WO2020183916A1 - Programme de calcul de taux de glycémie, procédé de calcul de taux de glycémie et dispositif de mesure de taux de glycémie - Google Patents

Programme de calcul de taux de glycémie, procédé de calcul de taux de glycémie et dispositif de mesure de taux de glycémie Download PDF

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Publication number
WO2020183916A1
WO2020183916A1 PCT/JP2020/001985 JP2020001985W WO2020183916A1 WO 2020183916 A1 WO2020183916 A1 WO 2020183916A1 JP 2020001985 W JP2020001985 W JP 2020001985W WO 2020183916 A1 WO2020183916 A1 WO 2020183916A1
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Prior art keywords
blood glucose
glucose level
sample
reagent
blood
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PCT/JP2020/001985
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English (en)
Japanese (ja)
Inventor
嘉哉 佐藤
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テルモ株式会社
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Priority to JP2021505557A priority Critical patent/JP7372310B2/ja
Publication of WO2020183916A1 publication Critical patent/WO2020183916A1/fr

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    • 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 first base material 1 and the second base material 2 may be colored if necessary.
  • the sample may be formed in a structure provided with an optical path for the measurement light to pass through. More specifically, the optical path can be secured by forming only the portion serving as the optical path with the transparent member or by cutting out a part of the colored member. Further, a reflective member may be provided on either one of the first base material 1 and the second base material 2 to reflect the light transmitted through the material to be measured for measurement.
  • each of the above other components may be used alone or in combination of two or more.
  • each of the above other components may be used alone or in combination of two or more.
  • q is 1 or 2, preferably 1.
  • R 3 is a methyl group or an ethyl group, and is preferably a methyl group.
  • the substitution position of -OR 3 is a substituent of benzothiazolyl group present in the 2-position of the tetrazole skeleton is not particularly limited, 4, 5, one of the 6-position, or 7 It may be.
  • the substitution position of -OR 3 is preferably attached to the 6-position of the benzothiazolyl group.
  • R 3 is a hydrogen atom, a methyl group or an ethyl group, and at least one is a methyl group or an ethyl group.
  • the substitution position of R 2 is not particularly limited, but is the 2-position, 3-position, 4-position, 5-position or 6-position of the substituted sulfophenyl group existing at the 3-position of the tetrazole skeleton.
  • at least one R 2 is in the 2nd and / or 4th position.
  • 4-methoxy-5-sulfophenyl group is preferable, 4-methoxy-3-sulfophenyl group, 2-methoxy-5-sulfophenyl group, 3-carboxy-4-methoxyphenyl group, or 4-methoxy-5- It is more preferably a sulfophenyl group, preferably a 4-methoxy-3-sulfophenyl group, a 4-methoxy-5-sulfophenyl group, or a 2-methoxy-5-sulfophenyl group. Of these, a 4-methoxy-3-sulfophenyl group is particularly preferable.
  • a buffer to the blood glucose level measuring reagent is not particularly limited, and a buffer generally used for measuring the concentration of biological components can be used in the same manner. Specifically, phosphate buffer, citrate buffer, citrate-phosphate buffer, trishydroxymethylaminomethane-HCl buffer (tris hydrochloride buffer), MES buffer (2-morpholinoetan sulfonic acid buffer).
  • the concentration of the buffering agent is not particularly limited, but is preferably 0.01 to 1.0 M at the time of preparing the blood glucose level measuring reagent solution.
  • the concentration of the buffering agent means the concentration (M, mol / L) of the buffering agent contained in the aqueous solution.
  • the pH of the buffer solution has no effect on biological components (for example, blood cells 62).
  • a pH adjuster may be added to the blood glucose level measuring reagent.
  • the type of pH adjuster is not particularly limited.
  • an acid hydroochloric acid, sulfuric acid, phosphoric acid, etc.
  • a base potassium hydroxide, sodium hydroxide, potassium carbonate, etc.
  • the pH adjuster may be used as it is or may be used in the form of an aqueous solution.
  • the amount of the pH adjuster is not particularly limited. The blood glucose level measuring reagent solution is adjusted so that the pH is near neutral, for example, about pH 5.0 to 8.0.
  • a solvent such as a surfactant or alcohol, metal ions, or salts may be added as appropriate according to the purpose when adjusting the blood glucose level measuring reagent.
  • the blood glucose level measuring system 500 includes a blood glucose level measuring chip 100 and a blood glucose level measuring device 110.
  • the blood collected from the subject can be introduced into the blood glucose level measuring chip 100.
  • the blood glucose level measuring device 110 measures the amount of glucose contained in the sample.
  • the amount of glucose in the sample can be measured by mixing and dissolving the blood glucose level measuring reagent described later in the sample. Thereby, when the sample is blood, the blood glucose level can be calculated.
  • a mixture or mixed solution of a sample (blood) and a blood glucose level measuring reagent is referred to as a sample.
  • the blood glucose level measuring chip 100 is attached to the tip of the blood glucose level measuring device 110.
  • the blood glucose level measuring chip 100 is removed from the blood glucose level measuring device 110 and discarded.
  • the blood glucose level measuring device 110 removes the display unit 111 that displays the measurement result or the operation content, the power button 112 that instructs the start and end of the blood glucose level measuring device 110, the operation button 113, and the blood glucose level measuring chip 100.
  • a removal lever 114 is provided.
  • the display unit 111 may be composed of a liquid crystal, an LED, or the like.
  • the blood glucose level measuring device 110 includes a mounting portion 22 for mounting the blood glucose level measuring chip 100.
  • the mounting unit 22 has an opening 21 located at the tip of the blood glucose level measuring device 110, and an accommodating portion 23 accommodating the blood glucose level measuring chip 100.
  • the opening 21 and the accommodating portion 23 are partitioned by an inner wall provided inside the mounting portion 22.
  • the blood glucose level measuring device 110 includes an optical measuring unit 24 that irradiates the sample with the measuring light and detects the measuring light transmitted through the sample.
  • the blood glucose level measuring device 110 includes a control unit 25 that calculates the blood glucose level of the sample based on the detection result of the optical measuring unit 24, and an eject pin 26 that interlocks with the removal lever 114 to remove the blood glucose level measuring chip 100. ..
  • the light receiving unit 32 may be composed of, for example, a photodiode (PD).
  • the light receiving unit 32 may be composed of another light receiving device such as a CCD (Charged Coupled Device) or a CMOS (Complementary Metal Oxide semiconductor) image sensor.
  • CCD Charge Coupled Device
  • CMOS Complementary Metal Oxide semiconductor
  • the irradiation unit 31 includes a first light emitting element 51 that emits light having a first wavelength, and a second light emitting element 52 that emits light having a second wavelength different from the first wavelength.
  • the first wavelength is a wavelength for detecting the amount of color development of the blood glucose level measuring reagent according to the amount of glucose (blood glucose level), and is selected from, for example, a wavelength included in the wavelength band of 600 to 920 nm.
  • the second wavelength is a wavelength for detecting the concentration of red blood cells in blood, and is selected from, for example, a wavelength included in the wavelength band of 510 to 590 nm.
  • the irradiation unit 31 may have a light emitting element having a wavelength selected from the above wavelength bands depending on the measurement method, or may have a light emitting element having a wavelength other than the above wavelength band. Good.
  • the blood glucose level measuring device 110 has a first space 41 and a second space 42 formed inside.
  • the irradiation unit 31 and the light receiving unit 32 are arranged in the first space 41 and the second space 42, respectively.
  • the first space 41 and the second space 42 face each other with the accommodating portion 23 interposed therebetween.
  • the first space 41 and the second space 42 sandwich the position where the reagent unit 30 on the blood glucose level measuring chip 100 is held. Oppose with.
  • the irradiation unit 31 may be arranged at a position where the irradiation light 33 can irradiate the bottom surface of the blood glucose level measuring chip 100 substantially perpendicularly. By doing so, the energy loss of the irradiation light 33 can be reduced. In order to suppress noise in the transmitted light measurement, it is preferable that the microbeads or the porous film are not arranged in the portion of the blood glucose level measuring chip 100 that corresponds to the optical path of the measurement light.
  • the irradiation unit 31 When the irradiation unit 31 is composed of a halogen lamp that irradiates white, the irradiation unit 31 may further include a spectroscopic filter that extracts only a specific wavelength as the irradiation light 33.
  • the irradiation unit 31 may include a condenser lens.
  • the blood glucose level measuring device 110 may further include a temperature sensor.
  • the temperature sensor measures the temperature of the sample.
  • the blood glucose level may be calculated by using this sample temperature as a correction value.
  • the control unit 25 acquires a detection signal from the light receiving unit 32 and calculates the blood glucose level of the sample (sample) based on the detection signal.
  • the control unit 25 may include, for example, a processor.
  • the control unit 25 may have a storage unit for storing various information and programs.
  • the storage unit may include, for example, a semiconductor memory.
  • the storage unit may be configured separately from the control unit 25.
  • the blood glucose level measuring device 110 can measure the blood glucose level of a sample by the following procedure, for example.
  • the measurement worker operates the power button 112 to activate the blood glucose level measuring device 110.
  • the measurement worker attaches the blood glucose level measuring chip 100 to the tip of the blood glucose level measuring device 110.
  • the blood glucose level measuring device 110 detects that the blood glucose level measuring chip 100 is attached, and measures the initial state in which the sample is not introduced by the irradiation unit 31 and the light receiving unit 32.
  • the measurement worker causes the blood of the subject to flow into the blood glucose level measuring chip 100 as a sample.
  • the blood of the subject collected by the blood glucose level measuring chip 100 is also referred to as a whole blood sample.
  • the blood glucose level measuring reagent and glucose in plasma 61 react at a rate corresponding to the temperature of the sample. Therefore, the blood glucose level measuring device 110 further calculates the blood glucose level of the sample based on the temperature of the sample, so that the measurement accuracy of the blood glucose level is improved.
  • the blood glucose level measuring device 110 may measure the temperature of the sample by a temperature sensor.
  • the blood glucose level measuring device 110 can calculate the blood glucose level based on the parameters including the amount of color development, the hematocrit value, and the temperature of the sample.
  • the relationship between the elapsed time after the reaction between glucose in plasma 61 and the blood glucose level measuring reagent starts and the amount of color development due to the reaction is non-linear.
  • the relationship between the elapsed time and the amount of color development becomes non-linear based on the following reasons (a) to (d).
  • B Glucose in the blood cells 62 flows out of the blood cells 62 (that is, in the plasma 61) as the glucose in the plasma 61 decreases.
  • C) Glucose in plasma 61 has at least two anomers present in equilibrium.
  • the reaction rate changes depending on the temperature of the sample.
  • the blood glucose level measuring system 500 is required to calculate the blood glucose level of the sample in the shortest possible time after collecting the sample on the blood glucose level measuring chip 100 and notify the measuring operator.
  • the blood glucose measuring device 110 is required to calculate the blood glucose level based on a non-linear relationship in which the elapsed time after the start of the reaction is short.
  • the blood glucose level measuring device 110 calculates the blood glucose level by solving an equation having a non-linear relationship for each measurement, the blood glucose level measuring device 110 requires a great deal of computing power. However, the blood glucose level measuring device 110 has a limited computing power, which is less than the required computing power, due to device cost or size restrictions. Therefore, it is difficult for the blood glucose measuring device 110 to solve the equation having a non-linear relationship for each measurement.
  • a calibration curve for associating the color development amount with the blood glucose level is prepared in advance based on the measured values of the color development amount and the blood glucose level. May be good.
  • the calibration curve may be expressed as a mathematical formula or as a table.
  • the sample has various parameters.
  • the sample can have at least a hematocrit value as a parameter.
  • the sample may have its temperature at the time of measurement as a parameter.
  • the hematocrit value and the temperature of the sample can be various values.
  • the blood glucose level calculation method can calculate a calibration curve that associates the color development amount with the blood glucose level for a sample for which parameters other than the blood glucose level are specified, based on a limited number of actually measured values.
  • a calibration curve that associates the color development amount with the blood glucose level for a sample in which parameters other than the blood glucose level are specified is also called a simple calibration curve.
  • the simple calibration curve may be calculated based on an intermediate relational expression that can be calculated with limited computing power. By calculating the simple calibration curve based on an intermediate relational expression, the amount of data prepared in advance can be reduced.
  • the blood glucose level calculation method can calculate an intermediate relational expression based on a limited number of actually measured values.
  • the intermediate relational expression may be an expression that can be solved algebraically.
  • a simple calibration curve can be easily calculated because the intermediate relational expression is an expression that can be solved algebraically.
  • the blood glucose level measuring device 110 may acquire the calculation result of the simple calibration curve in advance.
  • the blood glucose level measuring device 110 may acquire parameters including the hematocrit value or temperature of the sample collected on the blood glucose level measuring chip 100, and select a simple calibration curve based on the acquired contents.
  • the blood glucose level measuring device 110 may calculate the blood glucose level of the sample by measuring the color development amount of the sample in the blood glucose level measuring chip 100 and applying the measurement result to the selected simple calibration curve.
  • the blood glucose level measuring device 110 may acquire the calculation result of the intermediate relational expression in advance.
  • the blood glucose level measuring device 110 may acquire parameters including the hematocrit value or temperature of the sample collected on the blood glucose level measuring chip 100, and calculate a simple calibration curve from an intermediate relational expression based on the acquired contents. ..
  • the blood glucose level measuring device 110 may calculate the blood glucose level of the sample by measuring the color development amount of the sample in the blood glucose level measuring chip 100 and applying the measurement result to the calculated simple calibration curve.
  • the blood glucose level calculation method according to the present embodiment may be executed to calculate a calibration curve.
  • the blood glucose level measuring chip 100 is represented by a predetermined model exemplified in FIG.
  • the blood glucose level calculation method is a simple calibration curve or an intermediate by substituting the measured value of the color development value and the measured value of each parameter into the simultaneous equations describing a predetermined model and specifying the parameters of the simultaneous equations. It is possible to calculate various relational expressions.
  • the predetermined model represents the blood glucose level measuring chip 100 as a one-dimensional model specified by the coordinates of the Z axis along the chip thickness direction.
  • the first base material 1, the flow path 20, and the second base material 2 are laminated along the Z-axis direction.
  • the first base material 1 and the second base material 2 are positioned so as to face each other, thereby partitioning the flow path 20.
  • the surfaces of the first base material 1 and the second base material 2 on the flow path 20 side are orthogonal to the Z axis.
  • the distance between the first base material 1 and the second base material 2 is represented by L.
  • the state at the time when the sample flows into the blood glucose level measuring chip 100 is represented by the model shown in FIG.
  • the region corresponding to the flow path 20 in FIG. 5 is filled with the sample.
  • the specimen is whole blood and contains at least plasma 61 and blood cells 62.
  • the time when the sample flows in is also called the initial time.
  • the time is represented by t.
  • the sample flowing into the blood glucose level measuring chip 100 is mixed with the reagent unit 30 and reacts with the blood glucose level measuring reagent.
  • the blood glucose level measuring reagent dissolves in plasma 61 from the reagent section 30 and diffuses.
  • the arrow DA schematically represents the diffusion of the blood glucose level measuring reagent.
  • the blood glucose level measuring reagent reacts with glucose in the plasma 61.
  • the blood glucose level measuring reagent generates the colored dye 63.
  • the molecule of the colored dye 63 is present in the plasma 61 in a dissolved state.
  • the colored dye 63 diffuses into plasma 61 according to a concentration gradient.
  • the arrow DC schematically represents the diffusion of the colored dye 63.
  • the colored dye 63 in FIG. 7 exemplifies a portion (dark) in which a particularly large amount of dissolved colored dye 63 is present.
  • glucose is consumed by the reaction between the blood glucose level measuring reagent dissolved in the plasma 61 from the reagent unit 30 and glucose, and the amount of glucose in the plasma 61 is reduced.
  • Glucose diffuses in plasma 61 based on the concentration gradient.
  • Arrow DG1 schematically represents the diffusion of glucose.
  • the blood cell 62 has a transport mechanism (transporter, mainly GLUT-1) on the blood cell membrane that regulates the glucose concentration inside and outside the blood cell 62. By the action of this transport mechanism, glucose in the blood cells 62 flows out into the plasma 61.
  • the arrow DG2 schematically represents the transfer of glucose from blood cells 62 to plasma 61.
  • a given model can represent diffusion in the Z-axis direction, the concentration of each substance distributed in the Z-axis direction, and the change in concentration due to the reaction of each substance. That is, it can be said that the predetermined model is represented as a diffusion reaction model of a one-dimensional coordinate system.
  • the blood glucose level measuring reagent diffuses in plasma 61 as the elapsed time from the initial time increases. It is assumed that the blood glucose level measuring reagent contained in the reagent section 30 has a viscosity sufficiently higher than the viscosity of the sample at the initial time. That is, the reagent unit 30 is considered to be a solid.
  • the plasma 61 permeates the inside of the reagent section 30 from the surface thereof to reduce the viscosity of the blood glucose level measuring reagent contained in the reagent section 30.
  • the viscosity ( ⁇ ) of the blood glucose level measuring reagent contained in the reagent section 30 is represented by the following formula (1) as a general formula.
  • Equation (1) represents a so-called sigmoid function.
  • ⁇ is represented as a function of z and t.
  • K mS and n are constants that determine the shape of the sigmoid function.
  • ⁇ represents the maximum viscosity of the blood glucose level measuring reagent part applied to the reagent part 30, and is set to a viscosity sufficiently higher than the viscosity of the sample so that the reagent part 30 is regarded as a solid.
  • a and B are variables representing the concentration of the component contained in the blood glucose level measuring reagent, and are expressed as a function of z and t.
  • the blood glucose level measuring reagent contains a component having a relatively high molecular weight (for example, a molecular weight of 10,000 or more) such as an enzyme and a component having a relatively low molecular weight (for example, a molecular weight of less than 10,000) such as a dye.
  • A represents the concentration of the enzyme contained in the blood glucose level measuring reagent.
  • B is assumed to represent the concentration of a component other than the enzyme contained in the blood glucose level measuring reagent.
  • a and b are constants for weighting based on the molecular weight of the components represented by A and B.
  • the concentration of the high molecular weight component has a greater effect on the viscosity than the concentration of the low molecular weight component.
  • a is set to a value greater than b.
  • the components contained in the blood glucose level measuring reagent are divided into two types, a component represented by A and a component represented by B, but may be further divided into other components.
  • the components contained in the blood glucose level measuring reagent are increased, the number of terms contained in the portion represented by (a, A + b, B + 7) In the formula (1) is increased to more than two.
  • ⁇ Diffusion of glucose> In a stable aqueous glucose solution, a plurality of isomers (anomers) are present in an equilibrium state. Similarly, in plasma 61, glucose has a plurality of isomers in an equilibrium state. However, depending on the substrate specificity of the enzyme (GDH) used for the blood glucose level measuring reagent, the equilibrium state of these isomers is biased, so that the influence on the blood glucose level measuring reaction may not be negligible.
  • the enzyme (GDH) of the present embodiment uses ⁇ -glucose as a substrate to develop a color of a blood glucose level measuring reagent to produce a colored dye 63.
  • isomers other than ⁇ -glucose do not serve as a substrate for the enzyme (GDH) (do not react). Therefore, when ⁇ -glucose is consumed by the enzymatic reaction, isomerization of ⁇ -glucose to ⁇ -glucose proceeds in plasma 61, and the total number of molecules of glucose in plasma 61 decreases. As the number of glucose molecules in plasma 61 decreases, glucose in blood cells 62 flows out into plasma 61 by the transport mechanism present in the blood cell membrane. Glucose in the blood cell 62 flows out into the plasma 61 when the blood glucose level measuring reagent and the sample are mixed. In this embodiment, ⁇ -glucose and ⁇ -glucose are considered as glucose isomers having a large abundance ratio.
  • ⁇ -glucose flowing out of blood cells 62 is not considered in the present embodiment for simplification of the calculation formula, but may be considered.
  • D G represents the diffusion coefficient of glucose in pure water of 25 ° C..
  • the arrow with DG1 in FIG. 7 qualitatively represents the Z-axis diffusion of ⁇ -glucose in plasma 61.
  • the arrow with DG2 in FIG. 7 qualitatively represents the Z-axis outflow of ⁇ -glucose from blood cells 62 to plasma 61.
  • ⁇ 0 represents the viscosity of the sample.
  • the term represented by ( ⁇ + ⁇ 0 ) corrects the diffusion coefficient by the viscosity. That is, the higher the viscosity, the smaller the effective diffusion coefficient.
  • Vmax M represents the maximum outflow rate of glucose from blood cells 62 to plasma 61.
  • K mM is the Michaelis-Menten constant for outflow from inside blood cells 62 to plasma 61.
  • Vmax ⁇ represents the maximum rate of isomerization reaction between ⁇ -glucose and ⁇ -glucose.
  • K ⁇ is the rate constant of the isomerization reaction from ⁇ -glucose to ⁇ -glucose.
  • K ⁇ is the rate constant of the isomerization reaction from ⁇ glucose to ⁇ glucose.
  • Km ⁇ is the Michaelis-Menten constant of mutarotase, a type of enzyme. Mutarotase is contained in the sample when the sample is whole blood.
  • the first term on the right side of the formula (2) is a term representing the diffusion of ⁇ -glucose present in plasma 61 in the z-axis direction at the initial time.
  • the first term on the right side of the formula (3) is a term representing the diffusion of ⁇ -glucose flowing out of the blood cells 62 in the z-axis direction.
  • the first term on the right side of the formula (4) is a term representing the diffusion of ⁇ -glucose in plasma 61 in the z-axis direction.
  • the term for diffusion is described based on Fick's second law, which is the basic law of diffusion of matter.
  • the third term on the right side of the formula (2), the third term on the right side of the formula (3), and the second term on the right side of the formula (4) are terms representing the rate of the isomerization reaction between ⁇ -glucose and ⁇ -glucose. is there. ⁇ -glucose and ⁇ -glucose exist in an equilibrium state. The third term on the right side of equations (2) and (3) becomes a positive value when ⁇ -glucose increases. The second term on the right-hand side of equation (4) is given a minus sign so that it becomes a positive value when ⁇ -glucose increases.
  • the diffusion of the blood glucose level measuring reagent is represented by the following formula (5).
  • A is a variable representing the concentration of the component represented by A in the blood glucose level measuring reagent, and is represented as a function of z and t.
  • DA represents the diffusion coefficient of the component represented by A in the blood glucose level measuring reagent with respect to pure water at 25 ° C.
  • U A of the second term on the right side of the formula (5) is a reaction term representing the reaction rate of the component represented by A and ⁇ -glucose.
  • the reaction between the blood glucose level measuring reagent and ⁇ -glucose produces the colored dye 63.
  • the amount (C) of the colored dye 63 produced is calculated by the following formula (8).
  • C is represented as a function of t.
  • ⁇ C is the molar absorption constant of the colored dye 63.
  • Ht represents the hematocrit value of the sample.
  • R v represents the ratio of the solution in the blood cells 62.
  • the predetermined model is represented by the partial differential simultaneous equations described by the equations (1) to (8).
  • the blood glucose level calculation method includes, for example, the following procedure.
  • the operator flows a sample whose parameters such as blood glucose level, hematocrit value, and temperature are known into the blood glucose level measuring chip 100 mounted on the blood glucose level measuring device 110, and measures the absorbance (color development amount) (No. 1). 1 step).
  • the blood glucose level measuring device 110 measures the time change of the absorbance of the sample (third step).
  • the blood glucose level measuring device 110 may measure the absorbance until the time change of the absorbance becomes sufficiently small. When the time change of the absorbance becomes sufficiently small, it is considered that the reaction between the sample and the blood glucose level measuring reagent has proceeded sufficiently.
  • the absorbance at each time after the start of the reaction may be used to prepare a simple calibration curve by associating it with the parameters of the sample.
  • the parameters of the sample include parameters derived from the sample (blood) itself and parameters of the sample (mixture of blood and reagent).
  • a computer that calculates a simple calibration curve applies the measured data of the time change of the absorbance of a sample having known parameters obtained in the above procedure to a predetermined model, and thereby performs a simple calibration curve for a sample having a combination of unmeasured parameters.
  • the line can be calculated.
  • the blood glucose level measuring device 110 acquires the hematocrit value and temperature of the sample even when measuring the sample specified by the combination of unmeasured parameters, and matches the acquired value from the simple calibration curve calculated by the computer. You can select a simple calibration curve to be used.
  • the blood glucose level measuring device 110 can calculate the blood glucose level of the sample specified by the combination of unmeasured parameters by applying the measured value of the absorbance acquired in the first step to the selected simple calibration curve ( Second step).
  • known parameters include temperature, blood glucose level, and hematocrit value.
  • the third step may be performed prior to the first step and / or the second step.
  • the computer that calculates the simple calibration curve predicts the change in the absorbance of the sample when the unmeasured sample is flowed into the blood glucose level measuring chip 100 in the form of a modeling formula based on a predetermined model based on the measured data. it can.
  • a component having a relatively low molecular weight such as a dye is also referred to as a low molecular weight component.
  • the concentration of the low molecular weight component is expressed as W.
  • W is represented by the following equation (9).
  • W is represented as a function of z and t.
  • D W represents the diffusion coefficient of the low molecular weight component with respect to pure water at 25 ° C.
  • a component having a relatively high molecular weight such as a molecular weight of 10,000 or more
  • the concentration of the high molecular weight component is expressed as E.
  • E is represented by the following equation (10).
  • E is represented as a function of z and t.
  • DE represents the diffusion coefficient of the high molecular weight component with respect to pure water at 25 ° C.
  • ⁇ E is a coefficient that corrects the interaction of high molecular weight components.
  • the change in the concentration of ⁇ -glucose (G ⁇ ) in plasma 61 is described by the following formula (11).
  • the formula (11) is the same as the above formula (4).
  • the explanation of the variables included in the equation (11) is omitted.
  • the reaction in which an intermediate is produced by the reaction between the coloring reagent and ⁇ -glucose can also be considered.
  • the sample is whole blood, it is necessary to measure the amount of color development at the measurement wavelength in the wavelength range that is not easily affected by the hemoglobin in the sample.
  • the blood glucose level measuring reagent further contains a transition metal ion to chelate the formazan (intermediate) generated by the enzymatic reaction and the transition metal ion to measure a longer wavelength.
  • the colored dye 63 can be detected by the wavelength.
  • an intermediate (formazan before chelation formation) is produced as a precursor of the colored dye 63 by the reaction between the blood glucose level measuring reagent and ⁇ -glucose.
  • the concentration (F 1 ) of the intermediate produced by the reaction of ⁇ -glucose present in plasma 61 from the time of the initial time is represented by the following formula (15).
  • the concentration (F 2 ) of the intermediate produced by the reaction of ⁇ -glucose flowing out from the blood cells 62 is represented by the following formula (16).
  • F 1 and F 2 are represented as functions of z and t.
  • C 1 represents the concentration of the colored dye 63 that changes from the intermediate produced by the reaction of ⁇ -glucose present in the plasma 61 from the time of the initial time.
  • C 2 represents the concentration of the colored dye 63 that changes from the intermediate produced by the reaction of ⁇ -glucose flowing out of the blood cells 62.
  • D F represents the diffusion coefficient of the intermediate in pure water of 25 ° C..
  • the second term on the right side is a reaction term representing the reaction rate between the enzyme and ⁇ -glucose. The reaction rate is based on the concentration of the enzyme, the proportion of active enzyme, and the concentration of glucose.
  • K Ni is a constant representing the rate of change from the intermediate to the colored dye 63.
  • K F is a constant representing the rate of change from the colored dye 63 to the intermediate.
  • At least part of the intermediate changes to the colored dye 63.
  • the change in the concentration (C 1 ) of the colored dye 63 that changes from the intermediate produced by the reaction of ⁇ -glucose present in the plasma 61 from the time of the initial time is represented by the following formula (17).
  • the change in the concentration (C 2 ) of the colored dye 63 that changes from the intermediate produced by the reaction of ⁇ -glucose flowing out from the blood cells 62 is represented by the following formula (18).
  • C 1 and C 2 are represented as functions of z and t.
  • D C represents the diffusion coefficient of the color already dye 63 with respect to pure water of 25 ° C..
  • the reaction between the blood glucose level measuring reagent and ⁇ -glucose produces the colored dye 63.
  • W 0 is a constant for determining the initial value of W.
  • E 0 is a constant for determining the initial value of E.
  • BG represents the blood glucose level (unit: mg / dL) of the sample.
  • E d represents the concentration of the enzyme after 3 days of treatment at 60 ° C.
  • RM is a constant that converts the amount of enzyme activity into weight concentration. Since it is difficult to directly measure the following values, they are empirically adjusted values in order to fit the result of the above formula (19) to the color development amount (C) of some known samples.
  • Temp represents the temperature (unit: ° C.) of the sample. For ⁇ 0 , a directly measured value may be used.
  • the calculation method of the relational expression is not particularly limited, and a well-known method such as optimization by a polynomial can be used.
  • the temporal change of absorbance exemplified in FIG. A modeling equation was calculated to predict.
  • the horizontal axis represents time.
  • the vertical axis represents the absorbance of the sample.
  • the broken line represents a modeling formula that predicts the time change of absorbance.
  • a modeling formula in which the hematocrit value is used as a variable is shown for a sample having a blood glucose level of 400 mg / dL and a temperature of 25 ° C. The hematocrit value is changed from 0% to 70% at 10% intervals.
  • the graphs shown by solid lines represent the data obtained by actually measuring the time change of the absorbance of the sample having the parameters that are the premise of the prediction. Regardless of the hematocrit value from 0% to 70%, the error of the measured absorbance with respect to the absorbance of the modeling formula is within 10%. Therefore, the blood glucose level calculation method according to the present embodiment is a sample specified by a combination of unmeasured parameters by modeling the reaction between the blood glucose level measuring reagent and the sample in the blood glucose level measuring chip 100 with a predetermined model. The reaction in was predicted with high accuracy.
  • the blood glucose measuring device 110 can perform blood glucose in a short time without waiting from the start of the reaction between the sample and the blood glucose measuring reagent until the reaction sufficiently proceeds.
  • the value can be calculated. For example, even if it takes 10 seconds or more for the reaction between the sample and the blood glucose level measuring reagent to proceed sufficiently, the blood glucose level measuring device 110 measures the blood glucose level calculation result in a predetermined time of less than 10 seconds. Can be informed. As a result, the convenience of the blood glucose level measuring device 110 is improved.
  • the modeling formula calculated by the computer for calculating the simple calibration curve can be used as an intermediate relational expression for calculating the simple calibration curve for a sample of a combination of unmeasured parameters.
  • the blood glucose level calculation method it is possible to calculate a simple calibration curve for measuring the blood glucose level based on a small amount of actual measurement data. As a result, the development period of the blood glucose level measuring device 110 can be shortened and the development cost can be reduced.
  • each component or each step can be reconfigured so as not to be logically inconsistent, and a plurality of components or steps can be combined or divided into one. is there.

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Abstract

Afin de calculer le taux de glycémie d'un échantillon contenant du plasma et des cellules sanguines sur la base d'un résultat de mesure d'une quantité de coloration d'un pigment colorant sur une puce de mesure de taux de glycémie ayant un réactif qui réagit avec le glucose contenu dans l'échantillon et amène le pigment colorant à développer une couleur, ce programme de calcul de taux de glycémie amène un processeur à exécuter une première étape pour calculer une expression relationnelle entre le résultat de mesure et le taux de glycémie de l'échantillon sur la base d'un modèle prescrit. L'échantillon a des paramètres prescrits comprenant au moins le taux de glycémie. Le modèle prescrit est représenté sous la forme d'un modèle de réaction de diffusion d'un système de coordonnées unidimensionnel. Le modèle de réaction de diffusion est représenté par un changement de viscosité du réactif au cours du temps, un changement de concentration du glucose contenu dans le plasma au cours du temps, un changement de concentration du réactif au cours du temps, et un changement de quantité de coloration du réactif au cours du temps.
PCT/JP2020/001985 2019-03-11 2020-01-21 Programme de calcul de taux de glycémie, procédé de calcul de taux de glycémie et dispositif de mesure de taux de glycémie WO2020183916A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000262298A (ja) * 1999-03-15 2000-09-26 Fuji Photo Film Co Ltd 全血中のグルコース濃度もしくはコレステロール濃度の定量方法
US6168957B1 (en) * 1997-06-25 2001-01-02 Lifescan, Inc. Diagnostic test strip having on-strip calibration
WO2009081790A1 (fr) * 2007-12-20 2009-07-02 Terumo Kabushiki Kaisha Système de gestion d'un niveau mesuré de glycémie et appareil de mesure d'un niveau de glycémie
JP2015179038A (ja) * 2014-03-19 2015-10-08 テルモ株式会社 測定用チップ
WO2017122485A1 (fr) * 2016-01-12 2017-07-20 テルモ株式会社 Dispositif de mesure de composant, procédé de mesure de composant et programme de mesure de composant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6168957B1 (en) * 1997-06-25 2001-01-02 Lifescan, Inc. Diagnostic test strip having on-strip calibration
JP2000262298A (ja) * 1999-03-15 2000-09-26 Fuji Photo Film Co Ltd 全血中のグルコース濃度もしくはコレステロール濃度の定量方法
WO2009081790A1 (fr) * 2007-12-20 2009-07-02 Terumo Kabushiki Kaisha Système de gestion d'un niveau mesuré de glycémie et appareil de mesure d'un niveau de glycémie
JP2015179038A (ja) * 2014-03-19 2015-10-08 テルモ株式会社 測定用チップ
WO2017122485A1 (fr) * 2016-01-12 2017-07-20 テルモ株式会社 Dispositif de mesure de composant, procédé de mesure de composant et programme de mesure de composant

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