KR100868566B1 - Device for measuring glucose concentration and a method of measuring the concentration of glucose using the same - Google Patents

Abstract

The present invention provides an ion conductive medium including glucose oxidase, a first sensor unit including an extraction electrode, a working electrode, a counter electrode, and a reference electrode electrically connected to the ion conductive medium, and an ion conductive medium not containing glucose oxidase. A reverse iontophoretic device for measuring the concentration of glucose in the body, comprising a second sensor unit having the same configuration as the first sensor unit except for including a medium, wherein the glucose is measured by the first sensor unit at the time of glucose measurement. A reverse iontophoretic apparatus for measuring the concentration of glucose in the body, and a method for measuring glucose concentration using the same, which is configured to provide a corrected glucose concentration value obtained by subtracting the interference signal value measured from the second sensor unit from the glucose concentration value. to provide.

Glucose, reverse iontophoresis, interference

Description

Device for measuring glucose concentration and a method of measuring the concentration of glucose using the same

1 is a view showing a change in the amount of electricity generated from glucose extracted by a conventional reverse iontophoretic device.

2 is a view showing the electrode structure of the reverse iontophoretic device for measuring the concentration of glucose in the body including two conventionally known sensor unit.

3A and 3B are diagrams showing signal values measured by the first sensor unit of the reverse iontophoretic apparatus shown in FIG. 2.

4 is a view showing the electrode structure of the reverse iontophoretic device for measuring the concentration of glucose in the body including the two sensor unit of the present invention.

5 is a diagram illustrating an interference signal value generated from an interference substance measured by the second sensor unit.

6 is a diagram illustrating signal values measured from the first sensor unit and interference signal values generated from the interference material measured by the second sensor unit.

7a and 7b is a view showing the electrode structure of the reverse iontophoretic device for measuring the concentration of glucose in the body including the three sensor unit of the present invention.

8A, 8B, and 8C show a negative electrode having an electrode structure as shown in FIG. 7A, wherein the extraction electrode 10 of the first sensor unit and the extraction electrode 10a of the second sensor unit are formed as negative electrodes. 3 Applying a constant current during extraction and applying a constant voltage during analysis for 10 minutes using the extraction electrode of the sensor unit as a (+) electrode, and again, the extraction electrode 10 of the first sensor unit and the extraction electrode 10a of the second sensor unit ) And the same current and voltage are applied for 10 minutes using the (+) electrode and the extraction electrode 10b of the third sensor unit as the (-) electrode, and then the working electrodes (20, This is the result of measuring the current through 20a).

The present invention relates to a reverse iontophoretic device for measuring glucose concentration and a method for measuring glucose concentration in an individual using the same.

Conventional devices for measuring blood free blood glucose using iontophoresis and glucose extraction patches used therein have been disclosed. For example, Korean Patent Laid-Open Publication No. 1999-0077833 discloses a sampling system for monitoring the concentration of an analyte present in a biological system, comprising: a reservoir containing an enzyme capable of generating hydrogen peroxide by reacting with an ion conductive medium and an analyte; Sampling means for extracting the analyte from the biological system into the reservoir so that the concentration of the analyte in the reservoir that reacts with the enzyme to produce hydrogen peroxide is submillimolar, and is in operative contact with the reservoir; And a sensor element in operative contact with the reservoir, the electrochemical reaction with hydrogen peroxide produced in the reservoir to provide a detectable signal, measured in buffer at a geometric surface area in the range of about 0.1 to 3 cm ² , 0.6V. And a sensor element comprising an electrode having a background current in the range of about 2 to 60 nA or less and a sensitivity in the range of about 6 to 180 nA per μM of hydrogen peroxide when measured in buffer at 0.6 V. Is disclosed. In addition, Korean Patent Laid-Open Publication No. 2005-0026791 discloses an ion conductive contact portion in contact with the skin, an electrode portion provided on an opposite side of the surface of the ion conductive contact portion in contact with the skin, and an electric quantity measuring unit electrically connected to the electrode. And a monitor connected to the electricity measuring unit, the glucose measuring apparatus comprising: a working electrode to which a voltage for measuring blood glucose is applied; and a glucose surrounding body fluid through the skin to surround most of the periphery of the working electrode. A first extraction electrode to which a current to be extracted is applied, a counter electrode provided to surround most of the extraction electrode, and electrically connected through the working electrode and the ion conductive contact, and the counter electrode does not extend; A portion around the extraction electrode and including the working electrode and the reference potential electrode. It is separate from the analysis unit and the analysis unit, and discloses additional electrode of the non-blood glucose measurement device including the extract to a second extraction electrode for applying an extraction current to the skin with the first extraction electrode wherein the analysis portion. Glucose accumulated in the ion conductive contact, for example, hydrogel, generates hydrogen peroxide by reaction with glucose oxidase homogeneously immobilized on or inside the hydrogel, and the generated hydrogen peroxide is formed between the working electrode and the reference electrode. It is oxidized by the applied voltage to generate a current. 1 is a view showing a change in the amount of electricity generated from glucose extracted by a conventional reverse iontophoretic device. The detected amount of current is converted into glucose concentration by an algorithm set by using an area value.

When using a blood-free blood glucose measurement device and a glucose extracting patch used therein, the moisture content, pressure, temperature, and sensor of an ion-conducting medium caused by interfering substances and external factors that can be extracted simultaneously when extracting glucose through the skin There is a problem in that an incorrect and low sensitivity signal is obtained by reflecting a change in a signal generated from a change in internal contact resistance. Changes in moisture content, pressure, temperature, and contact resistance inside the ion-conducting medium are believed to be due to movement of the individual wearing the glucose measuring reverse iontophoresis device, food intake, stress level, and body temperature changes, It is not limited to the example. Therefore, according to the conventional glucose measuring apparatus and the method using the same, it was necessary to correct the interference signal caused by the interference substance and other external factors.

Accordingly, the present inventors have intensively researched to solve these problems, and have now completed the present invention.

SUMMARY OF THE INVENTION An object of the present invention is to provide a reverse iontophoretic device for measuring glucose, which can measure an accurate glucose concentration value by correcting a change in the amount of electricity caused by an interference substance and an external factor.

Another object of the present invention to provide a method for measuring the concentration of glucose in the body by using a glucose ion ion iontophoresis device of the present invention.

The present invention provides an ion conductive medium including glucose oxidase, a first sensor unit including an extraction electrode, a working electrode, a counter electrode, and a reference electrode electrically connected to the ion conductive medium, and an ion conductive medium not containing glucose oxidase. A reverse iontophoretic device for measuring the concentration of glucose in the body, comprising a second sensor unit having the same configuration as the first sensor unit except for including a medium, wherein the glucose is measured by the first sensor unit at the time of glucose measurement. A reverse iontophoretic device for measuring the concentration of glucose in the body is provided to provide a corrected glucose concentration value obtained by subtracting the interference signal value measured from the second sensor unit from the glucose concentration value.

In the present invention, "reverse iontophoresis" is understood in the art to extract a substance to be analyzed through the skin by applying an electric field to the skin surface. Such reverse iontophoretic techniques are well known in the art. For example, the use of reverse iontophoresis to extract ionic species (Na +, K +) through the skin surface is disclosed (Benjamin et al. (1954) J. Appl. Physiol. 6: 401). Examples of application of reverse iontophoresis to the extraction of various analytes through the skin surface are known (Glikfeld et al. (1989) Pharma. Engineering and Computing 16 (2): 125; Burnette, R. and Marrero, D. (1986)). J. Pharm. Sci. 75 (8); 738). It is also well known in the art for reverse iontophoresis devices. For example, Korean Patent Publication No. 1999-0077833, Korean Patent Publication No. 2005-0026791, and US Patent No. 5,954,685 disclose reverse iontophoresis devices. The reverse iontophoretic device of the present invention should be construed to include conventional configurations used in conventionally known reverse iontophoretic devices, with the exception of the configurations mentioned herein.

Throughout this specification, the ion conductive medium includes any medium that can move the ionic material when a current is applied. The ion conductive medium includes a conductive polymer gel and a hydrophilic polymer gel. Preferably, the ion conductive medium is an ion conductive hydrophilic polymer gel. If the ion conductive medium can provide the characteristics that can be electrically connected to the extraction electrode for extracting glucose in the cell hepatic fluid and the detection electrode for detecting the extracted glucose by the surface contacting the skin and reverse iontophoresis, respectively Any is included.

The enzyme included in the ion conductive medium includes any one that reacts with glucose to generate a chemical signal, and is preferably glucose oxidase. The chemical signal may be a substance formed by the enzyme from the glucose or a derivative thereof. For example, the chemical signal may be hydrogen peroxide. The enzyme is included in any one of the ion conductive media.

In the present invention, the glucose oxidase contained in the ion conductive medium may be homogeneously dispersed in the ion conductive medium. In addition, the glucose oxidase contained in the ion conductive medium may be homogeneously applied to the surface of the ion conductive medium.

The working electrode, the counter electrode and the reference electrode were extracted from intercellular fluids by transion electrophoresis, and glucose accumulated in the ion conductive medium reacted with the hydrogen peroxide produced by the reaction with glucose oxidase immobilized on the ion conductive medium. It serves as a detection electrode for detecting the electrical signal generated by oxidation.

Throughout this specification, the term “electrode” is used in its ordinary sense to refer to a component of an electrochemical cell through which electrical current can flow by contact with an electrolyte. Electrodes that are essential to both galvanic and electrolytic circuits may be composed of electrically conductive materials such as silver, lead, zinc, aluminum, copper, iron, nickel, mercury, graphite, gold, or platinum and oxides and their alloys. .

In the present invention, an "extraction electrode" refers to an electrode to which a current is applied in a sufficient amount so that the substance to be analyzed in the body through the skin can be extracted by reverse iontophoretic extraction. When a current is applied to the extraction electrodes, it is preferable that the current direction of each extraction electrode is alternately changed at regular intervals. "Counter electrode" means an electrode in an electrochemical circuit that acts to apply a constant voltage to the working electrode and the reference electrode to complete the electrochemical circuit. "Reference electrode" means an electrode that provides a reference potential. "Working electrode" means an electrode for measuring the amount of current generated by a redox reaction with an analyte by humanized voltage. In the reverse iontophoretic device of the present invention, the extraction electrode, the working electrode, The material of the counter electrode and the reference electrode is not particularly limited, but may be a platinum (Pt), gold (Au), silver (Ag), an electrode containing carbon (C), or a silver / silver chloride (Ag / AgCl) electrode. The electrodes may be manufactured on the substrate by any method known in the art, for example, a screen printing method and sputtering.

The reverse iontophoretic apparatus for measuring the concentration of glucose in the body of the present invention is a correction obtained by subtracting the interference signal value measured from the second sensor unit from the glucose concentration value measured at the first sensor unit at the time of measuring glucose To provide an established glucose concentration value. Since the ion-conducting medium of the first sensor unit contains glucose oxidase, the current value generated by the applied oxidative potential in the analysis of hydrogen peroxide generated by oxidizing the extracted glucose by the glucose oxidase is determined from glucose and other interference substances. Since the ion conductive medium of the second sensor unit does not contain glucose oxidase, the current value generated therefrom represents the current value generated from other interference materials except glucose. Therefore, the value obtained by subtracting the current value generated from the second sensor portion from the current value generated from the first sensor portion is a current value generated from the true glucose concentration from which the interference signal value is subtracted. The process of calculating the corrected glucose value may be performed by a microprocessor or a program in which an algorithm for performing the calculation process as described above is included.

In one embodiment of the reverse iontophoretic device of the present invention, in the reverse iontophoretic device of the present invention, the ion conductive medium is a hydrogel, and the extraction electrode of the first and second sensor units is partially cut off. The working electrode may be in the form of a circle located inside the ring shape of the extraction electrode, and the counter electrode and the reference electrode may be positioned to surround the outside of the ring shape of the extraction electrode in a line. The electrode structure used in the reverse iontophoretic device of the invention is not limited to these examples.

 One embodiment of the reverse iontophoretic device of the present invention, in the reverse iontophoretic device of the present invention, the measurement of the glucose concentration is the extraction of each of the first and second sensor unit in the state in which the ion conductive medium in contact with the skin of the individual After applying a current through the electrode for a predetermined time, and then changing the direction of the current to apply a current for a predetermined time to extract the glucose to the extraction electrode side (-) current applied, glucose extracted from the working electrode of the first sensor unit Hydrogen peroxide produced by oxidation by this glucose oxidase is corrected by subtracting the current value generated from other interference materials except glucose measured from the working electrode of the second sensor unit from the current value generated by the applied oxidation potential in the analysis. It may be to include the process of obtaining a glucose concentration value. That is, the current is applied in one direction for a certain time, for example, for about 10 minutes, and then again in a different direction. At this time, glucose is extracted into each ion conductive medium when the extraction electrodes in the first and second sensor units become negative electrodes. Therefore, the current value measured from the working electrode of the first sensor unit and the current value measured from the working electrode of the second sensor unit represent values measured at regular time intervals.

The present invention also includes the steps of contacting the skin of an individual with the ion conductive medium of the first and second sensor units of the reverse iontophoretic device for measuring the concentration of glucose in the body comprising the first and second sensor unit according to the present invention ;

Applying glucose for a predetermined time through each of the extraction electrodes of the first and second sensor units, and then changing the direction of the current to apply the current for a predetermined time to extract glucose toward the extraction electrode to which the negative current is applied; And

Measure the current value from the working electrodes of the first and second sensor units, and subtract the current value measured from the working electrode of the second sensor unit from the current value obtained from the working electrode of the first sensor unit to correct the glucose concentration value. It provides a method for measuring the concentration of glucose in the body, comprising the step of obtaining.

In the method of the present invention, the subject includes a mammal. The mammal may include, but is not limited to, humans, monkeys, pigs, cattle, horses, dogs, sheep, and cats.

In the method of the present invention, applying power to the extraction electrodes of the first and second sensor units may be any power supply means known in the art. The time to be applied can be selected by the skilled person in the appropriate time (eg 3 minutes).

In the method of the present invention, electrical signals generated from glucose and interference materials extracted in the ion conductive medium can be measured through the working electrode, counter electrode and reference electrode. The value obtained by subtracting the current value generated from the second sensor portion from the current value generated from the first sensor portion is a current value generated from the true glucose concentration from which the interference signal value is subtracted. The process of calculating the corrected glucose value may be performed by a microprocessor or a program in which an algorithm for performing the calculation process as described above is included. The corrected glucose value may be a value obtained by subtracting the area of the current value graph generated from the second sensor unit from the area of the current value graph generated from the first sensor unit.

The present invention also includes an ion conductive medium including glucose oxidase, a first sensor unit including an extraction electrode, a working electrode, a counter electrode and a reference electrode electrically connected to the ion conductive medium; A second sensor unit having the same configuration as the first sensor unit except for including an ion conductive medium containing no glucose oxidase; And a third sensor unit including an extraction electrode electrically connected to the extraction electrodes of the first and second sensor units, the apparatus for measuring the concentration of glucose in the body. It provides a reverse iontophoretic device for measuring the concentration of glucose in the body to provide a corrected glucose concentration value obtained by subtracting the interference signal value measured from the second sensor unit from the glucose concentration value measured in the.

In the reverse iontophoretic device (hereinafter also referred to as "three sensor apparatus") of the present invention comprising a first to third sensor portion, the reverse iontophoresis, the electrode and the first and second sensor portions as shown in the two sensor apparatus The same configuration as described above is as described in the two sensor apparatus.

The reverse iontophoretic apparatus of the present invention including the first to third sensor units may further include a third sensor unit including an extraction electrode in the two sensor devices. The third sensor unit is preferably spaced apart from the same distance as the first and second sensor unit. Extraction of glucose by reverse iontophoresis is performed by applying an alternating current direction between the extraction electrodes of the first and third sensor units and between the extraction electrodes of the second and third sensor units.

In one embodiment of the three-sensor device of the present invention, in the reverse iontophoretic device of the present invention comprising a first sensor unit to a third sensor unit, the ion conductive medium is a hydrogel, the first and second sensor unit In the extracting electrode is a portion of the ring shape is cut off, the working electrode is in the form of a circle located inside the ring shape of the extraction electrode, the counter electrode and the reference electrode line the outer ring shape of the extraction electrode The extraction electrode of the second sensor unit may be in a ring shape, but the electrode structure is not limited thereto.

In one embodiment of the three-sensor device of the present invention, in the reverse iontophoretic device of the present invention comprising the first to third sensor unit, the glucose concentration is measured in the state in which the ion conductive medium in contact with the skin of the individual In the first and the third sensor portion between the extraction electrode, and between the extraction electrode of the second and the third sensor portion a current is applied for a predetermined time, then the current is applied for a predetermined time by changing the direction of the current, The extraction electrodes of the first and second sensor units are applied in the same current direction to extract glucose toward the extraction electrode to which the negative current is applied, and the second sensor unit is extracted from the current value measured from the working electrode of the first sensor unit. It may include the step of obtaining the corrected glucose concentration value by subtracting the current value measured from the working electrode.

By making the directions of the currents applied to the first and second sensor units the same, glucose is extracted at the same time without time intervals in the ion conductive medium of the first and second sensor units. Thus, the corrected glucose concentration value is obtained without a time difference.

The present invention also includes the steps of contacting the skin of an individual with an ion conductive medium of the first to third sensor units of the reverse iontophoretic device for measuring the concentration of glucose in the body comprising the first to third sensor units of the present invention;

Applying current for a predetermined time between the extraction electrodes of the first and third sensor units and between the extraction electrodes of the second and third sensor units, and then applying a current for a predetermined time by changing the direction of the current. Extracting glucose toward the extraction electrode side to which a negative current is applied by applying the extraction electrodes of the first and second sensor units to be in the same current direction; And

Measure the current value from the working electrodes of the first and second sensor units, and subtract the current value measured from the working electrode of the second sensor unit from the current value obtained from the working electrode of the first sensor unit to correct the glucose concentration value. It provides a method for measuring the concentration of glucose in the body, comprising the step of obtaining.

In the method of the present invention, the subject includes a mammal. The mammal may include, but is not limited to, humans, monkeys, pigs, cattle, horses, dogs, sheep, and cats.

In the method of the present invention, applying a current between the extraction electrodes of the first and third sensor units and between the extraction electrodes of the second and third sensor units may be any power supply means known in the art. have. The time to be applied can be selected by the skilled person in the appropriate time (eg 3 minutes). At this time, since the extraction electrodes of the first and second sensor units are always applied in the same direction, glucose and interference materials are extracted to the ion conductive medium of the first and second sensor units at the same time, that is, without time difference.

In the method of the present invention, electrical signals generated from glucose and interference substances extracted in the ion conductive medium can be measured through the working electrode and the reference electrode. The value obtained by subtracting the current value generated from the second sensor portion from the current value generated from the first sensor portion is a current value generated from the true glucose concentration from which the interference signal value is subtracted. The process of calculating the corrected glucose value may be performed by a microprocessor or a program in which an algorithm for performing the calculation process as described above is included. The corrected glucose value may be a value obtained by subtracting the area of the current value graph generated from the second sensor unit from the area of the current value graph generated from the first sensor unit.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Example

Comparative example  : 2 Sensor part  For glucose measurement Station Ion Youngdong  Measurement of glucose concentration using the device and the same

In the present comparative example, a reverse iontophoretic device for measuring the concentration of glucose in the body including two sensor units having an electrode structure as shown in FIG. 2 was prepared, and glucose was extracted from a human subject using the reverse iontophoretic device. The concentration was measured.

2 is a view showing the electrode structure of the reverse iontophoretic device for measuring the concentration of glucose in the body including a conventionally known two sensor unit. As shown in FIG. 2, the first sensor part is composed of the extraction electrode 10, the working electrode 20, the counter electrode 30, and the reference electrode 40, and the second sensor part is composed of the extraction electrode 10a. Both sensor parts have different electrode structures themselves. In addition, the first sensor unit includes a glucose oxidase in an ion conductive medium electrically connected to the electrode structure, but the second sensor unit does not. The ion conductive medium is placed between the skin and the electrode structure at the time of glucose extraction and measurement, which is not shown in FIG. As shown in FIG. 2, an example of a reverse iontophoretic device for measuring the concentration of glucose in the body including a conventionally known two sensor unit is GluCall ^™ (KMH Corporation, Korea). In FIG. 2, the second sensor unit is simply configured as an extraction electrode, which is used to extract glucose and interferences through the skin, and since the electrode for detecting an electrical signal is not provided to correct the interference signal. Cannot be used.

In the comparative example, the extraction electrodes of the first and second sensor units, the counter electrode and the reference electrode of the first sensor unit were made of silver / silver chloride (Ag / AgCl), and the working electrodes of the first sensor unit were platinum (Pt). ) Material was used. The electrodes were formed by screen printing on an insulating polyethylene film known in the art.

3A and 3B are diagrams showing signal values measured by the first sensor unit of the reverse iontophoretic apparatus shown in FIG. 2. 3A and 3B show an extraction electrode 10 of the first sensor portion of the negative electrode and a extraction electrode 10a of the second sensor portion of the reverse iontophoretic device having the electrode structure as shown in FIG. By applying a current of 0.1mA for 3 minutes and an oxidation potential of 0.4V for 7 minutes to measure the current generated by the oxidation of hydrogen peroxide produced by the enzyme reaction with glucose oxidase to be. As shown in FIGS. 3A and 3B, the signal value is a signal value generated from glucose and other interfering signal materials extracted through the skin into the ion conductive medium of the first sensor part when the extraction electrode of the first sensor part is charged with (−). to be. The interference signal value is a combination of a signal generated from a material oxidized below an applied voltage of 0.4 V and a signal generated from moisture content, pressure, temperature, and change in contact resistance inside the sensor. Here, the change in moisture content, pressure, temperature and contact resistance inside the sensor is caused by the movement of an individual wearing the glucose measuring reverse iontophoretic device of the present invention, food intake, stress state, body temperature change, and the like. It is believed that the present invention is not limited to these examples.

3A and 3B, the ion conductive medium of the first sensor unit is a hydrogel made of acrylate, and a glucose oxidase was homogeneously distributed at a concentration of 200 units / ml inside the hydrogel. The hydrogel containing glucose oxidase is a radical polymerization reaction of 2-hydroxypropyl methacrylate (HEMA) and (N, N-dimethylamino) ethyl methacrylate (DMA) in the presence of 200 unit / ml glucose oxidase. It was obtained by.

3A and 3B, when extracting and measuring glucose through the skin using a conventional reverse iontophoretic device as shown in FIG. 2, ion conductivity caused by external factors as well as glucose and interference materials The change in the signal generated from the moisture content of the medium, the pressure, the temperature and the change in the contact resistance inside the sensor is reflected, thereby obtaining an incorrect and low sensitivity signal. In FIGS. 3A and 3B, the circled portions represent changes in signals resulting from moisture content, pressure, temperature, and change in contact resistance inside the sensor caused by external factors.

Example  1: 2 Sensor part  For glucose measurement Station Ion Youngdong  Measurement of glucose concentration using the device and the same

In the present embodiment, a reverse iontophoretic device for measuring the concentration of glucose in the body comprising a two-sensor unit having an electrode structure as shown in Figure 4, using a reverse iontophoretic device to extract glucose from a human subject The concentration was measured.

4 is a view showing the electrode structure of the reverse iontophoretic device for measuring the concentration of glucose in the body comprising two sensor units of the present invention. As shown in FIG. 4, the electrode structures of the first sensor unit and the second sensor unit are the same, and the first sensor unit includes glucose oxidase in an ion conductive medium electrically connected to the electrode structure. There is no difference. The ion conductive medium is placed between the skin and the electrode structure at the time of glucose extraction and measurement, which is not shown in FIG. In FIG. 4, 10, 20, 30, and 40 represent extraction electrodes, working electrodes, counter electrodes, and reference electrodes of the first sensor unit, respectively, and 10a, 20a, 30a, and 40a represent extraction electrodes, working electrodes of the second sensor unit, respectively; The counter electrode and the reference electrode are shown.

In the present embodiment, the extraction electrode, the counter electrode and the reference electrode of the first and second sensor units were made of silver / silver chloride (Ag / AgCl) and the working electrode was made of platinum (Pt). The electrodes were formed by screen printing on an insulating polyethylene film known in the art.

5 is a diagram illustrating an interference signal value generated from an interference substance measured by the second sensor unit. FIG. 5 is a reverse iontophoretic apparatus having an electrode structure as shown in FIG. 4, wherein the extraction electrode 10 of the first sensor unit is a positive electrode and the extraction electrode 10a of the second sensor unit is a negative electrode. It is the result of measuring the current generated by oxidation of hydrogen peroxide produced by the enzyme reaction with glucose oxidase by applying a current of 0.1 mA for 3 minutes and applying an oxidation potential of 0.4 V for 7 minutes. As shown in FIG. 5, the interference signal value is a signal value generated from glucose and other interference signal material extracted through the skin into the ion conductive medium of the second sensor part when the extraction electrode of the second sensor part is charged with (−). . The interfering signal value is a water content, pressure, temperature and sensor of the ion conductive medium and the signal generated from the material oxidized at the voltage of 0.4V or less, since the glucose conductive enzyme is not included in the ion conductive medium of the second sensor unit The signals generated from the change in the contact resistance inside are combined. Here, the change in moisture content, pressure, temperature and contact resistance inside the sensor is caused by the movement of an individual wearing the glucose measuring reverse iontophoretic device of the present invention, food intake, stress state, body temperature change, and the like. It is believed that the present invention is not limited to these examples. On the other hand, the signal value measured from the working electrode of the first sensor unit is the sum of the signal value resulting from oxidation of glucose to the interference signal value measured from the working electrode of the second sensor unit as described above. Therefore, by subtracting the signal value generated from the working electrode of the second sensor unit from the signal value generated from the working electrode of the first sensor unit, a signal generated from the glucose concentration from which the interference signal value is subtracted can be obtained. In FIG. 5, the ion conductive medium of the first sensor unit is a hydrogel made of an acrylate material, and a glucose oxidase was homogeneously distributed at a concentration of 200 units / ml in the hydrogel. The hydrogel containing glucose oxidase is a radical polymerization reaction of 2-hydroxypropyl methacrylate (HEMA) and (N, N-dimethylamino) ethyl methacrylate (DMA) in the presence of 200 unit / ml glucose oxidase. It was obtained by.

6 is a diagram illustrating signal values measured from the first sensor unit (above) and interference signal values generated from the interference material measured from the second sensor unit (below). In FIG. 6, the difference of the area of the signal value measured from the 2nd sensor part from the area of the signal value measured from the 1st sensor part shows the signal which generate | occur | produced from glucose. In Figure 6, the extraction and measurement of glucose is the same as described with respect to FIG.

In the process of reverse ionization, glucose is complex with the cationic material and is extracted with only the negative electrode in the form of a positive charge as a whole. Thus, the signal value of the first sensor part and the signal value of the second sensor part shown in FIG. There is a time difference of 10 minutes, which is the time taken to change direction. Therefore, in the case of using the apparatus and method for correcting the interference signal value as shown in Figs. 4 to 6, it is possible to simply correct without special equipment, but has a disadvantage in that there is a time delay.

Example  2: 3 Sensor part  For glucose measurement Station Ion Youngdong  Measurement of glucose concentration using the device and the same

In this embodiment, a reverse iontophoretic device for measuring the concentration of glucose in the body comprising a three-sensor unit having an electrode structure as shown in Figures 7a and 7b, and using the reverse iontophoretic device to collect glucose from a human subject Extracted and measured the concentration.

7a and 7b is a view showing the electrode structure of the reverse iontophoretic device for measuring the concentration of glucose in the body including the three sensor unit of the present invention. As shown in FIGS. 7A and 7B, the electrode structures of the first sensor unit and the second sensor unit are the same, and the first sensor unit includes glucose oxidase in an ion conductive medium electrically connected to the electrode structure. In the case of wealth, the difference is not. The ion conductive medium is placed between the skin and the electrode structure during glucose extraction and measurement, and is not shown in FIGS. 7A and 7B. The third sensor portion is configured to include only the extraction electrode. 7A and 7B, 10, 20, 30 and 40 represent the extraction electrode, the working electrode, the counter electrode and the reference electrode of the first sensor unit, respectively, and 10a, 20a, 30a and 40a respectively represent the extraction electrode and the work of the second sensor unit. An electrode, a counter electrode, and a reference electrode are shown, and 10b represents an extraction electrode of the third sensor unit. In the reverse iontophoretic apparatus for measuring the concentration of glucose in the body including the three sensor units of the present invention as shown in Figure 7a and 7b, between the first sensor unit and the extraction electrode of the third sensor unit and the second sensor unit and the second A program or a microprocessor may be provided to apply a current value between the extraction electrodes of the three sensor units, and to apply the current in the same direction to the extraction electrode of the first sensor unit and the extraction electrode of the second sensor unit.

In the present embodiment, the extraction electrodes of the first, second and third sensor units, the counter electrode and the reference electrode of the first and second sensor units are made of silver / silver chloride (Ag / AgCl) material. The working electrode of the 2 sensor unit was made of platinum (Pt) material. The electrodes were formed by screen printing on an insulating polyethylene film known in the art.

8A, 8B, and 8C show a negative electrode having an electrode structure as shown in FIG. 7A, wherein the extraction electrode 10 of the first sensor unit and the extraction electrode 10a of the second sensor unit are formed as negative electrodes. 3 Extracted glucose is produced by enzymatic reaction with glucose oxidase by applying an electric current of 0.1 mA for 3 minutes and an oxidation potential of 0.4 V for 7 minutes using the extraction electrode 10a of the sensor as a positive electrode. This is the result of measuring the electric current generated by the oxidation of hydrogen peroxide. 8A, 8B and 8C show the results of three measurements under the same conditions, respectively. The signal values of the first and second sensor parts as shown in Figs. 8A, 8B and 8C are measured without parallax because the extraction electrodes of the first and second sensor parts are charged in the same current direction at the time of glucose extraction. The interference signal value obtained from the working electrode of the second sensor unit is a signal generated from glucose and other interfering signal materials extracted through the skin into the ion conductive medium of the second sensor unit when the extraction electrode of the second sensor unit is charged with (−). Value. The interfering signal value is a water content, pressure, temperature and sensor of the ion conductive medium and the signal generated from the material oxidized at the voltage of 0.4V or less, since the glucose conductive enzyme is not included in the ion conductive medium of the second sensor unit The signals generated from the change in the contact resistance inside are combined. Here, the change in moisture content, pressure, temperature and contact resistance inside the sensor is caused by the movement of an individual wearing the glucose measuring reverse iontophoretic device of the present invention, food intake, stress state, body temperature change, and the like. It is believed that the present invention is not limited to these examples. On the other hand, the signal value measured from the working electrode of the first sensor unit is the sum of the signal value resulting from oxidation of glucose to the interference signal value measured from the working electrode of the second sensor unit as described above. Therefore, by subtracting the signal value generated from the working electrode of the second sensor unit from the signal value generated from the working electrode of the first sensor unit, a signal generated from the glucose concentration from which the interference signal value is subtracted can be obtained. In FIGS. 8A, 8B and 8C, circles indicate irregular variations in the glucose concentration measurement values due to external factors, and interference signals generated from the second sensor unit from signal values generated from the first sensor unit. By subtracting the value, it can be seen that correction can be made.

8A, 8B and 8C, the ion conductive medium of the first sensor unit is a hydrogel made of acrylate, and glucose oxidase was homogeneously distributed at a concentration of 200 unit / ml inside the hydrogel. The hydrogel containing glucose oxidase is a radical polymerization reaction of 2-hydroxypropyl methacrylate (HEMA) and (N, N-dimethylamino) ethyl methacrylate (DMA) in the presence of 200 unit / ml glucose oxidase. It was obtained by.

According to the reverse iontophoresis apparatus for measuring the concentration of glucose in the body of the present invention, it is possible to obtain a glucose concentration signal value from which noise signals generated by external factors as well as interference materials are removed.

 According to the method for measuring the concentration of glucose in the body of the present invention, the concentration of glucose in the body can be quickly measured with high sensitivity.

Claims (10)

An ion conductive medium including glucose oxidase, an extraction electrode electrically connected to the ion conductive medium, a first sensor unit and an ion conductive medium including a working electrode, a counter electrode and a reference electrode, an extraction electrically connected to the ion conductive medium A reverse iontophoretic device for measuring the concentration of glucose in the body, comprising a second sensor unit including an electrode, a working electrode, a counter electrode, and a reference electrode, wherein the glucose concentration value measured by the first sensor unit when measuring glucose A reverse iontophoretic device for measuring the concentration of glucose in the body which is configured to provide a corrected glucose concentration value obtained by subtracting the interference signal value measured from the second sensor unit from In the measurement of glucose concentration, the current is applied for a predetermined time through each extraction electrode of the first and second sensor units while the ion conductive medium is in contact with the skin of the individual, and then the current is applied for a predetermined time by changing the direction of the current. Extracting glucose toward the extraction electrode to which the negative current was applied, and subtracting the current value measured from the working electrode of the second sensor unit from the current value measured from the working electrode of the first sensor unit to obtain the corrected glucose concentration value. Reverse iontophoretic device for measuring the concentration of glucose in the body comprising the process of obtaining. The method of claim 1, wherein the ion conductive medium is a hydrogel, the extraction electrode in the first and second sensor portion is in the form of a ring cut part, the working electrode is located inside the ring of the extraction electrode In the form of a circle, the counter electrode and the reference electrode is positioned to surround the outer ring shape of the extraction electrode in a line, reverse iontophoretic apparatus for measuring the concentration of glucose in the body. delete The apparatus of claim 1, wherein the glucose oxidase is homogeneously dispersed in the ion conductive medium or homogeneously applied to the surface of the ion conductive medium. A first sensor unit including an ion conductive medium including glucose oxidase, an extraction electrode electrically connected to the ion conductive medium, a working electrode, a counter electrode, and a reference electrode; A second sensor unit including an ion conductive medium, an extraction electrode electrically connected to the ion conductive medium, a working electrode, a counter electrode, and a reference electrode; And A reverse iontophoretic device for measuring the concentration of glucose in the body, comprising a third sensor unit including an extraction electrode electrically connected to the extraction electrode of the first and second sensor unit, the glucose sensor in the first sensor unit when measuring Reverse iontophoretic apparatus for measuring the concentration of glucose in the body to provide a corrected glucose concentration value obtained by subtracting the interference signal value measured from the second sensor unit from the measured glucose concentration value. The method of claim 5, wherein the ion conductive medium is a hydrogel, the extraction electrode in the first and the second sensor portion is a ring shape of the cut part, the working electrode is located inside the ring shape of the extraction electrode The counter electrode and the reference electrode is positioned so as to surround the outer ring shape of the extraction electrode in a line, and the extraction electrode of the second sensor unit is a ring shape, the concentration of glucose in the body Reverse iontophoretic device for measurement. The method of claim 5, wherein the measurement of the glucose concentration is constant between the extraction electrodes of the first and third sensor units and the extraction electrodes of the second and third sensor units while the ion conductive medium is in contact with the skin of the individual. After applying a current for a time, and then applying a current for a predetermined time by changing the direction of the current, the extraction electrode of the first and second sensor unit is applied to be in the same current direction to the extraction electrode side applied (-) current Extracting glucose and subtracting the current value measured from the working electrode of the second sensor unit from the current value measured from the working electrode of the first sensor unit to obtain a corrected glucose concentration value. Reverse iontophoretic device for measuring the concentration of. The apparatus of claim 5, wherein the glucose oxidase is homogeneously dispersed in the ion conductive medium or homogeneously applied to the surface of the ion conductive medium. Contacting the skin of an individual with ion conductive media of the first and second sensor units of the reverse iontophoretic device for measuring the concentration of glucose in the body according to any one of claims 1, 2 and 4; Applying glucose for a predetermined time through each of the extraction electrodes of the first and second sensor units, and then changing the direction of the current to apply the current for a predetermined time to extract glucose toward the extraction electrode to which the negative current is applied; And Measure the current value from the working electrodes of the first and second sensor units, and subtract the current value measured from the working electrode of the second sensor unit from the current value obtained from the working electrode of the first sensor unit to correct the glucose concentration value. Obtaining the concentration of glucose in the body. Contacting the skin of the subject with an ion conductive medium of the first to third sensor units of the reverse iontophoretic device for measuring the concentration of glucose in the body according to any one of claims 5 to 8; Applying current for a predetermined time between the extraction electrodes of the first and third sensor units and between the extraction electrodes of the second and third sensor units, and then applying a current for a predetermined time by changing the direction of the current. Extracting glucose toward the extraction electrode side to which a negative current is applied by applying the extraction electrodes of the first and second sensor units to be in the same current direction; Measure the current value from the working electrodes of the first and second sensor units, and subtract the current value measured from the working electrode of the second sensor unit from the current value obtained from the working electrode of the first sensor unit to correct the glucose concentration value. Obtaining the concentration of glucose in the body.

Images