WO2018230571A1 - Blood collection tube - Google Patents

Blood collection tube Download PDF

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Publication number
WO2018230571A1
WO2018230571A1 PCT/JP2018/022455 JP2018022455W WO2018230571A1 WO 2018230571 A1 WO2018230571 A1 WO 2018230571A1 JP 2018022455 W JP2018022455 W JP 2018022455W WO 2018230571 A1 WO2018230571 A1 WO 2018230571A1
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Prior art keywords
blood
collection tube
blood collection
added
solution
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PCT/JP2018/022455
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French (fr)
Japanese (ja)
Inventor
久米　幸夫
恵 清水
信 蔵野
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国立大学法人東京大学
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Publication of WO2018230571A1 publication Critical patent/WO2018230571A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose

Definitions

  • the present invention relates to a blood collection tube.
  • glucose level is widely used in health checkups as an index for various diseases, and is particularly used for diagnosis of diabetes.
  • glucose is broken down by glycolytic enzymes in erythrocytes contained in the collected blood, the blood glucose level in the blood decreases with time.
  • a blood collection tube used for the treatment comprising a blood collection tube main body and a drug contained in the blood collection tube main body, the drug containing maltose, a fluoride salt, and a pH adjusting acid, and having a pH of Disclosed is a blood collection tube containing a liquid reagent in the range of 3.0 to 6.5 and / or containing it in a dry state.
  • Patent Document 2 provides a blood collection tube that prevents hemolysis of collected blood and that can effectively suppress a decrease in blood glucose level and that can stably measure the blood glucose level.
  • a blood collection tube used to measure a blood glucose level in blood and collects a predetermined amount of blood, and has a bottomed cylindrical blood collection tube body that is open at one end and closed at the other end.
  • a particulate drug attached to the inner wall of the blood collection tube main body, the drug being a water-soluble drug containing a glycolysis inhibitor and a blood anticoagulant, wherein the glycolysis inhibitor is collected from the blood Contains 1 to 5 mg D-mannose per 1 mL and 0.3 to 1.0 mg fluoride salt in terms of NaF, the blood anticoagulant is at least one of EDTA and / or heparin, and the drug is a blood collection tube It is attached to the inner wall of the main body by spraying and drying.
  • a blood collection tube in which the osmotic pressure of an aqueous solution when a drug adhering to the inner wall of the blood collection tube main body is dissolved with water equal to a predetermined amount of blood is 30 to 80 mOsm.
  • Blood collection tubes containing sodium fluoride and ethylenediaminetetraacetic acid (EDTA) are widely used at present, but there are individual differences, but when using the blood collection tubes, blood glucose levels in the blood will be increased by 4 hours after blood collection. It is known to decrease by about 10-20%.
  • EDTA ethylenediaminetetraacetic acid
  • the blood glucose level in the blood of a diabetic patient has decreased, for example, even after a lapse of about 4 hours. There are many (false negatives). In this way, when blood glucose is measured using a conventional blood collection tube, if it is determined to be negative in spite of being positive for diabetes, the progression of diabetes progresses and becomes severe without realizing it. There are concerns.
  • An object of the present invention is to provide a blood collection tube capable of suppressing a decrease in blood glucose level in an initial stage after blood collection (for example, after 4 hours from blood collection) and capable of measuring with excellent accuracy.
  • the present inventors have obtained blood collection by using a blood collection tube containing inorganic phosphate or adenosine phosphate.
  • the present inventors have found that it is possible to exert an excellent inhibitory effect on the lowering of blood glucose level in the later initial stage.
  • the present invention is as follows.
  • a cylindrical body having an upper end having an opening and a lower end having a bottom in the longitudinal direction;
  • a plug for closing the opening at the upper end Collection for measuring blood glucose level and / or HbA1c in blood containing at least one selected from the group consisting of inorganic phosphate and adenosine phosphate and salts thereof in the internal space of the cylindrical body.
  • Blood vessels (2)
  • the blood collection tube according to (1) which contains phosphoric acid as inorganic phosphoric acid.
  • the blood collection tube according to any one of (1) to (3) which contains one or more types of adenosine phosphate selected from the group consisting of ATP, ADP, and AMP, and salts thereof.
  • the blood collection tube according to any one of (1) to (4) containing 1 to 100 mg of adenosine phosphate or a salt thereof per 1 mL of collected blood.
  • the blood collection tube according to any one of (1) to (5) further containing a fluoride salt.
  • the blood collection tube of the present invention includes a cylindrical body having an upper end having an opening and a lower end having a bottom in the longitudinal direction, and a plug that closes the opening at the upper end. Further, the internal space of the cylindrical body contains one or more selected from the group consisting of inorganic phosphoric acid, adenosine phosphoric acid, and salts thereof (hereinafter also referred to as “inorganic phosphoric acid etc.”).
  • the upper end having an opening and the lower end having a bottom are both ends in the longitudinal direction of the cylindrical body.
  • the upper end is located above the lower end with respect to the ground so that blood can be drawn from the opening.
  • the lower end is located below the upper end with respect to the ground, and the collected blood is received with a bottom.
  • the cross section of a cylindrical body is cyclic
  • the cross section is circular as long as the cross section is circular or substantially circular.
  • the material of the cylindrical body is not particularly limited, and examples thereof include glass and plastics such as polyethylene terephthalate. In order to make the internal state visible, a colorless and transparent material is preferable.
  • the plug that closes the opening at the upper end of the cylindrical body is not particularly limited, and examples thereof include a rubber plug and a film plug. Further, in the blood collection tube, it is preferable that the stopper closes the opening at the upper end of the cylindrical body, and the internal space of the cylindrical body is decompressed. Since the internal space of the cylindrical body is depressurized, blood collection tends to be easy. The reduced pressure can be appropriately set according to the amount of blood collected and the degree of sealing of the internal space of the cylindrical body by the stopper.
  • the position of the internal space of the cylindrical body containing inorganic phosphate or the like is located on the lower end side of the upper end of the cylindrical body, so that the collected blood may come into contact with the inorganic phosphate or the like. It is preferable because it is easy.
  • inorganic phosphate, adenosine phosphate In order to contain inorganic phosphoric acid or the like in the internal space of the cylindrical body, for example, inorganic phosphoric acid or the like made into a solution may be added from the opening at the upper end, and then the solvent in the solution is dried to obtain a solid state.
  • An inorganic phosphoric acid etc. can be contained in the inside of a cylindrical body with this form. Inorganic phosphoric acid or the like is preferably an aqueous solution from the viewpoint of handleability.
  • the method of adding inorganic phosphoric acid or the like is not particularly limited, and examples thereof include dropping inorganic phosphoric acid or the like in an aqueous solution with a dropper or spraying with a spray coating apparatus.
  • Examples of the inorganic phosphoric acid and salts thereof of the present invention include phosphoric acid, phosphorous acid, hypophosphorous acid and salts thereof, phosphoric acid, phosphorous acid and hypophosphorous acid are preferred, and phosphoric acid is more preferred. . These can be used singly or in combination of two or more.
  • Examples of the inorganic phosphoric acid salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, alkali metal salts are preferable, and sodium salts are more preferable.
  • inorganic phosphoric acid or a salt thereof when inorganic phosphoric acid or a salt thereof is contained, it is preferable to contain inorganic phosphoric acid or a salt thereof in a range of 0.1 to 50 ⁇ L, and 0.5 to 20 ⁇ L per 1 mL of collected blood. More preferably, it is more preferably contained in the range of 1 to 5 ⁇ L, and still more preferably contained in the range of 2.5 to 5 ⁇ L.
  • adenosine phosphoric acid and salts thereof of the present invention examples include ATP (Adenosine TriPhosphate), ADP (Adenosine DiPhosphate), AMP (Adenosine MonoPhosphate) and salts thereof, and ATP and its salts are preferred. These can be used singly or in combination of two or more.
  • Examples of the salt of adenosine phosphate include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, alkali metal salts are preferable, and sodium salts are more preferable.
  • the salt of ATP is preferably a disodium salt.
  • the salt species such as alkali metals and alkaline earth metal salts mentioned above as salts of inorganic phosphoric acid can be similarly applied to the fluoride salt, acid for pH adjustment, and salt species of anticoagulant described later. It is.
  • adenosine phosphate or a salt thereof when adenosine phosphate or a salt thereof is contained, it is preferable to contain adenosine phosphate or a salt thereof in the range of 0.1 to 1000 mg, and 0.5 to 200 mg per 1 mL of collected blood. More preferably, it is contained in the range of 1 to 100 mg, more preferably in the range of 5 to 50 mg, still more preferably in the range of 10 to 20 mg, and in the range of 12 to 17 mg. It is very preferable to contain.
  • adenosine phosphoric acid or a salt thereof By containing 0.1 mg or more of adenosine phosphoric acid or a salt thereof, a decrease in blood glucose level in the initial stage after blood collection tends to be reliably suppressed.
  • containing 1000 mg or less of adenosine phosphoric acid or a salt thereof there is a tendency that errors in blood glucose level measurement can be suppressed.
  • the blood collection tube of the present invention may contain inorganic phosphoric acid or a salt thereof, and adenosine phosphoric acid or a salt thereof at the same time, or may contain only one of them.
  • the blood collection tube can contain known components used for blood collection tubes in addition to inorganic phosphoric acid and the like, if necessary.
  • a known glycolysis inhibitor a substance having an action of inhibiting glycolysis other than inorganic phosphoric acid (fluoride, D-mannose, monoiodoacetic acid, etc.) is used in combination with inorganic phosphoric acid, etc.
  • fluoride, D-mannose, monoiodoacetic acid, etc. is used in combination with inorganic phosphoric acid, etc.
  • the blood collection tube preferably further contains a fluoride salt.
  • the fluoride salt is not particularly limited, and examples thereof include sodium fluoride and potassium fluoride, and sodium fluoride is preferable. These can be used singly or in combination of two or more.
  • the fluoride salt is preferably contained in the range of 0.2 to 3.0 mg, more preferably in the range of 1.0 to 2.5 mg per 1 mL of collected blood. More preferably, it is contained in the range of -2.0 mg.
  • the blood collection tube may further contain a pH adjuster.
  • a pH adjuster For example, an acid for adjusting pH may be further contained in order to suppress metabolism of red blood cells in the collected blood, and for example, hemolysis of the collected blood (which may occur when the pH is 4 or less) is inhibited. Therefore, an acid for pH adjustment may be further contained, and a base for pH adjustment may further be contained.
  • a pH adjusting agent when it is in the pH range where the metabolism and hemolysis of red blood cells are suppressed, it is not necessary to further contain a pH adjusting agent.
  • the acid for adjusting the pH is not particularly limited, and examples thereof include ethylenediaminetetraacetic acid (EDTA), citric acid, succinic acid and salts thereof.
  • EDTA ethylenediaminetetraacetic acid
  • the salt of EDTA sodium salt, potassium salt
  • citric acid and salts thereof are also preferable. These can be used singly or in combination of two or more.
  • the blood collection tube may further contain an anticoagulant in order to more directly inhibit hemolysis of the collected blood.
  • an anticoagulant a known anticoagulant can be used, and is not particularly limited, but heparin and a salt thereof are preferable. These can be used singly or in combination of two or more.
  • the aqueous solution is preferably an aqueous solution using physiological saline from the viewpoint of stability of blood components such as hemolysis suppression.
  • the blood collection tube of the present invention is used to measure blood glucose level and / or HbA1c (Hemoglobin A1c) in blood, and suppresses a decrease in blood glucose level in the initial stage after blood collection (for example, 4 hours after blood collection). In addition to being able to do so, fluctuations in HbA1c can also be suppressed. Further, it is possible to measure with excellent accuracy by suppressing the occurrence of errors such as a positive error in blood glucose level.
  • HbA1c Hemoglobin A1c
  • Blood collection tubes and reagents used in Reference Examples, Examples and Comparative Examples were prepared as follows.
  • each blood collection tube contains physiological saline and various home-made additive solutions (EDTA-2K, sodium fluoride (NaF), mannose, 3.2% citric acid solution, phosphoric acid, monoiodoacetic acid, ATP-2Na, NADH , Adenosine, guanosine, cytosine, cytidine, hydroxyurea, ADP-1K, AMP) are added in the types and amounts shown in the experiment below, and the total solution volume is set to be constant, and the blood dilution rate is set. Aligned to certain conditions.
  • Blood centrifugation was performed at 3000 rpm (1710 g) for 3 minutes unless otherwise specified.
  • Blood collection tube Sekisui Medical Co., Ltd. II blood collection tube for blood glucose test (453557: 12.7 ⁇ 75.6mm EDTA-2K + NaF) used for blood glucose measurement was used. Called blood vessels.
  • Blood collection tube for serum Blood collection using Sekisui Medical Co., Ltd. Insepack (registered trademark) II-D high-speed coagulation type blood collection tube (473470: 12.7 ⁇ 75.6mm with high-speed coagulation accelerator / separator) Centrifugation was performed within 5 minutes, and the supernatant (serum) was used to separate blood cells for glycolysis.
  • the serum was used as a comparative control (an index for confirming that there was no blood glucose fluctuation due to a change in the state of the measuring device itself).
  • Blood collection tubes for blood count Antiglycolytic agents (inorganic phosphate) using blood collection tubes (NP-EK0255-2: 12.8 ⁇ 75mm EDTA-2K granules) for hematology test (EK) ⁇ EDTA-2K> from Nipro Corporation , Adenosine phosphate, mannose, citric acid, monoiodoacetic acid and other substances having an action to block the glycolytic system) were used as comparative controls.
  • Heparin blood collection tube Terumo Corporation Venoject II vacuum blood collection tube A heparin blood collection tube (VP-H050K: 13.2 ⁇ 78 mm sodium heparin) was used as a comparative control when no glycolysis inhibitor was contained.
  • Homemade blood collection tubes Various additive solutions (EDTA-2K additive solution, sodium fluoride (NaF) additive solution, mannose additive solution, citric acid additive) prepared in-house on YS Tube No. 7 (14910) of Toyo Equipment Science Co., Ltd. Solution, phosphoric acid addition solution, monoiodoacetic acid addition solution, ATP addition solution) were added and used in the types and amounts shown in the following experiment.
  • EDTA-2K additive solution sodium fluoride (NaF) additive solution, mannose additive solution, citric acid additive
  • EDTA-2K addition solution Wako Pure Chemical Industries EDTA-2K (340-01511) was used for addition, and a solution was prepared by adding 110 mg of EDTA-2K to 1 mL of purified water.
  • Mannose added solution Wako Pure Chemical Industries D-mannose (130-00872) was used for addition, and a solution was prepared by adding 110 mg of D-mannose to 1 mL of purified water.
  • Citric acid added solution Muto Chemical Co., Ltd. 3.2% citric acid solution (86231) was used.
  • Phosphoric acid addition solution Wako Pure Chemical Industries, Ltd. Phosphoric acid (164-02176) was used for addition, and a solution was prepared that was diluted 10 times with purified water.
  • Monoiodoacetic acid addition solution Wako Pure Chemical Industries, Ltd. Iodoacetic acid (91-00492) was used for addition, and a solution was prepared by adding 110 mg of monoiodoacetic acid to 1 mL of purified water.
  • ATP-2Na addition solution Oriental Yeast Co., Ltd. Adenosine-5′-triphosphate disodium (309-50513) was used for addition, and a solution was prepared by adding 250 mg of ATP-2Na to 1 mL of purified water.
  • ADP-1K addition solution Wako Pure Chemical Industries, Ltd.
  • Adenosine 5′-dipotassium monophosphate (303-50751) was used for addition, and a solution was prepared by adding 50 mg of ADP-1K to 1 mL of purified water.
  • AMP addition solution Wako Pure Chemical Industries Adenosine 5'-monophosphate (303-50491) was used for addition, and a solution was prepared by adding 50 mg of AMP to 1 mL of purified water.
  • NADH addition solution Wako Pure Chemical Industries ⁇ -diphosphopyridine nucleotide disodium (046-16231) was used for addition, and a solution was prepared by adding 110 mg of NADH to 1 mL of purified water.
  • Adenosine addition solution Wako Pure Chemical Industries Adenosine (015-24591) was used for addition, and a solution in which 110 mg of adenosine was added to 1 mL of purified water was prepared.
  • Guanosine addition solution Tokyo Chemical Industry Guanosine (015-12303) was used for addition, and a solution was prepared by adding 110 mg of guanosine to 1 mL of purified water.
  • Cytosine addition solution Wako Pure Chemical Industries cytosine (015-12303) was used for addition, and a solution was prepared by adding 110 mg of cytosine to 1 mL of purified water.
  • Cytidine addition solution Wako Pure Chemical Industries Cytidine (035-23231) was used for addition, and a solution was prepared by adding 110 mg of cytidine to 1 mL of purified water.
  • Hydroxyurea addition solution Wako Pure Chemical Industries, Ltd. Hydroxyurea (085-06653) was used for addition, and a solution was prepared by adding 110 mg of hydroxyurea to 1 mL of purified water.
  • each blood collection tube in Reference Example 1 and Comparative Examples 1 and 2 was prepared as follows, and the blood glucose level at each elapsed time at room temperature was measured. It was measured.
  • Reference example 1 serum blood collection tube: Comparative sample 1 using serum from which blood cells were removed by adding 200 ⁇ L of physiological saline and 2 mL of whole blood to the blood collection tube for serum (blood collection tube for blood count): 200 ⁇ L of physiological saline and 2 mL of whole blood were added to the blood vessels.
  • Comparative Example 2 Heparin blood collection tube: 200 ⁇ L of physiological saline and 2 mL of whole blood were added to the heparin blood collection tubes.
  • the serum of Reference Example 1 was centrifuged within 5 minutes after blood collection. Then, the blood glucose level was measured over time using a sample obtained by transferring the supernatant (serum) to another Spitz (the blood serum subjected to glycolysis was left at room temperature).
  • the blood glucose level was measured immediately after mixing, the supernatant (plasma) and blood cell layer were mixed and returned to whole blood, added to the blood collection tube, and allowed to stand at room temperature.
  • each blood collection tube in Comparative Examples 3 to 13 is prepared as follows, and the blood glucose level at each elapsed time at room temperature is measured. did.
  • Reference example 2 serum blood collection tube
  • Comparative example 3 blood glucose test blood collection tube
  • serum blood collection tube blood glucose test collection 200 ⁇ L of physiological saline and 2 mL of whole blood were added to the blood vessels.
  • Comparative Example 4 Homemade blood collection tube: 180 ⁇ L of physiological saline, 20 ⁇ L of EDTA-2K added solution and 2 mL of whole blood were added to the homemade blood collection tube.
  • Comparative Example 5 (Mannose 2.2 mg) : Saline 160 ⁇ L, mannose added solution 20 ⁇ L, EDTA-2K added solution 20 ⁇ L and whole blood 2 mL added to homemade blood collection tube
  • Comparative Example 6 (Mannose 4.4 mg): Saline 140 ⁇ L, mannose added solution 40 ⁇ L, homemade blood collection tube Add 20 ⁇ L of EDTA-2K and 2 mL of whole blood Comparative Example 7 (Mannose 6.6 mg): Add 120 ⁇ L of physiological saline, 60 ⁇ L of mannose, 20 ⁇ L of EDTA-2K, and 2 mL of whole blood to homemade blood collection tube Comparative Example 8 (Mannose 8.8mg): 100 ⁇ L of physiological saline in homemade blood collection tube, 80 ⁇ m of mannose added solution L,
  • Comparative Example 12 (citric acid 2.56 mg): 100 ⁇ L of physiological saline, 80 ⁇ L of citric acid added solution, 20 ⁇ L of EDTA-2K added solution and whole blood Add 2 mL Comparative Example 13 (citric acid 5.12 mg): Add 20 ⁇ L of physiological saline, 160 ⁇ L of citric acid added solution, 20 ⁇ L of EDTA-2K added solution, and 2 mL of whole blood to homemade blood collection tube
  • the homemade blood collection tube (Comparative Example 4) showed the same results as the blood collection tube for blood count (Comparative Example 1).
  • Glycolytic inhibitor D-mannose was found to have a positive error in blood glucose levels as the amount of addition was increased, and in addition to the glycolysis inhibitor D-mannose, it was confirmed that the blood glucose level decreased over time.
  • “positive error” means that the blood glucose level is measured as a value larger than the true value.
  • each blood collection tube in Reference Examples 3 to 9 was prepared as described below, and the blood glucose level was measured at each elapsed time at room temperature.
  • Reference Example 3 (Clotting Blood Collection Tubes): 200 ⁇ L of physiological saline and 2 mL of whole blood were added to the blood sampling blood collection tube
  • Reference Example 4 (NADH): Saline 180 ⁇ L, NADH added solution 20 ⁇ L and Add 2 mL of whole blood Reference Example 5
  • Adenosine Add 180 ⁇ L of physiological saline to blood collection tube for blood count, add 20 ⁇ L of adenosine-added solution and 2 mL of whole blood Reference Example 6 (Guanosine): Add 180 mL of physiological saline to blood collection tube for blood count Add 20 ⁇ L of guanosine-added solution and 2 mL of whole blood Reference Example 7 (cytosine): Add 180 ⁇ L of physiological saline, 20
  • Comparative Example 14 blood glucose test blood collection tube: 200 ⁇ L of physiological saline and 2 mL of whole blood were added to the blood glucose test blood collection tube
  • Example 1 physiological saline 160 ⁇ L, phosphate added to the blood glucose test blood collection tube Add 40 ⁇ L of solution (10-fold phosphate) and 2 mL of whole blood
  • Example 2 Blood collection tube for blood glucose test 140 ⁇ L of saline, phosphate-added solution (10-fold phosphate) 60 ⁇ L and whole blood Add 2mL
  • Example 3 Phosphate 8 ⁇ L: Add 160 ⁇ L of physiological saline, 80 ⁇ L of phosphate-added solution (10X phosphoric acid) and 2mL of whole blood to blood
  • each blood collection tube in Comparative Example 15 and Examples 4 to 9 is prepared as follows, and blood glucose at each elapsed time at room temperature. The value was measured.
  • Comparative Example 15 blood glucose test blood collection tube: 200 ⁇ L of physiological saline and 2 mL of whole blood were added to the blood glucose test blood collection tube.
  • Example 4 (phosphate 2 ⁇ L, EDTA-2K): physiological saline 140 ⁇ L to blood glucose test blood collection tube , 20 ⁇ L of phosphate-added solution (10-fold phosphoric acid), 40 ⁇ L of EDTA-2K-added solution and 2 mL of whole blood were added
  • Example 5 (phosphate 4 ⁇ L, EDTA-2K): 120 ⁇ L of physiological saline in a blood glucose test tube 40 ⁇ L of phosphate-added solution (10-fold phosphoric acid), 40 ⁇ L of EDTA-2K-added solution and 2 mL of whole blood were added.
  • Example 6 (phosphate 6 ⁇ L, EDTA-2K): 100 ⁇ L of physiological saline in a blood glucose test tube 60 ⁇ L of acid-added solution (10-fold phosphoric acid), 40 ⁇ L of EDTA-2K-added solution and 2 mL of whole blood were added.
  • Example 7 (8 ⁇ L of phosphate, EDTA-2K): 80 ⁇ L of physiological saline in blood collection tube for blood glucose test Addition solution (10-fold phosphoric acid) 80 ⁇ L, EDTA-2K addition solution 40 ⁇ L and whole blood 2 mL were added.
  • Example 8 (ATP-2Na 12.5 mg): Saline 150 ⁇ L, ATP-2Na addition solution to blood collection tube for blood glucose test 50 Add ⁇ L and 2 mL of whole blood
  • Example 9 (ATP-2Na 25 mg): Add 100 ⁇ L of physiological saline, 100 ⁇ L of ATP-2Na added solution, and 2 mL of whole blood to blood collection tube for blood glucose test
  • Example 10 100 ⁇ L of physiological saline, 100 ⁇ L of ATP-2Na added solution and 2 mL of whole blood were added to a blood collection tube for blood glucose test
  • Example 11 Blood collection tube for blood glucose test 75 ⁇ L of physiological saline, 125 ⁇ L of ATP-2Na added solution and 2 mL of whole blood were added.
  • Example 12 (ATP-2Na 37.5 mg): 50 ⁇ L of physiological saline, 150 ⁇ L of ATP-2Na added solution and 2 mL of whole blood were added to the blood glucose test tube.
  • Addition Example 13 (ATP-2Na 50 mg): Add 200 ⁇ L of ATP-2Na added solution and 2 mL of whole blood to blood collection tube for blood glucose test
  • each blood collection tube in Comparative Examples 16 to 17 and Examples 14 to 19 was prepared as follows, and at each elapsed time at room temperature. The blood glucose level was measured.
  • Comparative Example 16 (Clotting blood collection tube): 200 ⁇ L of physiological saline and 2 mL of whole blood were added to the blood sampling tube.
  • Example 14 (AMP 10 mg): 200 ⁇ L of AMP-added solution and the whole blood sampling tube.
  • Example 15 (ADP-1K 10 mg): 200 ⁇ L of ADP-1K added solution and 2 mL of whole blood were added to the blood collection tube for blood count test
  • Example 16 (ATP-2Na 50 mg): Blood collection tube for blood count test 200 ⁇ L of ATP-2Na added solution and 2 mL of whole blood added Comparative Example 17 (blood collection tube for blood count test): 200 ⁇ L of physiological saline and 2 mL of whole blood were added to the blood glucose test tube
  • Example 17 (AMP 10 mg): Blood glucose test
  • Example 18 (ADP-1K 10 mg): 200 ⁇ L of ADP-1K added solution and 2 mL of whole blood were added to a blood glucose test tube
  • Example 19 (ATP-2Na 50 mg) ) : Add 200 ⁇ L of ATP-2Na added solution and 2mL of whole blood to blood collection tube for blood glucose test
  • ATP-2Na, ADP-1K, and AMP were all confirmed to have a glycolytic inhibitory effect.
  • the effect of inhibiting glycolysis was strong in the order of ATP-2Na, ADP-1K, and AMP.
  • sodium fluoride contained in blood glucose blood collection tubes it was confirmed that the glycolytic inhibitory effect of ATP-2Na, ADP-1K, and AMP became stronger. Hemolysis was not observed in any blood collection tube (Comparative Examples 16-17, Examples 14-19) until at least 8 hours later.
  • Comparative Example 18 blood glucose test blood collection tube: 2 mL of whole blood was added to the blood glucose test blood collection tube Comparative Example 19 (blood glucose test blood collection tube): 200 ⁇ L of physiological saline and 2 mL of whole blood were added to the blood glucose test blood collection tube
  • Example 20 (2 ⁇ L of phosphate): 100 ⁇ L of physiological saline, 20 ⁇ L of phosphate-added solution (10-fold phosphoric acid), 80 ⁇ L of EDTA-2K-added solution, and 2 mL of whole blood are added to a blood glucose test tube.
  • Example 21 (phosphate) 4 ⁇ L): 100 ⁇ L of physiological saline, 40 ⁇ L of phosphate-added solution (10-fold phosphoric acid), 60 ⁇ L of EDTA-2K-added solution and 2 mL of whole blood were added to the blood glucose test tube.
  • Example 22 Blood glucose 100 ⁇ L of physiological saline, 100 ⁇ L of ATP-2Na added solution, and 2 mL of whole blood are added to the blood collection tube for examination
  • Example 23 (ATP-2Na 50 mg): 200 ⁇ L of ATP-2Na added solution and 2 mL of whole blood are added to the blood collection tube for blood glucose testing
  • the specimens in the blood collection tubes of Comparative Examples 18 to 19 and Examples 20 to 23 were measured for HbA1c with Tosoh Corporation automatic glycohemoglobin analyzer HLC-723G9. The results are summarized below.

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Abstract

Provided is a blood collection tube for measuring blood glucose levels and/or blood HbAlc levels, said blood collection tube comprising a tubular body having an upper end provided with an opening and a bottomed lower end along the longitudinal direction and a cap closing the opening at the upper end, wherein at least one member selected from the group consisting of inorganic phosphoric acid and adenosine phosphate is housed in the space inside the tubular body.

Description

採血管Blood collection tube
　本発明は、採血管に関する。 The present invention relates to a blood collection tube.
　血糖値（グルコース値）の測定は、様々な疾患に対する指標として健康診断等に広く用いられ、特に糖尿病の診断に用いられている。しかし、採血された血液に含まれる赤血球内の解糖系酵素によりグルコースが解糖されるため、時間経過により血液中の血糖値は低下する。 Measurement of blood sugar level (glucose level) is widely used in health checkups as an index for various diseases, and is particularly used for diagnosis of diabetes. However, since glucose is broken down by glycolytic enzymes in erythrocytes contained in the collected blood, the blood glucose level in the blood decreases with time.
　これまでにも、解糖阻止作用を有する薬剤を備えた採血管が提案されている。
　例えば、特許文献1には、採血管を用いて採取した血液中の血糖値及び/またはヘモグロビンA1c値の変動を効果的に抑制することができ、血糖値及び/またはヘモグロビンA1c値を安定的に測定することができ、しかも採血直後に冷蔵保存といった煩雑な作業を行う必要がない、採血管及び薬剤組成物を提供することを目的として、血液中の血糖値及び/またはヘモグロビンA1c値を測定するのに用いられる採血管であって、採血管本体と、採血管本体内に収容された薬剤とを備え、該薬剤が、マルトースと、フッ化物塩と、pH調整用酸とを含み、pHが3.0～6.5の範囲とされている液状試薬を含有する/または、更に、乾燥して収容した採血管が開示されている。 Hitherto, blood collection tubes provided with a drug having a glycolytic inhibitory action have been proposed.
For example, in Patent Document 1, fluctuations in blood glucose level and / or hemoglobin A1c value in blood collected using a blood collection tube can be effectively suppressed, and blood glucose level and / or hemoglobin A1c value can be stably stabilized. Measure blood glucose level and / or hemoglobin A1c level in blood for the purpose of providing a blood collection tube and a pharmaceutical composition that can be measured and does not require complicated work such as refrigerated storage immediately after blood collection A blood collection tube used for the treatment, comprising a blood collection tube main body and a drug contained in the blood collection tube main body, the drug containing maltose, a fluoride salt, and a pH adjusting acid, and having a pH of Disclosed is a blood collection tube containing a liquid reagent in the range of 3.0 to 6.5 and / or containing it in a dry state.
　また、特許文献2には、採取された血液の溶血を防止し、しかも、血糖値の低下を効果的に抑制でき、血糖値を安定に測定することを可能とする採血管を提供することを目的として、血液中の血糖値を測定するのに用いられ、所定量の血液が採取される採血管であって、一端が開口し他端が閉塞してなる有底筒状の採血管本体と、採血管本体の内壁に付着されている粒子状の薬剤とを備え、薬剤が解糖阻止剤及び血液抗凝固剤を含む水溶性の薬剤であって、解糖阻止剤が、採取される血液1mL当たり、1～5mgのD-マンノース及びNaF量換算で0.3～1.0mgのフッ化物塩を含み、血液抗凝固剤が、EDTA及び／またはへパリンの少なくとも１種であり、薬剤が、採血管本体の内壁にスプレー塗布し乾燥させることにより粒子状で付着されており、採血管に採取される血液の所定量と等量の水で採血管本体の内壁に付着されている薬剤を溶解した際の水溶液の浸透圧が30～80mOsmの範囲にある、採血管が開示されている。 Patent Document 2 provides a blood collection tube that prevents hemolysis of collected blood and that can effectively suppress a decrease in blood glucose level and that can stably measure the blood glucose level. As a purpose, it is a blood collection tube used to measure a blood glucose level in blood and collects a predetermined amount of blood, and has a bottomed cylindrical blood collection tube body that is open at one end and closed at the other end. And a particulate drug attached to the inner wall of the blood collection tube main body, the drug being a water-soluble drug containing a glycolysis inhibitor and a blood anticoagulant, wherein the glycolysis inhibitor is collected from the blood Contains 1 to 5 mg D-mannose per 1 mL and 0.3 to 1.0 mg fluoride salt in terms of NaF, the blood anticoagulant is at least one of EDTA and / or heparin, and the drug is a blood collection tube It is attached to the inner wall of the main body by spraying and drying. A blood collection tube is disclosed in which the osmotic pressure of an aqueous solution when a drug adhering to the inner wall of the blood collection tube main body is dissolved with water equal to a predetermined amount of blood is 30 to 80 mOsm.
特許第5435797号Patent No. 5435797 特許第5822385号Patent No. 5822385
　しかしながら、特許文献1及び2に開示されるような従来の採血管を用いる場合においては、解糖阻止作用を有する薬剤を採血管内に備えていても、時間経過による血液中の血糖値の低下を防止することには未だ改善の余地がある。また、採血は、様々な医療現場において行われるため、採血から血糖値等の測定まで必ずしも迅速に行うことはできない事情があるため、時間経過自体を少なくすることは難しい。 However, in the case of using a conventional blood collection tube as disclosed in Patent Documents 1 and 2, even if a drug having antiglycolytic action is provided in the blood collection tube, the blood sugar level in the blood is reduced over time. There is still room for improvement in prevention. Moreover, since blood collection is performed at various medical sites, there is a situation in which it is not always possible to quickly perform from blood collection to measurement of a blood sugar level or the like, and therefore it is difficult to reduce the time lapse itself.
　フッ化ナトリウム及びエチレンジアミン四酢酸(EDTA)を含む採血管は現状広く用いられているが、個人差はあるものの、その採血管を用いた場合に採血後の4時間までに血液中の血糖値が約10～20%程度低下することが知られている。 Blood collection tubes containing sodium fluoride and ethylenediaminetetraacetic acid (EDTA) are widely used at present, but there are individual differences, but when using the blood collection tubes, blood glucose levels in the blood will be increased by 4 hours after blood collection. It is known to decrease by about 10-20%.
　よって、従来の採血管を用いて血糖値を測定すると、4時間程度の時間経過によっても、例えば糖尿病患者の血液中の血糖値が低下してしまったがために、糖尿病について陰性と判定されることが数多い（偽陰性）。このように、従来の採血管を用いて血糖値を測定すると、本来は糖尿病について陽性であったにも関わらず陰性と判断されてしまうと、気づかない間に糖尿病の進行が進み重症化してしまう懸念が存在する。 Therefore, when the blood glucose level is measured using a conventional blood collection tube, the blood glucose level in the blood of a diabetic patient has decreased, for example, even after a lapse of about 4 hours. There are many (false negatives). In this way, when blood glucose is measured using a conventional blood collection tube, if it is determined to be negative in spite of being positive for diabetes, the progression of diabetes progresses and becomes severe without realizing it. There are concerns.
　本発明は、採血後の初期段階（例えば、採血後4時間経過後）における血糖値の低下を抑制することのできる、優れた精度で測定可能な採血管を提供することを目的とする。 An object of the present invention is to provide a blood collection tube capable of suppressing a decrease in blood glucose level in an initial stage after blood collection (for example, after 4 hours from blood collection) and capable of measuring with excellent accuracy.
　本発明者らは、採血管に採取した血液におけるグルコースの解糖の進行を抑制するために様々な化合物を検討した結果、無機リン酸やアデノシンリン酸を含有する採血管を用いることにより、採血後の初期段階における血糖値の低下に対する優れた抑制効果を発揮し得ることを見出し、本発明を完成させた。 As a result of examining various compounds for suppressing the progress of glycolysis of glucose in blood collected in a blood collection tube, the present inventors have obtained blood collection by using a blood collection tube containing inorganic phosphate or adenosine phosphate. The present inventors have found that it is possible to exert an excellent inhibitory effect on the lowering of blood glucose level in the later initial stage.
　すなわち、本発明は、以下に示す通りである。
(1)
　開口を有する上端と有底を有する下端とを長手方向に有する筒状体と、
　前記上端の開口を塞ぐ栓と、を備え、
　前記筒状体の内部空間に、無機リン酸及びアデノシンリン酸、並びにこれらの塩からなる群より選択される1種以上を含有する、血液中の血糖値及び／又はHbA1cを測定するための採血管。
(2)
　無機リン酸としてリン酸を含有する、(1)に記載の採血管。
(3)
　採取される血液1mLに対して、無機リン酸を1～5μLの範囲で含有する、(1)又は(2)に記載の採血管。
(4)
　ATP、ADP、及びAMP、並びにこれらの塩からなる群より選択される1種以上のアデノシンリン酸を含有する、(1)～(3)のいずれかに記載の採血管。
(5)
　採取される血液1mLに対して、アデノシンリン酸又はその塩を1～100mgの範囲で含有する、(1)～(4)のいずれかに記載の採血管。
(6)
　フッ化塩をさらに含有する、(1)～(5)のいずれかに記載の採血管。 That is, the present invention is as follows.
(1)
A cylindrical body having an upper end having an opening and a lower end having a bottom in the longitudinal direction;
A plug for closing the opening at the upper end,
Collection for measuring blood glucose level and / or HbA1c in blood containing at least one selected from the group consisting of inorganic phosphate and adenosine phosphate and salts thereof in the internal space of the cylindrical body. Blood vessels.
(2)
The blood collection tube according to (1), which contains phosphoric acid as inorganic phosphoric acid.
(3)
The blood collection tube according to (1) or (2), which contains 1 to 5 μL of inorganic phosphate per 1 mL of collected blood.
(Four)
The blood collection tube according to any one of (1) to (3), which contains one or more types of adenosine phosphate selected from the group consisting of ATP, ADP, and AMP, and salts thereof.
(Five)
The blood collection tube according to any one of (1) to (4), containing 1 to 100 mg of adenosine phosphate or a salt thereof per 1 mL of collected blood.
(6)
The blood collection tube according to any one of (1) to (5), further containing a fluoride salt.
　以下、本発明の採血管及びその具体的な実施形態を説明することにより、本発明を明らかにする。 Hereinafter, the present invention will be clarified by describing the blood collection tube of the present invention and specific embodiments thereof.
（採血管）
　本発明の採血管は、開口を有する上端と有底を有する下端とを長手方向に有する筒状体と、上端の開口を塞ぐ栓とを備える。また、筒状体の内部空間に、無機リン酸及びアデノシンリン酸、並びにこれらの塩からなる群より選択される1種以上（以下、「無機リン酸等」ともいう。）を含有する。 (Blood collection tube)
The blood collection tube of the present invention includes a cylindrical body having an upper end having an opening and a lower end having a bottom in the longitudinal direction, and a plug that closes the opening at the upper end. Further, the internal space of the cylindrical body contains one or more selected from the group consisting of inorganic phosphoric acid, adenosine phosphoric acid, and salts thereof (hereinafter also referred to as “inorganic phosphoric acid etc.”).
（筒状体）
　開口を有する上端と有底を有する下端とは、筒状体の長手方向の両端部であり、採血管の使用時に、上端は地面に対して下端よりも上部に位置して、開口から血液を採取し、下端は地面に対して上端よりも下部に位置し、採取された血液を有底で受け止める。また、筒状体は、その断面が環状であることが好ましい。断面が環状とは、断面が円形又は略円形であればよい。 (Tubular body)
The upper end having an opening and the lower end having a bottom are both ends in the longitudinal direction of the cylindrical body.When the blood collection tube is used, the upper end is located above the lower end with respect to the ground so that blood can be drawn from the opening. The lower end is located below the upper end with respect to the ground, and the collected blood is received with a bottom. Moreover, it is preferable that the cross section of a cylindrical body is cyclic | annular. The cross section is circular as long as the cross section is circular or substantially circular.
　筒状体の素材としては、特に限定されないが、例えばガラスや、ポリエチレンテレフタラート等のプラスチックが挙げられる。内部の状態を視認可能とするため、好ましくは無色透明の素材が好ましい。 The material of the cylindrical body is not particularly limited, and examples thereof include glass and plastics such as polyethylene terephthalate. In order to make the internal state visible, a colorless and transparent material is preferable.
　筒状体の上端の開口を塞ぐ栓としては、特に限定されないが、例えばゴム栓、及びフィルム栓が挙げられる。また、採血管において、栓が筒状体の上端の開口を塞いでおり、筒状体の内部空間が減圧されていることが好ましい。筒状体の内部空間が減圧されていることにより、採血管への採血が容易になる傾向にある。減圧は、採血量、栓による筒状体の内部空間の密封度に応じて適宜設定できる。 The plug that closes the opening at the upper end of the cylindrical body is not particularly limited, and examples thereof include a rubber plug and a film plug. Further, in the blood collection tube, it is preferable that the stopper closes the opening at the upper end of the cylindrical body, and the internal space of the cylindrical body is decompressed. Since the internal space of the cylindrical body is depressurized, blood collection tends to be easy. The reduced pressure can be appropriately set according to the amount of blood collected and the degree of sealing of the internal space of the cylindrical body by the stopper.
　本発明では、無機リン酸等を含有する筒状体の内部空間の位置は、筒状体の上端よりも下端側であることが、採血した血液が無機リン酸等に対して接触することが容易であるため好ましい。 In the present invention, the position of the internal space of the cylindrical body containing inorganic phosphate or the like is located on the lower end side of the upper end of the cylindrical body, so that the collected blood may come into contact with the inorganic phosphate or the like. It is preferable because it is easy.
（無機リン酸、アデノシンリン酸）
　筒状体の内部空間に無機リン酸等を含有させるためには、例えば上端の開口から溶液とした無機リン酸等を添加すればよく、その後に溶液中の溶媒を乾燥させれば、固体状の形態で筒状体の内部に無機リン酸等を含有させることができる。無機リン酸等は、取扱い性の観点から、水溶液とすることが好ましい。 (Inorganic phosphate, adenosine phosphate)
In order to contain inorganic phosphoric acid or the like in the internal space of the cylindrical body, for example, inorganic phosphoric acid or the like made into a solution may be added from the opening at the upper end, and then the solvent in the solution is dried to obtain a solid state. An inorganic phosphoric acid etc. can be contained in the inside of a cylindrical body with this form. Inorganic phosphoric acid or the like is preferably an aqueous solution from the viewpoint of handleability.
　無機リン酸等を添加する方法は、特に限定されず、例えば、水溶液とした無機リン酸等をスポイトで滴下することや、スプレー塗布装置によってスプレーすることが挙げられる。 The method of adding inorganic phosphoric acid or the like is not particularly limited, and examples thereof include dropping inorganic phosphoric acid or the like in an aqueous solution with a dropper or spraying with a spray coating apparatus.
　本発明の無機リン酸及びその塩としては、リン酸、亜リン酸、次亜リン酸及びそれらの塩が挙げられ、リン酸、亜リン酸及び次亜リン酸が好ましく、リン酸がより好ましい。これらは1種を単独で又は2種以上を組み合わせて用いることができる。 Examples of the inorganic phosphoric acid and salts thereof of the present invention include phosphoric acid, phosphorous acid, hypophosphorous acid and salts thereof, phosphoric acid, phosphorous acid and hypophosphorous acid are preferred, and phosphoric acid is more preferred. . These can be used singly or in combination of two or more.
　無機リン酸の塩としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられ、アルカリ金属塩が好ましく、ナトリウム塩がより好ましい。 Examples of the inorganic phosphoric acid salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, alkali metal salts are preferable, and sodium salts are more preferable.
　無機リン酸又はその塩を含有する場合には、採取される血液1mLに対して、無機リン酸又はその塩を0.1～50μLの範囲で含有することが好ましく、0.5～20μLの範囲で含有することがより好ましく、1～5μLの範囲で含有することがさらに好ましく、2.5～5μLの範囲で含有することがよりさらに好ましい。 When inorganic phosphoric acid or a salt thereof is contained, it is preferable to contain inorganic phosphoric acid or a salt thereof in a range of 0.1 to 50 μL, and 0.5 to 20 μL per 1 mL of collected blood. More preferably, it is more preferably contained in the range of 1 to 5 μL, and still more preferably contained in the range of 2.5 to 5 μL.
　本発明のアデノシンリン酸及びその塩としては、ATP（Adenosine TriPhosphate）、ADP（Adenosine DiPhosphate）、AMP（Adenosine MonoPhosphate）及びこれらの塩が挙げられ、ATP及びその塩が好ましい。これらは1種を単独で又は2種以上を組み合わせて用いることができる。 Examples of adenosine phosphoric acid and salts thereof of the present invention include ATP (Adenosine TriPhosphate), ADP (Adenosine DiPhosphate), AMP (Adenosine MonoPhosphate) and salts thereof, and ATP and its salts are preferred. These can be used singly or in combination of two or more.
　アデノシンリン酸の塩としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられ、アルカリ金属塩が好ましく、ナトリウム塩がより好ましい。
　ATPの塩としては、二ナトリウム塩であることが好適である。
　上記で無機リン酸等の塩として挙げたアルカリ金属、アルカリ土類金属塩等の塩種は、後述するフッ化塩、pH調整用酸及び抗血液凝固剤の塩種としても、同様に適用可能である。 Examples of the salt of adenosine phosphate include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, alkali metal salts are preferable, and sodium salts are more preferable.
The salt of ATP is preferably a disodium salt.
The salt species such as alkali metals and alkaline earth metal salts mentioned above as salts of inorganic phosphoric acid can be similarly applied to the fluoride salt, acid for pH adjustment, and salt species of anticoagulant described later. It is.
　アデノシンリン酸又はその塩を含有する場合には、採取される血液1mLに対して、アデノシンリン酸又はその塩を0.1～1000mgの範囲で含有することが好ましく、0.5～200mgの範囲で含有することがより好ましく、1～100mgの範囲で含有することがさらに好ましく、5～50mgの範囲で含有することがよりさらに好ましく、10～20mgの範囲で含有することがさらにより好ましく、12～17mgの範囲で含有することが極めて好ましい。アデノシンリン酸又はその塩を0.1mg以上含有することにより、採血後の初期段階における血糖値の低下を確実に抑制することができる傾向にある。アデノシンリン酸又はその塩を1000mg以下含有することにより、血糖値の測定における誤差を抑制することができる傾向にある。 When adenosine phosphate or a salt thereof is contained, it is preferable to contain adenosine phosphate or a salt thereof in the range of 0.1 to 1000 mg, and 0.5 to 200 mg per 1 mL of collected blood. More preferably, it is contained in the range of 1 to 100 mg, more preferably in the range of 5 to 50 mg, still more preferably in the range of 10 to 20 mg, and in the range of 12 to 17 mg. It is very preferable to contain. By containing 0.1 mg or more of adenosine phosphoric acid or a salt thereof, a decrease in blood glucose level in the initial stage after blood collection tends to be reliably suppressed. By containing 1000 mg or less of adenosine phosphoric acid or a salt thereof, there is a tendency that errors in blood glucose level measurement can be suppressed.
　本発明の採血管は、無機リン酸又はその塩、及びアデノシンリン酸又はその塩を同時に含有してもよく、いずれかのみを含有してもよい。 The blood collection tube of the present invention may contain inorganic phosphoric acid or a salt thereof, and adenosine phosphoric acid or a salt thereof at the same time, or may contain only one of them.
　採血管は、必要に応じて、無機リン酸等以外にも採血管に用いられる公知の成分を含有することができる。特に、公知の解糖阻止剤として、無機リン酸等以外の解糖系を阻止する作用を有する物質（フッ化塩、D-マンノース、モノヨード酢酸等）を、無機リン酸等と併用することにより、採血後における血糖値の低下をさらに抑制することや、採血後の初期段階以降（例えば、採血後4時間超～24時間経過後）における血糖値の低下をもより抑制することができる。これらは1種を単独で又は2種以上を組み合わせて用いることができる。特に、採血管は、フッ化塩をさらに含有することが好ましい。 The blood collection tube can contain known components used for blood collection tubes in addition to inorganic phosphoric acid and the like, if necessary. In particular, as a known glycolysis inhibitor, a substance having an action of inhibiting glycolysis other than inorganic phosphoric acid (fluoride, D-mannose, monoiodoacetic acid, etc.) is used in combination with inorganic phosphoric acid, etc. Further, it is possible to further suppress a decrease in blood glucose level after blood collection, and to further suppress a decrease in blood glucose level after the initial stage after blood collection (for example, after more than 4 hours to 24 hours have elapsed after blood collection). These can be used singly or in combination of two or more. In particular, the blood collection tube preferably further contains a fluoride salt.
　フッ化塩としては、特に限定されないが、例えばフッ化ナトリウム及びフッ化カリウムが挙げられ、フッ化ナトリウムが好ましい。これらは1種を単独で又は2種以上を組み合わせて用いることができる。 The fluoride salt is not particularly limited, and examples thereof include sodium fluoride and potassium fluoride, and sodium fluoride is preferable. These can be used singly or in combination of two or more.
　フッ化塩を含有する場合には、採取される血液1mLに対して、フッ化塩を0.2～3.0mgの範囲で含有することが好ましく、1.0～2.5mgの範囲で含有することがより好ましく1.5～2.0mgの範囲で含有することがさらに好ましい。 When the fluoride salt is contained, the fluoride salt is preferably contained in the range of 0.2 to 3.0 mg, more preferably in the range of 1.0 to 2.5 mg per 1 mL of collected blood. More preferably, it is contained in the range of -2.0 mg.
　採血管は、pH調整剤をさらに含有してもよい。例えば採血した血液中の赤血球の代謝を抑制するためにpH調整用酸をさらに含有してもよく、また例えば採血した血液の溶血（pHが4以下であると生じる場合がある。）を阻害するためにpH調整用酸をさらに含有してもよく、pH調整用塩基をさらに含有してもよい。当然、赤血球の代謝や溶血が抑制されるpHの領域内にある場合には、pH調整剤をさらに含有せずともよい。 The blood collection tube may further contain a pH adjuster. For example, an acid for adjusting pH may be further contained in order to suppress metabolism of red blood cells in the collected blood, and for example, hemolysis of the collected blood (which may occur when the pH is 4 or less) is inhibited. Therefore, an acid for pH adjustment may be further contained, and a base for pH adjustment may further be contained. Of course, when it is in the pH range where the metabolism and hemolysis of red blood cells are suppressed, it is not necessary to further contain a pH adjusting agent.
　pH調整用酸としては、特に限定されないが、例えばエチレンジアミン四酢酸（EDTA）、クエン酸、コハク酸及びそれらの塩が挙げられ、EDTAの塩（ナトリウム塩、カリウム塩）がpH調整の機能だけでなくキレート形成の機能を有する観点から好ましく、クエン酸及びその塩も好ましい。これらは1種を単独で又は2種以上を組み合わせて用いることができる。 The acid for adjusting the pH is not particularly limited, and examples thereof include ethylenediaminetetraacetic acid (EDTA), citric acid, succinic acid and salts thereof. The salt of EDTA (sodium salt, potassium salt) can be used only for adjusting pH. From the viewpoint of having a chelate-forming function, citric acid and salts thereof are also preferable. These can be used singly or in combination of two or more.
　採血管は、採血した血液の溶血をより直接的に阻害するために、抗血液凝固剤をさらに含有してもよい。抗血液凝固剤は、公知の抗血液凝固剤を利用することが可能であり、特に限定されないが、ヘパリン及びその塩が好ましい。これらは1種を単独で又は2種以上を組み合わせて用いることができる。 The blood collection tube may further contain an anticoagulant in order to more directly inhibit hemolysis of the collected blood. As the anticoagulant, a known anticoagulant can be used, and is not particularly limited, but heparin and a salt thereof are preferable. These can be used singly or in combination of two or more.
　無機リン酸等を水溶液とする場合における水溶液は、溶血抑制等の血液成分の安定性の観点から、生理食塩水を用いた水溶液であることが好ましい。 In the case where inorganic phosphoric acid or the like is used as an aqueous solution, the aqueous solution is preferably an aqueous solution using physiological saline from the viewpoint of stability of blood components such as hemolysis suppression.
（用途）
　本発明の採血管は、血液中の血糖値及び／又はHbA1c（Hemoglobin A1c）を測定するために用いられ、採血後の初期段階（例えば、採血後4時間経過後）における血糖値の低下を抑制することのできる以外にも、HbA1cの変動も抑制することができる。また、血糖値の正誤差等の誤差が生じることも抑制し、優れた精度で測定可能である。 (Use)
The blood collection tube of the present invention is used to measure blood glucose level and / or HbA1c (Hemoglobin A1c) in blood, and suppresses a decrease in blood glucose level in the initial stage after blood collection (for example, 4 hours after blood collection). In addition to being able to do so, fluctuations in HbA1c can also be suppressed. Further, it is possible to measure with excellent accuracy by suppressing the occurrence of errors such as a positive error in blood glucose level.
　以下に示す実施例に基づき、本発明をさらに詳しく説明するが、これらの実施例は、特許請求の範囲に記載した本発明の範囲を制限するものではない。 The present invention will be described in more detail based on the following examples, but these examples do not limit the scope of the present invention described in the claims.
　参考例、実施例及び比較例に用いる採血管及び試薬は、下記のように準備した。なお、各採血管には、生理食塩水や自家製で調製した各種添加溶液（EDTA-2K、フッ化ナトリウム(NaF)、マンノース、3.2%クエン酸溶液、リン酸、モノヨード酢酸、ATP-2Na、NADH、アデノシン、グアノシン、シトシン、シチジン、ヒドロキシウレア、ADP-1K、AMP）を下記実験で示す種類及び量で添加し、それらの合計した溶液量が一定となるように設定し、血液の希釈率を一定条件に揃えた。また、血液の遠心操作は、特に断らない限りは3000rpm(1710g)で3分間遠心した。
　採血管：血糖測定に用いられている積水メディカル株式会社のインセパック（登録商標）II血糖検査用採血管（453557: 12.7×75.6mm EDTA-2K+NaF）を使用した（以下、「血糖検査用採血管」という。）。
　血清用採血管：積水メディカル株式会社のインセパック（登録商標）II-D高速凝固タイプ採血管(473470: 12.7×75.6mm 高速凝固促進剤・分離剤入り)を使用し、解糖が始まらないよう採血後5分以内に遠心を行い、その上清（血清）を用いることで解糖を行う血球と分離した。その血清を比較対照（測定機器自体の状態変化による血糖変動がないことを確認する指標）として使用した。
　血算用採血管：ニプロ株式会社の血液学検査(EK)〈EDTA-2K〉用採血管(NP-EK0255-2: 12.8×75mm EDTA-2K顆粒)を使用し解糖阻止剤（無機リン酸、アデノシンリン酸、マンノース、クエン酸、モノヨード酢酸等の解糖系を阻止する作用を有する物質）を含まない場合の比較対照として使用した。
　ヘパリン採血管：テルモ株式会社のベノジェクトII真空採血管　ヘパリン用採血管(VP-H050K: 13.2×78mm ヘパリンナトリウム)を使用し解糖阻止剤を含まない場合の比較対照として使用した。
　自家製採血管：東洋器材科学株式会社のYSチューブ7号(14910)に自家製で調製した下記の各種添加溶液（EDTA-2K添加溶液、フッ化ナトリウム(NaF)添加溶液、マンノース添加溶液、クエン酸添加溶液、リン酸添加溶液、モノヨード酢酸添加溶液、ATP添加溶液）を下記実験で示す種類及び量で添加し、使用した。
　EDTA-2K添加溶液：添加用として和光純薬工業　EDTA-2K (340-01511)を使用し、EDTA-2K 110mgを精製水1mLに添加した溶液を調製した。
　マンノース添加溶液：添加用として和光純薬工業　D-マンノース (130-00872)を使用し、D-マンノース 110mgを精製水1mLに添加した溶液を調製した。
　クエン酸添加溶液：武藤化学株式会社3.2%クエン酸溶液(86231)を使用した。
　リン酸添加溶液：添加用として和光純薬工業　リン酸 (164-02176)を使用し、精製水で10倍に希釈に添加した溶液を調製した。
　モノヨード酢酸添加溶液：添加用として和光純薬工業　ヨード酢酸 (91-00492)を使用し、モノヨード酢酸110mgを精製水1mLに添加した溶液を調製した。
　ATP-2Na添加溶液：添加用としてオリエンタル酵母工業株式会社　アデノシン-5'-三リン酸二ナトリウム（309-50513）を使用し、ATP-2Na 250mgに対し精製水1mLに添加した溶液を調製した。
　ADP-1K添加溶液：添加用として和光純薬工業　アデノシン 5'-二リン酸一カリウム (303-50751)を使用し、ADP-1K 50mgを精製水1mLに添加した溶液を調製した。
　AMP添加溶液：添加用として和光純薬工業　アデノシン 5'-一リン酸(303-50491)を使用し、AMP 50mgを精製水1mLに添加した溶液を調製した。
　NADH添加溶液：添加用として和光純薬工業　β-ジホスホピリジンヌクレオチド二ナトリウム (046-16231)を使用し、NADH 110mgを精製水1mLに添加した溶液を作成した。
　アデノシン添加溶液：添加用として和光純薬工業　アデノシン (015-24591)を使用し、アデノシン 110mgを精製水1mLに添加した溶液を調製した。
　グアノシン添加溶液：添加用として東京化学工業　グアノシン (015-12303)を使用し、グアノシン 110mgを精製水1mLに添加した溶液を調製した。
　シトシン添加溶液：添加用として和光純薬工業　シトシン (015-12303)を使用し、シトシン 110mgを精製水1mLに添加した溶液を調製した。
　シチジン添加溶液：添加用として和光純薬工業　シチジン (035-23231)を使用し、シチジン 110mgを精製水1mLに添加した溶液を調製した。
　ヒドロキシウレア添加溶液：添加用として和光純薬工業　ヒドロキシ尿素 (085-06653)を使用し、ヒドロキシウレア 110mgを精製水1mLに添加した溶液を調製した。 Blood collection tubes and reagents used in Reference Examples, Examples and Comparative Examples were prepared as follows. In addition, each blood collection tube contains physiological saline and various home-made additive solutions (EDTA-2K, sodium fluoride (NaF), mannose, 3.2% citric acid solution, phosphoric acid, monoiodoacetic acid, ATP-2Na, NADH , Adenosine, guanosine, cytosine, cytidine, hydroxyurea, ADP-1K, AMP) are added in the types and amounts shown in the experiment below, and the total solution volume is set to be constant, and the blood dilution rate is set. Aligned to certain conditions. In addition, blood centrifugation was performed at 3000 rpm (1710 g) for 3 minutes unless otherwise specified.
Blood collection tube: Sekisui Medical Co., Ltd. II blood collection tube for blood glucose test (453557: 12.7 × 75.6mm EDTA-2K + NaF) used for blood glucose measurement was used. Called blood vessels.)
Blood collection tube for serum: Blood collection using Sekisui Medical Co., Ltd. Insepack (registered trademark) II-D high-speed coagulation type blood collection tube (473470: 12.7 × 75.6mm with high-speed coagulation accelerator / separator) Centrifugation was performed within 5 minutes, and the supernatant (serum) was used to separate blood cells for glycolysis. The serum was used as a comparative control (an index for confirming that there was no blood glucose fluctuation due to a change in the state of the measuring device itself).
Blood collection tubes for blood count: Antiglycolytic agents (inorganic phosphate) using blood collection tubes (NP-EK0255-2: 12.8 × 75mm EDTA-2K granules) for hematology test (EK) <EDTA-2K> from Nipro Corporation , Adenosine phosphate, mannose, citric acid, monoiodoacetic acid and other substances having an action to block the glycolytic system) were used as comparative controls.
Heparin blood collection tube: Terumo Corporation Venoject II vacuum blood collection tube A heparin blood collection tube (VP-H050K: 13.2 × 78 mm sodium heparin) was used as a comparative control when no glycolysis inhibitor was contained.
Homemade blood collection tubes: Various additive solutions (EDTA-2K additive solution, sodium fluoride (NaF) additive solution, mannose additive solution, citric acid additive) prepared in-house on YS Tube No. 7 (14910) of Toyo Equipment Science Co., Ltd. Solution, phosphoric acid addition solution, monoiodoacetic acid addition solution, ATP addition solution) were added and used in the types and amounts shown in the following experiment.
EDTA-2K addition solution: Wako Pure Chemical Industries EDTA-2K (340-01511) was used for addition, and a solution was prepared by adding 110 mg of EDTA-2K to 1 mL of purified water.
Mannose added solution: Wako Pure Chemical Industries D-mannose (130-00872) was used for addition, and a solution was prepared by adding 110 mg of D-mannose to 1 mL of purified water.
Citric acid added solution: Muto Chemical Co., Ltd. 3.2% citric acid solution (86231) was used.
Phosphoric acid addition solution: Wako Pure Chemical Industries, Ltd. Phosphoric acid (164-02176) was used for addition, and a solution was prepared that was diluted 10 times with purified water.
Monoiodoacetic acid addition solution: Wako Pure Chemical Industries, Ltd. Iodoacetic acid (91-00492) was used for addition, and a solution was prepared by adding 110 mg of monoiodoacetic acid to 1 mL of purified water.
ATP-2Na addition solution: Oriental Yeast Co., Ltd. Adenosine-5′-triphosphate disodium (309-50513) was used for addition, and a solution was prepared by adding 250 mg of ATP-2Na to 1 mL of purified water.
ADP-1K addition solution: Wako Pure Chemical Industries, Ltd. Adenosine 5′-dipotassium monophosphate (303-50751) was used for addition, and a solution was prepared by adding 50 mg of ADP-1K to 1 mL of purified water.
AMP addition solution: Wako Pure Chemical Industries Adenosine 5'-monophosphate (303-50491) was used for addition, and a solution was prepared by adding 50 mg of AMP to 1 mL of purified water.
NADH addition solution: Wako Pure Chemical Industries β-diphosphopyridine nucleotide disodium (046-16231) was used for addition, and a solution was prepared by adding 110 mg of NADH to 1 mL of purified water.
Adenosine addition solution: Wako Pure Chemical Industries Adenosine (015-24591) was used for addition, and a solution in which 110 mg of adenosine was added to 1 mL of purified water was prepared.
Guanosine addition solution: Tokyo Chemical Industry Guanosine (015-12303) was used for addition, and a solution was prepared by adding 110 mg of guanosine to 1 mL of purified water.
Cytosine addition solution: Wako Pure Chemical Industries cytosine (015-12303) was used for addition, and a solution was prepared by adding 110 mg of cytosine to 1 mL of purified water.
Cytidine addition solution: Wako Pure Chemical Industries Cytidine (035-23231) was used for addition, and a solution was prepared by adding 110 mg of cytidine to 1 mL of purified water.
Hydroxyurea addition solution: Wako Pure Chemical Industries, Ltd. Hydroxyurea (085-06653) was used for addition, and a solution was prepared by adding 110 mg of hydroxyurea to 1 mL of purified water.
実験方法
　血糖の測定にはアークレイ株式会社　アダムス グルコース ＧＡ-1171を使用した。
　血清に関しては採血後5分以内に遠心分離して、その上清（血清）を別のスピッツに移したものを検体として継時的に血糖値を測定した（解糖を行う血球は除去した血清を室温放置した。）。
　血清以外の採血管に関しては、遠心分離して血球と上清（血漿）とを分け、分けた上清（血漿）を血糖値の測定に用いた。また測定後には速やかに上清（血漿）と血球との混和を行い、全血に戻してから採血管に添加し、室温に放置した。 Experimental Method For measurement of blood glucose, ARKRAY, Inc. Adams Glucose GA-1171 was used.
Serum was centrifuged within 5 minutes after blood collection, and the supernatant (serum) was transferred to another Spitz sample, and blood glucose was measured over time (serum from which blood cells to be glycosylated were removed). Was allowed to stand at room temperature).
For blood collection tubes other than serum, the blood cells and the supernatant (plasma) were separated by centrifugation, and the separated supernatant (plasma) was used for the measurement of blood glucose level. After the measurement, the supernatant (plasma) and blood cells were immediately mixed, returned to whole blood, added to the blood collection tube, and allowed to stand at room temperature.
［実験1］血糖検査用採血管の解糖阻止効果
　以下、参考例1及び比較例1～2における各採血管は、下記のように準備し、室温放置下での各経過時間における血糖値を測定した。
　参考例1（血清用採血管）：血清用採血管に生理食塩水200μLと全血2mLを添加し、血球を除去した血清を用いた
　比較例1 (血算用採血管)：血算用採血管に生理食塩水200μLと全血2mLを添加
　比較例2 (ヘパリン採血管)：ヘパリン採血管に生理食塩水200μLと全血2mLを添加
　参考例1の血清に関しては採血後5分以内に遠心分離して、その上清（血清）を別のスピッツに移したものを検体として継時的に血糖値を測定した（解糖を行う血球は除去した血清を室温放置した。）。
　比較例1～2は血糖値の測定後は速やかに混和を行い上清（血漿）と血球層を混ぜ全血に戻してから採血管に添加し、室温に放置した。 [Experiment 1] Glycolysis inhibitory effect of blood collection tube for blood glucose test In the following, each blood collection tube in Reference Example 1 and Comparative Examples 1 and 2 was prepared as follows, and the blood glucose level at each elapsed time at room temperature was measured. It was measured.
Reference example 1 (serum blood collection tube): Comparative sample 1 using serum from which blood cells were removed by adding 200 μL of physiological saline and 2 mL of whole blood to the blood collection tube for serum (blood collection tube for blood count): 200 μL of physiological saline and 2 mL of whole blood were added to the blood vessels. Comparative Example 2 (Heparin blood collection tube): 200 μL of physiological saline and 2 mL of whole blood were added to the heparin blood collection tubes. The serum of Reference Example 1 was centrifuged within 5 minutes after blood collection. Then, the blood glucose level was measured over time using a sample obtained by transferring the supernatant (serum) to another Spitz (the blood serum subjected to glycolysis was left at room temperature).
In Comparative Examples 1 and 2, the blood glucose level was measured immediately after mixing, the supernatant (plasma) and blood cell layer were mixed and returned to whole blood, added to the blood collection tube, and allowed to stand at room temperature.
実験1結果
Figure JPOXMLDOC01-appb-T000001
 血糖値　単位mg/dL Experiment 1 results
Figure JPOXMLDOC01-appb-T000001
 Blood glucose level mg / dL
　血球を除去した解糖が起こらない状態（参考例1）では血糖値の経時的な変動は認められず、測定装置自体の誤差による血糖値変動も認められなかった。
　解糖阻止剤の入っていない比較例1～2の採血管では血糖値が継時的に大きく減少し、明らかに解糖が経時的に進んでいることが確認された。 In the state where glycolysis without removing blood cells did not occur (Reference Example 1), no change in blood glucose level over time was observed, and no change in blood glucose level due to errors in the measuring device itself was observed.
In the blood collection tubes of Comparative Examples 1 and 2 that did not contain a glycolysis inhibitor, the blood glucose level significantly decreased over time, and it was confirmed that glycolysis progressed with time.
［実験2］解糖阻止効果が従来報告されている物質の検証
　以下、比較例3～13における各採血管は、下記のように準備し、室温放置下での各経過時間における血糖値を測定した。
　参考例2 (血清用採血管)：血清用採血管に生理食塩水200μLと全血2mLを添加し、血球を除去した血清を用いた
　比較例3 (血糖検査用採血管)：血糖検査用採血管に生理食塩水200μLと全血2mLを添加
　比較例4 (自家製採血管)：自家製採血管に生理食塩水180μL、EDTA-2K添加溶液20μLおよび全血2mLを添加
　比較例5 (マンノース2.2mg)：自家製採血管に生理食塩水160μL、マンノース添加溶液20μL、EDTA-2K添加溶液20μLおよび全血2mLを添加
　比較例6 (マンノース4.4mg)：自家製採血管に生理食塩水140μL、マンノース添加溶液40μL、EDTA-2K添加溶液20μLおよび全血2mLを添加
　比較例7 (マンノース6.6mg)：自家製採血管に生理食塩水120μL、マンノース添加溶液60μL、EDTA-2K添加溶液20μLおよび全血2mLを添加
　比較例8 (マンノース8.8mg)：自家製採血管に生理食塩水100μL、マンノース添加溶液80μL、EDTA-2K添加溶液20μLおよび全血2mLを添加
　比較例9 (マンノース11mg)：自家製採血管に生理食塩水80μL、マンノース添加溶液100μL、EDTA-2K添加溶液20μLおよび全血2mLを添加
　比較例10 (モノヨード酢酸11mg)：自家製採血管に生理食塩水80μL、モノヨード酢酸添加溶液100μL、EDTA-2K添加溶液20μLおよび全血2mLを添加
　比較例11 (モノヨード酢酸16.5mg)：自家製採血管にモノヨード酢酸添加溶液150μL、EDTA-2K添加溶液20μLおよび全血2mLを添加
　比較例12 (クエン酸2.56mg)：自家製採血管に生理食塩水100μL、クエン酸添加溶液80μL、EDTA-2K添加溶液20μLおよび全血2mLを添加
　比較例13 (クエン酸5.12mg)：自家製採血管に生理食塩水20μL、クエン酸添加溶液160μL 、EDTA-2K添加溶液20μLおよび全血2mLを添加 [Experiment 2] Verification of substances for which glycolysis inhibitory effect has been reported conventionally In the following, each blood collection tube in Comparative Examples 3 to 13 is prepared as follows, and the blood glucose level at each elapsed time at room temperature is measured. did.
Reference example 2 (serum blood collection tube): Comparative example 3 (blood glucose test blood collection tube) using serum from which blood cells were removed by adding 200 μL of physiological saline and 2 mL of whole blood to the serum blood collection tube: blood glucose test collection 200 μL of physiological saline and 2 mL of whole blood were added to the blood vessels. Comparative Example 4 (Homemade blood collection tube): 180 μL of physiological saline, 20 μL of EDTA-2K added solution and 2 mL of whole blood were added to the homemade blood collection tube. Comparative Example 5 (Mannose 2.2 mg) : Saline 160 μL, mannose added solution 20 μL, EDTA-2K added solution 20 μL and whole blood 2 mL added to homemade blood collection tube Comparative Example 6 (Mannose 4.4 mg): Saline 140 μL, mannose added solution 40 μL, homemade blood collection tube Add 20 μL of EDTA-2K and 2 mL of whole blood Comparative Example 7 (Mannose 6.6 mg): Add 120 μL of physiological saline, 60 μL of mannose, 20 μL of EDTA-2K, and 2 mL of whole blood to homemade blood collection tube Comparative Example 8 (Mannose 8.8mg): 100 μL of physiological saline in homemade blood collection tube, 80 μm of mannose added solution L, 20 μL of EDTA-2K added solution and 2 mL of whole blood were added. Comparative Example 9 (Mannose 11 mg): 80 μL of physiological saline, 100 μL of mannose added solution, 20 μL of EDTA-2K added solution, and 2 mL of whole blood were added to the homemade blood collection tube. 10 (monoiodoacetic acid 11 mg): 80 μL of physiological saline added to home-made blood collection tube, 100 μL of monoiodoacetic acid addition solution, 20 μL of EDTA-2K addition solution and 2 mL of whole blood Comparative Example 11 (monoiodoacetic acid 16.5 mg) 150 μL of added solution, 20 μL of EDTA-2K added solution and 2 mL of whole blood were added. Comparative Example 12 (citric acid 2.56 mg): 100 μL of physiological saline, 80 μL of citric acid added solution, 20 μL of EDTA-2K added solution and whole blood Add 2 mL Comparative Example 13 (citric acid 5.12 mg): Add 20 μL of physiological saline, 160 μL of citric acid added solution, 20 μL of EDTA-2K added solution, and 2 mL of whole blood to homemade blood collection tube
実験2結果
Figure JPOXMLDOC01-appb-T000002
 血糖値　単位mg/dL Experiment 2 results
Figure JPOXMLDOC01-appb-T000002
 Blood glucose level mg / dL
　自家製採血管（比較例4）は血算用採血管（比較例1）と同様な成績を示した。
　解糖阻止剤D-マンノースはその添加量の増量に従い血糖値に正誤差が生じることが認められ、さらに解糖阻止剤D-マンノースを添加した系では継時的な血糖値の低下が確認された（比較例5～9）。ここで、「正誤差」とは、血糖値が真の値よりも大きい値として測定されることを意味する。例えば本実験における採血直後（経過時間0時間）の真の値が112 mg/dLであるとすれば、D-マンノースの添加量が大きい比較例7～9における採血直後の測定値は+4 mg/dLの誤差を確認できる。
　モノヨード酢酸を含有する採血管では激しい溶血が確認され、モノヨード酢酸による酸性化の影響から血球の破壊が確認された（比較例10～11）。また、解糖阻止効果も血糖検査用採血管とほぼ同等であった。
　クエン酸添加の採血管（比較例12～13）において溶血は認められなかったが、解糖阻止効果も認められなかった。 The homemade blood collection tube (Comparative Example 4) showed the same results as the blood collection tube for blood count (Comparative Example 1).
Glycolytic inhibitor D-mannose was found to have a positive error in blood glucose levels as the amount of addition was increased, and in addition to the glycolysis inhibitor D-mannose, it was confirmed that the blood glucose level decreased over time. (Comparative Examples 5 to 9). Here, “positive error” means that the blood glucose level is measured as a value larger than the true value. For example, if the true value immediately after blood collection in this experiment (elapsed time 0 hour) is 112 mg / dL, the measured value immediately after blood collection in Comparative Examples 7 to 9 in which the amount of D-mannose added is large is +4 mg The error of / dL can be confirmed.
Vigorous hemolysis was confirmed in blood collection tubes containing monoiodoacetic acid, and destruction of blood cells was confirmed due to the effect of acidification by monoiodoacetic acid (Comparative Examples 10 to 11). In addition, the antiglycolytic effect was almost the same as that of blood collection tubes.
Although hemolysis was not observed in the citric acid-added blood collection tubes (Comparative Examples 12 to 13), no antiglycolytic effect was observed.
［実験3］核酸類似物質添加効果
　以下、参考例3～9における各採血管は、下記のように準備し、室温放置下での各経過時間における血糖値を測定した。
　参考例3 (血算用採血管)：血算用採血管に生理食塩水200μLと全血2mLを添加
　参考例4 (NADH)：血算用採血管に生理食塩水180μL、NADH添加溶液20μLおよび全血2mLを添加
　参考例5 (アデノシン)：血算用採血管に生理食塩水180μL、アデノシン添加溶液20μLおよび全血2mLを添加
　参考例6 (グアノシン)：血算用採血管に生理食塩水180μL、グアノシン添加溶液20μLおよび全血2mLを添加
　参考例7 (シトシン)：血算用採血管に生理食塩水180μL、シトシン添加溶液20μLおよび全血2mLを添加
　参考例8 (シチジン)：血算用採血管に生理食塩水180μL、シチジン添加溶液20μLおよび全血2mLを添加
　参考例9 (ヒドロキシウレア)：血算用採血管に生理食塩水180μL、ヒドロキシウレア添加溶液20μLおよび全血2mLを添加 [Experiment 3] Effect of addition of nucleic acid-like substance Hereinafter, each blood collection tube in Reference Examples 3 to 9 was prepared as described below, and the blood glucose level was measured at each elapsed time at room temperature.
Reference Example 3 (Clotting Blood Collection Tubes): 200 μL of physiological saline and 2 mL of whole blood were added to the blood sampling blood collection tube Reference Example 4 (NADH): Saline 180 μL, NADH added solution 20 μL and Add 2 mL of whole blood Reference Example 5 (Adenosine): Add 180 μL of physiological saline to blood collection tube for blood count, add 20 μL of adenosine-added solution and 2 mL of whole blood Reference Example 6 (Guanosine): Add 180 mL of physiological saline to blood collection tube for blood count Add 20 μL of guanosine-added solution and 2 mL of whole blood Reference Example 7 (cytosine): Add 180 μL of physiological saline, 20 μL of cytosine-added solution, and 2 mL of whole blood to the blood sampling tube Reference Example 8 (cytidine): Collect for blood counting Add 180 μL of physiological saline to the blood vessel, 20 μL of cytidine added solution and 2 mL of whole blood Reference Example 9 (Hydroxyurea): Add 180 μL of physiological saline, 20 μL of hydroxyurea added solution and 2 mL of whole blood to the blood collection tube
実験3結果
Figure JPOXMLDOC01-appb-T000003
 血糖値　単位mg/dL Experiment 3 results
Figure JPOXMLDOC01-appb-T000003
 Blood glucose level mg / dL
　実験3では優れた解糖阻止効果を示す物質はなかった。 In Experiment 3, there was no substance showing an excellent antiglycolytic effect.
［実験4］リン酸添加効果
　以下、比較例14及び実施例1～3における各採血管は、下記のように準備し、室温放置下での各経過時間における血糖値を測定した。
　比較例14 (血糖検査用採血管)：血糖検査用採血管に生理食塩水200μLと全血2mLを添加
　実施例1 (リン酸4μL)：血糖検査用採血管に生理食塩水160μL、リン酸添加溶液（10倍したリン酸）40μLおよび全血2mLを添加
　実施例2 (リン酸6μL)：血糖検査用採血管に生理食塩水140μL、リン酸添加溶液（10倍したリン酸）60μLおよび全血2mLを添加
　実施例3 (リン酸8μL)：血糖検査用採血管に生理食塩水160μL、リン酸添加溶液（10倍したリン酸）80μLおよび全血2mLを添加 [Experiment 4] Phosphate addition effect Hereinafter, each blood collection tube in Comparative Example 14 and Examples 1 to 3 was prepared as described below, and the blood glucose level was measured at each elapsed time at room temperature.
Comparative Example 14 (blood glucose test blood collection tube): 200 μL of physiological saline and 2 mL of whole blood were added to the blood glucose test blood collection tube Example 1 (phosphate 4 μL): physiological saline 160 μL, phosphate added to the blood glucose test blood collection tube Add 40 μL of solution (10-fold phosphate) and 2 mL of whole blood Example 2 (phosphate 6 μL): Blood collection tube for blood glucose test 140 μL of saline, phosphate-added solution (10-fold phosphate) 60 μL and whole blood Add 2mL Example 3 (Phosphate 8μL): Add 160μL of physiological saline, 80μL of phosphate-added solution (10X phosphoric acid) and 2mL of whole blood to blood glucose test tube
実験4結果
Figure JPOXMLDOC01-appb-T000004
 血糖値　単位mg/dL Experiment 4 results
Figure JPOXMLDOC01-appb-T000004
 Blood glucose level mg / dL
　リン酸の添加量の増量に従って解糖阻止効果の増強を認めた。ただし、リン酸の添加量が最も多い実施例3ではわずかに溶血が確認された。 Increased antiglycolytic effect was observed as the amount of phosphoric acid added increased. However, slight hemolysis was confirmed in Example 3 with the largest amount of phosphoric acid added.
［実験5］ATP-2Na、リン酸＋EDTA-2Kの増量効果
　以下、比較例15及び実施例4～9における各採血管は、下記のように準備し、室温放置下での各経過時間における血糖値を測定した。
　比較例15 (血糖検査用採血管)：血糖検査用採血管に生理食塩水200μLと全血2mLを添加
　実施例4 (リン酸2μL, EDTA-2K )：血糖検査用採血管に生理食塩水140μL、リン酸添加溶液（10倍したリン酸）20μL、EDTA-2K添加溶液40μLおよび全血2mLを添加
　実施例5 (リン酸4μL, EDTA-2K )：血糖検査用採血管に生理食塩水120μL、リン酸添加溶液（10倍したリン酸）40μL、EDTA-2K添加溶液40μLおよび全血2mLを添加
　実施例6 (リン酸6μL, EDTA-2K )：血糖検査用採血管に生理食塩水100μL、リン酸添加溶液（10倍したリン酸）60μL、EDTA-2K添加溶液40μLおよび全血2mLを添加
　実施例7 (リン酸8μL, EDTA-2K )：血糖検査用採血管に生理食塩水80μL、リン酸添加溶液（10倍したリン酸）80μL、EDTA-2K添加溶液40μLおよび全血2mLを添加
　実施例8 (ATP-2Na 12.5mg)：血糖検査用採血管に生理食塩水150μL、ATP-2Na添加溶液50μLおよび全血2mLを添加
　実施例9 (ATP-2Na 25mg)：血糖検査用採血管に生理食塩水100μL、ATP-2Na添加溶液100μLおよび全血2mLを添加 [Experiment 5] Increasing effect of ATP-2Na, phosphoric acid + EDTA-2K Hereinafter, each blood collection tube in Comparative Example 15 and Examples 4 to 9 is prepared as follows, and blood glucose at each elapsed time at room temperature. The value was measured.
Comparative Example 15 (blood glucose test blood collection tube): 200 μL of physiological saline and 2 mL of whole blood were added to the blood glucose test blood collection tube. Example 4 (phosphate 2 μL, EDTA-2K): physiological saline 140 μL to blood glucose test blood collection tube , 20 μL of phosphate-added solution (10-fold phosphoric acid), 40 μL of EDTA-2K-added solution and 2 mL of whole blood were added Example 5 (phosphate 4 μL, EDTA-2K): 120 μL of physiological saline in a blood glucose test tube 40 μL of phosphate-added solution (10-fold phosphoric acid), 40 μL of EDTA-2K-added solution and 2 mL of whole blood were added. Example 6 (phosphate 6 μL, EDTA-2K): 100 μL of physiological saline in a blood glucose test tube 60 μL of acid-added solution (10-fold phosphoric acid), 40 μL of EDTA-2K-added solution and 2 mL of whole blood were added. Example 7 (8 μL of phosphate, EDTA-2K): 80 μL of physiological saline in blood collection tube for blood glucose test Addition solution (10-fold phosphoric acid) 80 μL, EDTA-2K addition solution 40 μL and whole blood 2 mL were added. Example 8 (ATP-2Na 12.5 mg): Saline 150 μL, ATP-2Na addition solution to blood collection tube for blood glucose test 50 Add μL and 2 mL of whole blood Example 9 (ATP-2Na 25 mg): Add 100 μL of physiological saline, 100 μL of ATP-2Na added solution, and 2 mL of whole blood to blood collection tube for blood glucose test
実験5結果
Figure JPOXMLDOC01-appb-T000005
 血糖値　単位mg/dL Experiment 5 results
Figure JPOXMLDOC01-appb-T000005
 Blood glucose level mg / dL
　リン酸の添加量を上記範囲で増量しても解糖阻止効果は増強しなかったが、EDTA-2K添加により、リン酸の添加量の増量によっても溶血が抑えられていることが確認された。
　ATP-2Naの添加は、その増量に従って解糖阻止効果の増強を認めた上に、溶血を認めなかった。 Even if the amount of phosphoric acid added was increased within the above range, the antiglycolytic effect was not enhanced, but it was confirmed that the addition of EDTA-2K suppressed hemolysis even when the amount of phosphoric acid added was increased. .
Addition of ATP-2Na not only showed hemolysis but also enhanced the antiglycolytic effect according to the increased amount.
［実験6］ATP-2Naの増量効果
　以下、実施例10～13における各採血管は、下記のように準備し、室温放置下での各経過時間における血糖値を測定した。
　実施例10 (ATP-2Na 25mg)：血糖検査用採血管に生理食塩水100μL、ATP-2Na添加溶液100μLおよび全血2mLを添加
　実施例11 (ATP-2Na 31.25mg)：血糖検査用採血管に生理食塩水75μL、ATP-2Na添加溶液125μLおよび全血2mLを添加
　実施例12 (ATP-2Na 37.5mg)：血糖検査用採血管に生理食塩水50μL、ATP-2Na添加溶液150μLおよび全血2mLを添加
　実施例13 (ATP-2Na 50mg)：血糖検査用採血管にATP-2Na添加溶液200μLおよび全血2mLを添加 [Experiment 6] Effect of increasing ATP-2Na In the following, each blood collection tube in Examples 10 to 13 was prepared as described below, and the blood glucose level was measured at each elapsed time at room temperature.
Example 10 (ATP-2Na 25 mg): 100 μL of physiological saline, 100 μL of ATP-2Na added solution and 2 mL of whole blood were added to a blood collection tube for blood glucose test Example 11 (ATP-2Na 31.25 mg): Blood collection tube for blood glucose test 75 μL of physiological saline, 125 μL of ATP-2Na added solution and 2 mL of whole blood were added. Example 12 (ATP-2Na 37.5 mg): 50 μL of physiological saline, 150 μL of ATP-2Na added solution and 2 mL of whole blood were added to the blood glucose test tube. Addition Example 13 (ATP-2Na 50 mg): Add 200 μL of ATP-2Na added solution and 2 mL of whole blood to blood collection tube for blood glucose test
実験6結果
Figure JPOXMLDOC01-appb-T000006
 血糖値　単位mg/dl Experiment 6 results
Figure JPOXMLDOC01-appb-T000006
 Blood glucose unit mg / dl
　血糖検査用採血管にATP-2Naを添加してもほとんど溶血は認めなかった。また、その解糖阻止効果は2mL血液に対して、ATP-2Na 25mg（250mg/mLのATP-2Naを100μL）以上添加することで、24時間までの解糖阻止効果が確認された（若干の測定値変動については測定装置自体の性能の変動幅としての目安である3%の範囲内であった。）。 Even when ATP-2Na was added to the blood collection tube for blood glucose test, almost no hemolysis was observed. In addition, the antiglycolytic effect was confirmed by adding more than 25 mg ATP-2Na (100 μL of 250 mg / mL ATP-2Na) to 2 mL blood (somewhat The measured value fluctuation was within the range of 3%, which is a standard as the fluctuation range of the performance of the measuring device itself.)
［実験7］ATP-2Na、ADP-1K、AMP添加効果
　以下、比較例16～17及び実施例14～19における各採血管は、下記のように準備し、室温放置下での各経過時間における血糖値を測定した。
　比較例16 (血算検査用採血管)：血算検査用採血管に生理食塩水200μLおよび全血2mLを添加
　実施例14 (AMP 10mg)：血算検査用採血管にAMP添加溶液200μLおよび全血2mLを添加
　実施例15 (ADP-1K 10mg)：血算検査用採血管にADP-1K添加溶液200μLおよび全血2mLを添加
　実施例16 (ATP-2Na 50mg)：血算検査用採血管にATP-2Na添加溶液200μLおよび全血2mLを添加
　比較例17 (血算検査用採血管)：血糖検査用採血管に生理食塩水200μLおよび全血2mLを添加
　実施例17 (AMP 10mg)：血糖検査用採血管にAMP添加溶液200μLおよび全血2mLを添加
　実施例18 (ADP-1K 10mg)：血糖検査用採血管にADP-1K添加溶液200μLおよび全血2mLを添加
　実施例19 (ATP-2Na 50mg)：血糖検査用採血管にATP-2Na添加溶液200μLおよび全血2mLを添加 [Experiment 7] Effects of adding ATP-2Na, ADP-1K, and AMP Hereinafter, each blood collection tube in Comparative Examples 16 to 17 and Examples 14 to 19 was prepared as follows, and at each elapsed time at room temperature. The blood glucose level was measured.
Comparative Example 16 (Clotting blood collection tube): 200 μL of physiological saline and 2 mL of whole blood were added to the blood sampling tube. Example 14 (AMP 10 mg): 200 μL of AMP-added solution and the whole blood sampling tube. 2 mL of blood was added Example 15 (ADP-1K 10 mg): 200 μL of ADP-1K added solution and 2 mL of whole blood were added to the blood collection tube for blood count test Example 16 (ATP-2Na 50 mg): Blood collection tube for blood count test 200 μL of ATP-2Na added solution and 2 mL of whole blood added Comparative Example 17 (blood collection tube for blood count test): 200 μL of physiological saline and 2 mL of whole blood were added to the blood glucose test tube Example 17 (AMP 10 mg): Blood glucose test Example 18 (ADP-1K 10 mg): 200 μL of ADP-1K added solution and 2 mL of whole blood were added to a blood glucose test tube Example 19 (ATP-2Na 50 mg) ) ： Add 200μL of ATP-2Na added solution and 2mL of whole blood to blood collection tube for blood glucose test
実験7 結果
Figure JPOXMLDOC01-appb-T000007
 血糖値　単位mg/dl Experiment 7 results
Figure JPOXMLDOC01-appb-T000007
 Blood glucose unit mg / dl
　ATP-2Na、ADP-1K、及びAMPのいずれにも解糖阻止効果が確認できた。
　解糖阻止の効力はATP-2Na、ADP-1K、AMPの順で強かった。
　血糖用採血管に含まれるフッ化ナトリウムの存在下では、よりATP-2Na、ADP-1K、AMPの解糖阻止効果が強くなることが確認された。
　溶血はいずれの採血管（比較例16～17、実施例14～19）においても少なくとも8時間後までは認めなかった。
　8時間以降は従来からの血糖測定に用いられている血糖用採血管（比較例17、実施例17～19）でわずかに確認されたが、比較例17の採血管と比べATP-2Na、ADP-1K、AMPの添加された採血管における溶血は軽減されていた。特にATP-2Na添加（実施例19）では12時間まで溶血は起こらなかった。
　24時間後に測定したHbA1cはいずれの採血管でも正常の範囲であり、対照と比較したパターン上の差も認められなかった。 ATP-2Na, ADP-1K, and AMP were all confirmed to have a glycolytic inhibitory effect.
The effect of inhibiting glycolysis was strong in the order of ATP-2Na, ADP-1K, and AMP.
In the presence of sodium fluoride contained in blood glucose blood collection tubes, it was confirmed that the glycolytic inhibitory effect of ATP-2Na, ADP-1K, and AMP became stronger.
Hemolysis was not observed in any blood collection tube (Comparative Examples 16-17, Examples 14-19) until at least 8 hours later.
After 8 hours, it was confirmed slightly in the blood glucose blood collection tube (Comparative Example 17 and Examples 17 to 19) used for conventional blood glucose measurement, but compared with the blood collection tube of Comparative Example 17, ATP-2Na, ADP Hemolysis in the blood collection tube to which -1K and AMP were added was reduced. In particular, hemolysis did not occur until 12 hours when ATP-2Na was added (Example 19).
HbA1c measured after 24 hours was in the normal range in any blood collection tube, and there was no pattern difference compared to the control.
［実験8］リン酸及びATP-2Na添加におけるHbA1c測定への影響確認
　以下、比較例18～19及び実施例20～23における各採血管は、下記のように準備し、室温放置下での各経過時間におけるHbA1cを測定した。
　比較例18 (血糖検査用採血管)：血糖検査用採血管に全血2mLを添加
　比較例19 (血糖検査用採血管)：血糖検査用採血管に生理食塩水200μLと全血2mLを添加
　実施例20 (リン酸2μL)：血糖検査用採血管に生理食塩水100μL、リン酸添加溶液（10倍したリン酸）20μL、EDTA-2K添加溶液80μLおよび全血2mLを添加
　実施例21 (リン酸4μL)：血糖検査用採血管に生理食塩水100μL、リン酸添加溶液（10倍したリン酸）40μL、EDTA-2K添加溶液60μLおよび全血2mLを添加
　実施例22 (ATP-2Na 25mg)：血糖検査用採血管に生理食塩水100μL、ATP-2Na添加溶液100μLおよび全血2mLを添加
　実施例23 (ATP-2Na 50mg)：血糖検査用採血管にATP-2Na添加溶液200μLおよび全血2mLを添加
　上記の比較例18～19及び実施例20～23の採血管中の検体を東ソー株式会社　自動グリコヘモグロビン分析計　HLC-723G9にてHbA1cを測定した。結果を下記にまとめた。 [Experiment 8] Confirmation of influence on HbA1c measurement by addition of phosphoric acid and ATP-2Na Hereinafter, each blood collection tube in Comparative Examples 18 to 19 and Examples 20 to 23 is prepared as follows, and each sample is allowed to stand at room temperature. HbA1c at the elapsed time was measured.
Comparative Example 18 (blood glucose test blood collection tube): 2 mL of whole blood was added to the blood glucose test blood collection tube Comparative Example 19 (blood glucose test blood collection tube): 200 μL of physiological saline and 2 mL of whole blood were added to the blood glucose test blood collection tube Example 20 (2 μL of phosphate): 100 μL of physiological saline, 20 μL of phosphate-added solution (10-fold phosphoric acid), 80 μL of EDTA-2K-added solution, and 2 mL of whole blood are added to a blood glucose test tube. Example 21 (phosphate) 4 μL): 100 μL of physiological saline, 40 μL of phosphate-added solution (10-fold phosphoric acid), 60 μL of EDTA-2K-added solution and 2 mL of whole blood were added to the blood glucose test tube. Example 22 (ATP-2Na 25 mg): Blood glucose 100 μL of physiological saline, 100 μL of ATP-2Na added solution, and 2 mL of whole blood are added to the blood collection tube for examination Example 23 (ATP-2Na 50 mg): 200 μL of ATP-2Na added solution and 2 mL of whole blood are added to the blood collection tube for blood glucose testing The specimens in the blood collection tubes of Comparative Examples 18 to 19 and Examples 20 to 23 were measured for HbA1c with Tosoh Corporation automatic glycohemoglobin analyzer HLC-723G9. The results are summarized below.
実験8 結果
Figure JPOXMLDOC01-appb-T000008
 HbA1c 測定値　(%) Experiment 8 result
Figure JPOXMLDOC01-appb-T000008
 HbA1c measured value (%)
　24時間後まで、いずれの検体でもそのパターン上の変化は認められなかった（表8）。
　リン酸及びATP-2Naの添加は従来の採血管と比較して溶血を認めず、24時間までの放置後でもパターンや測定値への影響は認められなかった。 Until 24 hours, no change in the pattern was observed in any specimen (Table 8).
Addition of phosphoric acid and ATP-2Na showed no hemolysis as compared with the conventional blood collection tube, and no effect on the pattern or measured value was observed even after standing for up to 24 hours.

Claims (6)

  1. 　開口を有する上端と有底を有する下端とを長手方向に有する筒状体と、
    　前記上端の開口を塞ぐ栓と、を備え、
    　前記筒状体の内部空間に、無機リン酸及びアデノシンリン酸並びにこれらの塩からなる群より選択される1種以上を含有する、血液中の血糖値及び／又はHbA1cを測定するための採血管。     A cylindrical body having an upper end having an opening and a lower end having a bottom in the longitudinal direction;
    A plug for closing the opening at the upper end,
    A blood collection tube for measuring blood glucose level and / or HbA1c in blood containing at least one selected from the group consisting of inorganic phosphate and adenosine phosphate and salts thereof in the internal space of the cylindrical body .
  2. 　無機リン酸としてリン酸を含有する、請求項1に記載の採血管。 2. The blood collection tube according to claim 1, comprising phosphoric acid as inorganic phosphoric acid.
  3. 　採取される血液1mLに対して、無機リン酸を1～5μLの範囲で含有する、請求項１又は2に記載の採血管。 3. The blood collection tube according to claim 1 or 2, which contains 1 to 5 μL of inorganic phosphate per 1 mL of collected blood.
  4. 　ATP、ADP、及びAMP並びにこれらの塩からなる群より選択される1種以上のアデノシンリン酸を含有する、請求項1～3のいずれか一項に記載の採血管。 The blood collection tube according to any one of claims 1 to 3, comprising one or more adenosine phosphates selected from the group consisting of ATP, ADP, and AMP and salts thereof.
  5. 　採取される血液1mLに対して、アデノシンリン酸又はその塩を1～100mgの範囲で含有する、請求項1～4のいずれか一項に記載の採血管。 5. The blood collection tube according to any one of claims 1 to 4, which contains 1 to 100 mg of adenosine phosphate or a salt thereof per 1 mL of collected blood.
  6. 　フッ化塩をさらに含有する、請求項1～5のいずれか一項に記載の採血管。 The blood collection tube according to any one of claims 1 to 5, further comprising a fluoride salt.
PCT/JP2018/022455 2017-06-16 2018-06-12 Blood collection tube WO2018230571A1 (en)

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JPS61258174A (en) * 1985-05-10 1986-11-15 Kyoto Ikagaku Kenkyusho:Kk Method for prohibiting glycolysis in blood
JPS63106563A (en) * 1986-06-26 1988-05-11 Yatoron:Kk Glycolysis inhibitor
JPH0295261A (en) * 1988-09-30 1990-04-06 Sekisui Chem Co Ltd Glycolysis blocking agent
US5204267A (en) * 1991-12-17 1993-04-20 Osborn Laboratories, Inc. Method of glucose stabilization and analysis in dried blood spot samples
JPH085629A (en) * 1994-06-16 1996-01-12 Terumo Corp Method for preserving blood or blood cell
JP5435797B2 (en) * 2010-02-26 2014-03-05 積水メディカル株式会社 Blood collection tube and pharmaceutical composition for measuring blood glucose level and / or hemoglobin A1c level
US20150208644A1 (en) * 2012-08-09 2015-07-30 Petra Weser-Bisse Composition and use of substances for the in vitro stabilization of glucose, lactate and homocysteine in blood

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61258174A (en) * 1985-05-10 1986-11-15 Kyoto Ikagaku Kenkyusho:Kk Method for prohibiting glycolysis in blood
JPS63106563A (en) * 1986-06-26 1988-05-11 Yatoron:Kk Glycolysis inhibitor
JPH0295261A (en) * 1988-09-30 1990-04-06 Sekisui Chem Co Ltd Glycolysis blocking agent
US5204267A (en) * 1991-12-17 1993-04-20 Osborn Laboratories, Inc. Method of glucose stabilization and analysis in dried blood spot samples
JPH085629A (en) * 1994-06-16 1996-01-12 Terumo Corp Method for preserving blood or blood cell
JP5435797B2 (en) * 2010-02-26 2014-03-05 積水メディカル株式会社 Blood collection tube and pharmaceutical composition for measuring blood glucose level and / or hemoglobin A1c level
US20150208644A1 (en) * 2012-08-09 2015-07-30 Petra Weser-Bisse Composition and use of substances for the in vitro stabilization of glucose, lactate and homocysteine in blood

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