as a powder, an aqueous solution or an aqueous suspension. The inorganic acid salt of magnesium may be used alone or in combination of two or more. As described above, magnesium sulfate and its hydrated salt are particularly preferable. Further, as long as the object of the present invention is not impaired, a conventionally known substance having an anticoagulant effect as described above may be appropriately used in combination.

The blood collection container of the present invention means a container such as a blood collection tube, a blood collection bottle, a blood collection bag, or the like for collecting or storing blood for a blood test, for whole blood, for separating serum, for analyzing sugar, and the like. Although the shape of the container itself is not particularly limited, a vacuum blood collection tube is most suitable as the container. is there. This vacuum blood collection tube is usually put into practical use as a vacuum blood collection system combined with accessory devices such as a holder and a blood collection needle. As a material of these blood collection containers, a resin such as a thermoplastic resin, a thermosetting resin or a modified natural resin, or glass can be used.

Examples of the thermoplastic resin include polyethylene, polypropylene, poly-4-methylpentene-11, polystyrene, polymethyl methacrylate, polyvinyl chloride, polyethylene terephthalate, polybutylene terephthalate, styrene-acrylonitrile copolymer, and styrene. Mono-butadiene copolymer, styrene-isoprene copolymer, styrene-maleic anhydride copolymer, styrene-acrylic acid copolymer, styrene-methyl methacrylate copolymer, ethylene-propylene copolymer, ethylene-acrylic acid Copolymers, ethylene monoacrylate copolymers, polyvinyl alcohol acetalized compounds, polyvinyl alcohol butyralized compounds, etc. are examples of thermosetting resins such as unsaturated polyester resins, epoxy resins, and epoxy resins. Kishi acrylate resins, and examples of the modified natural resins, cellulose acetate, propyl propionic acid, cellulose acetate butyrate, E chill cellulose, Echirukichin like are used.

As the glass, for example, a silicate glass such as a soda-lime glass, a phosphoric acid glass, a borate glass, or a quartz glass is preferably used.

The capacity of the blood collection container is appropriately selected depending on the purpose of use of the container, but is usually in the range of 2 to 2 nil.

In the present invention, the amount of inorganic salt of magnesium housed in the blood collection container, per blood l ml for preparative adopted, usually 3 to 5 O mg, preferably 3. 1 5~3 1. 5 mg _c The blood collection container of the present invention may be of a vacuum type in which a cap made of, for example, butyl rubber is provided and the inside is evacuated, or may be of a non-vacuum type. Types are preferred. Further, before or after storing the inorganic acid salt of magnesium, the magnesium salt can be sterilized if necessary.

Example

Next, the present invention will be described in more detail with reference to Examples. It is not limited at all.

At Pharmacopoeia magnesium sulfate (MgS0 ₄ * 7H ₂ 0) crystalline powder, creating a 6.3% HitoshiCho溶solution (solution prepared by dissolving Pharmacopeia magnesium sulfate crystals 6.3 mg at lral saline), Eiken ( This solution was added to tube No. 3 (polyethylene test tube) manufactured by Co., Ltd., and 50, 100, 200, 300, 500 1 Zml whole blood (magnesium sulfate 3.15, 6.3, 12.6, 18.9, 25.2) , 31.5 mg / ml whole blood), mixed with the collected blood, mixed well, allowed to stand, and the time required for the blood to start coagulating was measured by visual observation.

Magnesium nitrate as well as comparative experiment _{_{[Mg (N0 3) 2 '}} 6H 2 0, Wako Pure Chemical Industries, Ltd.], zinc sulfate [ZnS0 ₄ * 7H ₂ 0, USA Sigma] was measured time of blood coagulation by .

Table 1 shows the results.

Table 1

Volume (nig / ml) Time to start coagulation Hemolysis

MgS0 ₄ · 7H ₂ 0 3.15 6 hours without facilities 6.3 48 hours None Example 12.6 to 31.5 None 48 hours or more

_{_{Mg (N0 3) 2 · 6H}} 2 0 coagulation there after 1 30 minutes

5 After 24 hours, small aggregates Yes

48 hours later, aggregation

Ratio 10 Immediately after blood collection, small black mass

30 Small black mass immediately after blood collection Yes 24 hours later, muddy

48 hours later, solidified

Example Zn S0 ₄ · 7H ₂ 0 1 became sol immediately after mild

5 Immediately after the sol became hemolyzed

10 Coagulation started immediately

50 Coagulation started immediately Regarding the stability of the present blood for the measurement of whole blood count, for example, in the case of 12.6 mg Zml blood magnesium sulfate, the whole blood count is stable up to 8 hours. Similarly, the use of a blood coagulation test (PT, ΑΡΤΤ) can be measured in the same manner with 12.6 mg / ml blood of local magnesium sulfate in 30 to 50 seconds of PT and about 3 minutes of A A. Industrial applicability

The anticoagulant of the present invention can be applied to blood tests of all chemical, biochemical and blood items, is versatile, has an excellent effect of preventing blood coagulation, and its effect is stable. Moreover, it is inexpensive and has high practical value.

Claims

The scope of the claims

1. An anticoagulant containing an inorganic acid salt of magnesium as an active ingredient.

2. The blood coagulation inhibitor according to claim 1, wherein the inorganic salt of magnesium is magnesium sulfate or a hydrate thereof.

3. The anticoagulant according to claim 1, which is used for a blood test.

4. A blood collection container containing a magnesium mineral salt in the container.

5. The blood collection container according to claim 4, wherein the inorganic salt of magnesium is magnesium sulfate or a hydrate thereof.