JPS59125052A - Continuous measuring device for blood sugar value - Google Patents

Abstract

PURPOSE:To enable continuous measurement of the fluctuating blood sugar value of a patient without retardation by constituting a measuring part of a membrane for immobilizing glucose oxidizing enzyme and a hydrogen peroxide electrode having >=3:1 area ratio of a silver cathode and a platinum anode in measuring the concn. of the glucose in a sample liquid contg. glucose divided by incorporating a gaseous substance of 1/3-2 times volume of sample liquid in the continuous liquid flow of said sample. CONSTITUTION:A tube 38 for supplying a gaseous substance, for example, air, provided with a pump 36 is connected to a mixing tube 28 to divide the flow of a dilute blood by the air. The divided samples of the dilute blood are transferred to a measuring part 46 for a blood sugar value. The part 46 is constituted of, for example, an enzyme electrode 56 and a flow cell 59, and is capable of detecting, with time, the output corresponding to the blood sugar value of the samples of the dilute blood divided by the gaseous substance and supplied via an nozzle 58. The output obtd. with the electrode 56 is fed, via an amplifier, to an arithmetic circuit for the blood sugar value, by which the blood sugar value is calculated. If the ratio of the area of the silver cathode/the area of the platinum cathode of the hydrogen peroxide electrode is >=3, the measured value in a high concn. region does not show a low value as compared to the true value and the linearity in the output is assured.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a blood glucose level continuous measuring device, and more particularly to a blood glucose level continuous measuring device that continuously collects a small amount of blood from a patient and continuously measures the fluctuating blood glucose level of the patient without delay. It is.

1r1 [Glucose value is a barometer that indicates the state of sugar metabolism in the living body and is the main biological information. Diseases that cause abnormal blood sugar levels include diabetes, liver disease, endocrine disease,
There are many metabolic diseases, central nervous system diseases, etc. Blood sugar levels also fluctuate due to physiological causes such as food intake, interactivity, stress (emotions, infection, pregnancy, fever, surgery), etc. In normal people, blood sugar levels are kept within a relatively narrow range of 0 to 20 W/dt, and do not show abnormally high or low values. The reason why the blood sugar level maintains such a dynamic equilibrium state is that the living body has a mechanism for increasing blood sugar level and a mechanism for consuming it, and there is a balance between the two.

However, if this balance is disrupted for some reason, the blood sugar level will show an abnormal value, and medical treatment will be required. Depending on the patient, blood sugar levels may fluctuate rapidly over a short period of time, and continuous monitoring of blood sugar levels is required as diagnostic information for treatment. In addition, blood sugar levels are closely related to the secretion of hormones such as insulin, glucagon, growth hormone, and thyroid hormone, as well as the administration of certain drugs, and blood sugar levels are also important for testing and research related to these. There is a need for continuous monitoring of The present invention relates to a continuous blood glucose level measuring device developed to meet these medical needs.

In recent years, with the remarkable development of sensor technology and measuring instrument technology, glucose sensors for measuring sugar chains have been developed, and continuous blood glucose level measuring devices using these sensors have been put into practical use. These conventional blood glucose level continuous measuring devices generally include a means for continuously collecting blood while injecting two anticoagulant drugs, a means for diluting the collected blood, a means for transporting the diluted blood, and a means for transporting the blood to be transported. It consists of a means for continuously contacting the blood glucose level and measuring the blood glucose level, and a means for continuously discharging the measured blood. Enzyme electrodes, which have a very short reaction time of 7 minutes or less, are widely used as means for measuring blood glucose levels by contacting blood with blood. .

The purpose of using a continuous blood glucose level measuring device is generally to detect abnormal blood a!
The purpose of this method is to measure and monitor the blood glucose level of a patient expected to exhibit I (11'f) over a long period of time.

However, it cannot be said that the conventional blood glucose level continuous measuring device F fully satisfies these objectives. In other words, the following problems exist.

/ Enzyme electrodes using enzyme membranes with immobilized glucose oxidase tend to have a lower output than the true blood glucose level in high concentration regions, and lack output linearity.

2. Proteins and fats contained in the blood adhere to the membrane of the enzyme electrode, so the output characteristics of the enzyme m-pole change over time.

Therefore, the present inventors have conducted intensive research to overcome all the drawbacks of the conventional blood glucose 11-mu continuous measuring device and to obtain a device that can continuously measure blood glucose levels. The sample liquid flow is divided by mixing a gas with a volume twice that of the sample liquid, and the glucose concentration in the divided sample liquid is determined between the glucose oxidase immobilized membrane and the silver cathode. All the problems of the conventional continuous blood glucose level measuring device 6 can be solved by measuring with an enzyme'* electrode characterized by comprising a platinum anode with an area ratio of 3 or more and a hydrogen peroxide electrode. I figured it out.

We also prototyped a device with the above-mentioned characteristics, and were able to confirm a continuous blood glucose level measuring device with extremely excellent characteristics.

The general purpose of the present invention is to maintain output linearity in a high concentration region without showing a low value, and to maintain output linearity even after long hours of operation due to membrane contamination caused by white matter, white matter, etc. contained in the blood. It is an object of the present invention to provide a continuous measuring device for sugar level in which the output characteristics do not change over time.

The gas used in the apparatus according to the present invention is mixed mainly to divide the sample flow and prevent fouling of the membrane, and air is preferable, but oxygen, carbon dioxide, Nitrogen, inert gas, etc., or a mixture thereof may also be used.

The means for mixing the gas into the sample flow is to connect the sample supply tube containing glucose with the gas supply tube, and forcefully mix the gas into the sample flow using a pump or the like to separate the sample flow. , t, 'Ij. It has been found from experiments that mixing the gas in a volume that is twice as large as the sample flow is effective in preventing 7υ deviations.

One enzyme electrode used in the present invention is composed of a glucose oxidase (hereinafter abbreviated as GOD) immobilized membrane and a hydrogen peroxide electrode consisting of a silver cathode and a platinum anode.

Next, the glucose in the sample solution undergoes the next solubilization reaction at GOD.

Glutooth 10, +H, O-1 → Glucon C narrow 10H2
0°Hydrogen peroxide generated in the above reaction is detected with a hydrogen peroxide electrode.

The hydrogen peroxide electrode measures hydrogen peroxide generated according to the reaction formula below.

Platinum (electrode: City axis - → 2H++O) + Su θ - Silver cathode:
Ot +'lH"+'le-□ uH>0 As a result of intensive research, the inventors have found that the cause of the low output in the high blood sugar concentration region and the lack of linearity in the output is due to a large amount of We discovered that this is because when generated hydrogen peroxide is oxidized with a platinum anode, a reduction reaction of oxygen commensurate with the reaction at the silver cathode does not occur at the silver cathode. As a result of examining the area of the silver cathode, it was revealed that the area of silver needs to be at least three times, preferably at least twice, the area of the platinum anode.

Next, embodiments of the blood glucose continuous measurement device according to the present invention will be described in detail below with reference to the accompanying drawings.

Figure 1 shows a system diagram of the device of the present invention, with reference to Ministry No. I
O is a double lumen catheter constituting the means for collecting blood. This catheter 10 pumps a heparin solution as an anticoagulant for blood from a reservoir/2 to a pump/4.
1. Blood is collected from the living body under the action of a pump/l while being supplied through the pump. Blood collection tube! The ff+ liquid sucked into B is supplied to the mixing tube 2g and diluted with a diluent. The diluted liquid is pumped from the storage tank 30 by pump j'2
The diluent is supplied to the mixing tube 2g by the diluent supply tube 3≠ led out through the diluent supply tube 3≠. Also, this mixing tube 2g is a gas body equipped with a pump 3A, in this case an air supply tube 3
g is connected to divide the flow of diluted blood with air, which improves the mixing of the blood and diluent, and also serves to prevent the enzyme electrode from becoming contaminated. The diluted blood sample divided by the gaseous body is sent to the blood sugar level measuring section t1. Transferred to Party B.

For example, as shown in FIG. 2, the blood glucose level measuring section≠t is the enzyme electrode j6 and 70-7! By supplying a diluted blood sample divided by a gaseous body to the enzyme membrane Vjts6 configured and arranged in this way through the sample supply nozzle str, the enzyme electrode j& can continuously supply the sample. The output corresponding to the blood sugar level can be detected over time. j7 is an enzyme membrane with GOD immobilized;
to represents the sample discharge nozzle.

Hydrogen peroxide used in enzyme electrodes? The 1'L pole 70 is composed of a platinum anode 72 and a silver cathode 71, for example, as shown in FIG. In this example, the platinum area is 3. Is the silver area 332- for /-? One pole was used. 73 is a lead wire, and 7 is a connector. Table 1. The output obtained from the enzyme electrode st is sent to a blood sugar level calculation circuit via an amplifier, and the blood sugar level is calculated.

In addition, when the blood sugar output 4/j has a certain amplitude due to the mixing of a gaseous body, the output value may be converted into a semicircular form if necessary.

<Example/> The effect of mixing a gaseous body into the continuous flow of a sample according to the present invention was investigated using drained blood collected from a domestic rabbit as a sample. A glycolytic inhibitor (fluorinated IJum) was added in advance to the drained blood collected from domestic rabbits to prevent fluctuations in blood sugar levels. Figure 3 shows comparative data when a gas is mixed into the continuous flow of the sample liquid and when it is not. The solid line represents continuous blood sugar measurement data when a gaseous body is mixed, and the broken line represents data when a gaseous body is not mixed. If no gas is mixed,
Even though the blood sugar level of the sample did not change, the output value showed a tendency to decrease over time, and from the start of measurement /0 minutes
Later, the value was about /θ~/j% lower than the starting value.

On the other hand, when a gas body is mixed in, the output power II'I shows a substantially constant value over time, and it is clear that a stable output value can be obtained by mixing a gas body. In this experimental example, a gas having a volume of approximately % of the sample liquid was mixed.

<Example 1> The output characteristics were investigated when the areas of the platinum anode and silver cathode of the hydrogen peroxide electrode were changed. Silver + 1 + i 411v Platinum area value is approximately /, 1.3.10. ,．． 20°30.410.
FIG. 5 shows the results of determining the output value when an electrode with jrO was prepared and a high-concentration gluten standard solution was used as a sample. The black circles are measurement examples using a standard solution with a glucose concentration of /, 000 cape/di as a sample, and the white circles are measurement examples using a standard solution with a glucose concentration of SOOη/d. Silver/Platinum 4 (In the case of an electrode with Q of about /, -, the value will be lower than the true value as shown in the data in Figure 5, but in the case of an electrode with a value of 3 or more, the concentration will be the same as that of the standard solution. The output value was shown.

As a result of this experiment, if the value of hydrogen peroxide TM, silver cathode area/platinum anode area of the electrode is 3 or more, the measured value in the high concentration region will not show a lower value than the true value, and the output ik m It became clear that sex is secured. Furthermore, it is clear that the value of silver cathode area/platinum anode area is extremely stable when it is greater than g.

The preferred embodiments and experimental examples for demonstrating the effects of the present invention have been described above, but the present invention is not limited thereto, and many improvements and changes may be made without departing from the spirit of the present invention. Needless to say.

[Brief explanation of drawings]

FIG. 1 is a system diagram showing an embodiment of the blood glucose level continuous measuring device according to the present invention, FIG. 1 is a sectional view of a blood glucose measuring section used in the device of the present invention, and FIG. The configuration diagram of the hydrogen oxide electrode, Figure 1 is a custom-made diagram showing the effect of gas mixture,
Figure j' is a graph showing the relationship between the area ratio of the silver cathode and the platinum anode and the Glutooth standard solution output characteristics. 10...Double lumen catheter/, 2...Storage tank/l...Pump/l.
...Pump! o1m death/silicon tubule)
t...Blood collection system, 21...Mixing tube 3θ...
・Storage m 3.2... Pump 3g... Diluent supply pipe 36... Pump 3r... Gas supply pipe 4I! o...Mixed filter 2...Blood sugar level measuring section, f...Enzyme electrode j7...fl membrane
Sample supply nozzle...
・Flow cell to... ・Sample bait, output nozzle name! ...Waste liquid + V X and ... box
Body 70...Hydrogen peroxide electrode 7/...Silver cathode 72.
...Platinum anode 73...Lead wire 7Hiro...Connector TIME (min) Fig. 5 Ag/Pt Rati.

Claims (1)

[Claims] The continuous flow of sample liquid containing glucose is divided into two parts by mixing twice the volume of gas from urine in the sample liquid, and the glucose concentration in the divided sample liquid is adjusted to A continuous blood glucose level determination device characterized by measuring with an oxidase electrode.