Sensor

Abstract

To provide a sensor capable of easily detecting selectively vancomycin in a liquid sample.SOLUTION: A sensor 1 includes an electrode to detect vancomycin by contact with a liquid sample S containing vancomycin, and an alcohol oxidation catalyst 8 disposed on an electrode 4.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to a sensor. [Background technology]

[0002] There are known sensors that selectively detect specific components contained in body fluids such as blood and saliva, and liquid samples such as water. As this type of sensor, for example, there is known a sensor that selectively measures the concentration of a drug in the body by utilizing antibody-antigen receptor binding or ligand-receptor binding (for example, Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2010 / 082497 Summary of the Invention [Problem to be solved by the invention]

[0004] The above-mentioned conventional sensors have problems such as insufficient selectivity for drugs and a short shelf life of reagents such as receptors (eg, about six months), leaving room for improvement.

[0005] An object of the present invention is to provide a sensor that can easily and selectively detect vancomycin contained in a liquid sample with a simple configuration. [Means for solving the problem]

[0006] The means for solving the above problems are as follows. <1> A sensor having an electrode for contacting a liquid sample containing vancomycin to detect said vancomycin, the sensor comprising an alcohol oxidation catalyst disposed on said electrode.

[0007] <2> The present invention relates to a catalyst layer comprising the alcohol oxidation catalyst and a base material supporting the alcohol oxidation catalyst, the catalyst layer being disposed on the electrode, the content of the alcohol oxidation catalyst in the catalyst layer being 11.1% by mass or more and 29.6% by mass or less. <1> The sensor according to claim 1 . Effect of the Invention

[0008] According to the present invention, it is possible to provide a sensor that can easily and selectively detect vancomycin contained in a liquid sample with a simple configuration. [Brief description of the drawings]

[0009] [Figure 1] 1 is a top view of a sensor according to a first embodiment. [Diagram 2] Cross section of line AA in Figure 1 [Diagram 3] Enlarged cross-sectional view of the working electrode and catalyst layer [Figure 4] Table showing the amount of catalyst contained in the catalyst layers of Examples 1 to 4 and the carbon layer of Comparative Example 1 [Diagram 5] FIG. 1 is a schematic explanatory diagram showing a verification method using the sensor of the first embodiment. [Figure 6] Graph showing the relationship between the sensor output (sensitivity) and the catalyst content (mass%) for vancomycin, and the relationship between the sensor output (sensitivity) and the catalyst content (mass%) for amikacin [Figure 7] Graph showing the relationship between S / N and catalyst content (mass%) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] <Embodiment 1> A sensor 1 according to a first embodiment of the present invention will be described with reference to Fig. 1 to Fig. 3. Fig. 1 is a top view of the sensor 1 according to the first embodiment, and Fig. 2 is a cross-sectional view taken along the line AA in Fig. 1.

[0011] The sensor 1 is a device for detecting vancomycin contained in a liquid sample. The sensor 1 is used, for example, to grasp the blood concentration of vancomycin during therapeutic drug monitoring (TDM) using vancomycin in combination with another drug (e.g., amikacin). In this case, blood corresponds to the liquid sample.

[0012] The sensor 1 is generally in the shape of a plate extending in the left-right direction of Fig. 1. In this specification, the right side of Fig. 1 is referred to as the front end side of the sensor 1, and the left side of Fig. 1 is referred to as the rear end side of the sensor 1.

[0013] The sensor 1 mainly includes a main body 2, a container 3, a working electrode 4, a counter electrode 5, a reference electrode 6, and a catalyst layer .

[0014] The main body 2 is made of a plurality of ceramic green sheets (three in this embodiment) that are stacked and sintered (ceramic substrate), and has an overall plate shape. For ease of explanation, the sintered portion of the lowermost ceramic green sheet in the main body 2 is referred to as the "first layer 21," the sintered portion of the ceramic green sheet stacked on top of that is referred to as the "second layer 22," and the sintered portion of the ceramic green sheet stacked on top of that (i.e., the uppermost ceramic green sheet) is referred to as the "third layer 23."

[0015] The ceramic green sheet used for the main body 2 is not particularly limited as long as the surface (particularly the bottom surface 31) of the housing portion 3 described below exhibits hydrophilicity, and any known ceramic green sheet can be used.

[0016] For example, ceramic powder such as aluminum oxide (Al2O3), aluminum nitride (AlN), yttrium oxide (Y2O3), etc. may be mixed with a sintering aid, a binder (such as an organic binder), a plasticizer, etc. using a solvent, and the resulting slurry-like mixture may be formed into a thin plate using a known method such as a doctor blade method, and used as a ceramic green sheet.

[0017] The thickness of the ceramic green sheets is not particularly limited and may be set to, for example, 0.1 mm or more and 0.7 mm or less. The thicknesses of the ceramic green sheets used in the main body 2 may be the same as each other or may be different from each other. In the main body 2 of this embodiment, ceramic green sheets having the same thickness are used.

[0018] The storage section 3 is a portion into which a liquid sample (blood, etc.) is placed, and is formed as a concave recess on the upper surface 1a side of the sensor 1. The upper surface 1a of the sensor 1 is made of the upper surface of the third layer 23. The storage section 3 is disposed so as to be biased toward the tip side (right side in FIG. 1) of the rectangular upper surface 1a extending in the front-rear direction in a plan view. Note that a terminal section is disposed on the rear end side (left side in FIG. 1), as described below.

[0019] The storage section 3 has a bottom surface 31 and a wall surface 32 disposed so as to surround the bottom surface 31. The bottom surface 31 is made of a part of the upper surface of the second layer 22 of the main body section 2, and has a flat surface (planar shape). The third layer 23 of the main body section 2 is formed with an opening 23a penetrating in the thickness direction, and the upper surface of the second layer 22 exposed from the opening 23a constitutes the bottom surface 31 of the storage section 3. As shown in FIG. 1, the opening 23a has a square shape in a plan view.

[0020] The wall surface 32 surrounds the bottom surface 31 and extends in the thickness direction of the main body 2. Such a wall surface 32 is formed by a frame-shaped end surface of an opening 23a formed in the third layer 23.

[0021] 2, the bottom surface 31 of the storage section 3 has a square shape when viewed from above. That is, the bottom surface 31 has a square shape when viewed from above, and the wall surfaces 32 surrounding the bottom surface 31 are also disposed to have a square shape.

[0022] The surfaces of the storage section 3 (i.e., the bottom surface 31 and the wall surface 32) are hydrophilic. In this specification, "hydrophilic" refers to a contact angle with water that is less than 90°. The contact angle of the bottom surface 31 and the wall surface 32 is preferably 60° or less, more preferably 55° or less, and even more preferably 50° or less. If the bottom surface 31 and the wall surface 32 are hydrophilic, when a liquid sample such as blood is placed in the storage section 3, the liquid sample easily spreads out in a planar shape within the storage section 3, and is easily brought into contact with an electrode (such as the counter electrode 5) described below.

[0023] Cylindrical electrode holes 31a, 31b, and 31c into which a working electrode 4, a counter electrode 5, and a reference electrode 6 are filled are formed on the bottom surface 31 of the storage section 3. The electrode holes 31a, 31b, and 31c are provided so as to penetrate the second layer 22 of the main body section 2 in the thickness direction. In the case of this embodiment, the electrode hole 31a is filled with a catalyst layer 7 as well as the working electrode 4, as will be described later.

[0024] The working electrode 4, the counter electrode 5, and the reference electrode 6 constitute a so-called three-electrode electrochemical cell. The working electrode 4 is formed by filling the electrode hole 31a with an electrode material for the working electrode 4. The working electrode 4 is cylindrical and extends along the thickness direction (vertical direction) of the main body 2. In this embodiment, the thickness (height) of the working electrode 4 is smaller than the depth of the electrode hole 31a. Therefore, in the electrode hole 31a, the upper surface 4a of the working electrode 4 is disposed on the inner side than the upper side (bottom surface 31 side) of the electrode hole 31a. The upper surface 4a of the working electrode 4 is circular, and the catalyst layer 7 is disposed in a laminated form on the upper surface 4a. As the electrode material for the working electrode 4, for example, a molecular imprint material having a molecular template, an enzyme, or the like is used. The molecular imprint material is obtained by copolymerizing a functional monomer having affinity for vancomycin and a crosslinking monomer, or the like, in the presence of vancomycin (template). The redox current at the working electrode 4 depends on the concentration of vancomycin, and therefore, by measuring the current, the amount of vancomycin can be quantitatively measured.

[0025] The counter electrode 5 has a cylindrical shape extending in the vertical direction, and an upper surface 5a is exposed from the upper side (bottom surface 31 side) of the electrode hole 31b. The upper surface 5a is circular and is disposed so as to be flush with the bottom surface 31. As an electrode material for the counter electrode 5, for example, platinum paste is used.

[0026] The reference electrode 6 has a cylindrical shape extending in the vertical direction, and an upper surface 6a is exposed from the upper side (bottom surface 31 side) of the electrode hole 31c. The upper surface 6a is circular and is disposed so as to be flush with the bottom surface 31. As an electrode material for the reference electrode 6, for example, a mixed paste of silver (Ag) and silver chloride (AgCl) is used.

[0027] The catalyst layer 7 is a layered member that contains a predetermined amount of alcohol oxidation catalyst 8 and is laminated on the upper surface 4a of the working electrode 4. FIG. 3 is an enlarged cross-sectional view of the working electrode 4 and the vicinity of the catalyst layer 7. The enlarged cross-sectional view of FIG. 3 is an enlarged view of a part of the cross-sectional view of FIG. 2. The catalyst layer 7 has at least the alcohol oxidation catalyst 8 and a base material 9 that supports the alcohol oxidation catalyst 8. Such a catalyst layer 7 has a cylindrical shape with approximately the same diameter as the working electrode 4, and is placed on the working electrode 4. There are no particular limitations on the base material 9, so long as it supports the alcohol oxidation catalyst and is inactive against the detection target vancomycin and its interfering drugs. For example, carbon is used as the base material 9.

[0028] The alcohol oxidation catalyst is a catalyst that preferentially oxidizes an alcohol group (hydroxyl group) of an interfering drug having a smaller molecular weight than vancomycin. Examples of interfering drugs having a smaller molecular weight than vancomycin include amikacin, acetaminophenone, clindamycin, and gentamicin.

[0029] The alcohol oxidation catalyst is not particularly limited as long as it does not impair the object of the present invention, but for example, 2-hydroxy-2-azaadamantane is preferably used.

[0030] Vancomycin and the interfering drugs have hydroxyl groups like alcohols, and are therefore oxidized by the alcohol oxidation catalyst. However, the interfering drugs have smaller molecular weights than vancomycin, and are therefore more susceptible to oxidation by the alcohol oxidation catalyst than vancomycin. Therefore, there is a difference in the susceptibility of the oxidation reaction by the alcohol oxidation catalyst between vancomycin and the interfering drugs.

[0031] Incidentally, the interfering drug oxidized by the alcohol oxidation catalyst cannot be detected by the sensor 1. Similarly, vancomycin cannot be detected by the sensor 1 if it is oxidized by the alcohol oxidation catalyst.

[0032] The catalyst layer 7 is obtained by, for example, drying a paste-like composition obtained by mixing an alcohol oxidation catalyst, carbon powder, a solvent, etc. The catalyst layer 7 is preferably liquid-permeable (i.e., porous). The upper surface 7a of the catalyst layer 7 is disposed so as to be flush with the bottom surface 31.

[0033] The content (mass%) of the alcohol oxidation catalyst in the catalyst layer 7 is not particularly limited as long as it does not impair the object of the present invention, but is preferably 5% by mass to 40% by mass, more preferably 5% by mass to 35% by mass. When the content (mass%) is in the range of 11.1% by mass to 29.6% by mass, the sensor 1 can selectively detect vancomycin, in particular.

[0034] 1, the working electrode 4, the counter electrode 5, and the reference electrode 6 on which the catalyst layer 7 is laminated are arranged to form a triangle while maintaining a distance between each other on the bottom surface 31 of the storage section 3. In the case of this embodiment, the counter electrode 5 is arranged on the most front end side, and the working electrode 4 and the reference electrode 6 on which the catalyst layer 7 is laminated are arranged on the rear end side of the counter electrode 5.

[0035] The sensor 1 further includes a first conductive path 40, a second conductive path 50, a third conductive path 60, a first terminal portion (working electrode terminal portion) 45, a second terminal portion (counter electrode terminal portion) 55, and a third terminal portion (reference electrode terminal portion) 65.

[0036] The first conductive path 40, the second conductive path 50, and the third conductive path 60 are formed independently of one another inside the main body 2 of the sensor 1. As shown in Fig. 1, the first conductive path 40, the second conductive path 50, and the third conductive path 60 are shaped to extend generally in the front-to-rear direction.

[0037] The working electrode 4 is connected to one end of the first conductive path 40, and the first terminal 45 is connected to the other end. The counter electrode 5 is connected to one end of the second conductive path 50, and the second terminal 55 is connected to the other end. The reference electrode 6 is connected to one end of the third conductive path 60, and the third terminal 65 is connected to the other end.

[0038] The first conductive path 40, the second conductive path 50 and the third conductive path 60 each include a plurality of vias and a plurality of layered (thin film) wiring portions electrically connected to each other, and share a basic configuration.

[0039] The second terminal portion 55 is made of a layered conductive member having a rectangular shape in a plan view, and is formed on the upper surface of the third layer 23 (i.e., the upper surface 1a of the sensor 1). As shown in Fig. 1, the second terminal portion 55 is formed on the rear end side of the upper surface 1a. The second terminal portion 55 is formed on the upper surface 1a of the sensor 1 so that its longitudinal direction is along the front-rear direction of the sensor 1 and is disposed approximately in the center in a direction perpendicular to the front-rear direction (i.e., the short side direction of the sensor 1).

[0040] The first terminal portion 45 and the third terminal portion 65 are each made of a layered conductive member having a rectangular shape in a plan view, and are formed on the top surface 1a of the sensor 1 further forward (toward the accommodation portion 3) than the second terminal portion 55. The first terminal portion 45 and the third terminal portion 65 are formed on the top surface 1a of the sensor 1 so that their respective longitudinal directions run along the short side direction of the sensor 1 and so that they face each other while maintaining a gap therebetween in the short side direction of the sensor 1.

[0041] The sensor 1 having the above-mentioned configuration is manufactured, for example, by the following method. First, three ceramic green sheets are prepared and processed to form the first layer 21, the second layer 22, and the third layer 23. For example, the ceramic green sheet for the first layer 21 is printed with a metallization paste for forming the wiring portion of the second conductive path 50. The ceramic green sheet for the second layer 22 is formed (drilled) with the electrode hole 31a, etc., drilled with a metallization paste for forming the vias of the second conductive path 50, etc., filled with the metallization paste, printed with the metallization paste for forming the wiring portion of the second conductive path 50, etc. The ceramic green sheet for the third layer 23 is drilled with a hole for forming the opening 23a, drilled with a metallization paste for forming the vias of the second conductive path, etc., filled with the metallization paste, printed with the metallization paste for forming the first terminal portion 45, the second terminal portion 55, etc.

[0042] These ceramic green sheets are then stacked, thermocompressed, and cut to obtain a laminate of ceramic green sheets. The resulting laminate is fired to sinter the ceramic green sheets, thereby obtaining the main body 2 of the sensor 1. Next, the electrode holes 31a, 31b, and 31c provided in the main body 2 are filled with electrode materials for the working electrode 4, counter electrode 5, and reference electrode 6, respectively, and dried at a temperature of 150° C. to obtain the sensor 1 having the components other than the catalyst layer 7.

[0043] The catalyst layer 7 is obtained by preparing a paste-like composition obtained by mixing an alcohol oxidation catalyst, carbon powder, a solvent, etc., filling the electrode hole 31a with the composition in a layered form on the working electrode 4, and then drying it. In this manner, the sensor 1 of this embodiment is manufactured.

[0044] When using the sensor 1 of the present embodiment 1 to detect vancomycin in a liquid sample (blood) containing an interfering drug, for example, a predetermined amount of the liquid sample is dropped onto the bottom surface 31 of the storage unit 3. The sensor 12 is disposed so that the bottom surface of the storage unit 3 is approximately horizontal.

[0045] The amount of liquid sample placed on bottom surface 31 is set, for example, so that the upper surface 7a of catalyst layer 7, the upper surface 5a of counter electrode 5, and the upper surface 6a of reference electrode 6 arranged on bottom surface 31 are all sufficiently covered with the liquid sample, and so that the liquid sample does not overflow from storage section 3.

[0046] In the sensor 1 of this embodiment, when a liquid sample containing drugs (vancomycin, interfering drugs) is supplied into the storage section 3, the interfering drugs contained in the liquid sample are preferentially oxidized by the alcohol oxidation catalyst rather than vancomycin in the catalyst layer 7 laminated on the working electrode 4. As described above, the interfering drugs have a smaller molecular weight than vancomycin and are therefore more susceptible to oxidation by the alcohol oxidation catalyst than vancomycin.

[0047] Such interfering drugs in the liquid sample are oxidized and inactivated before reaching the working electrode 4 and are not detected by the working electrode 4. Therefore, the liquid sample that reaches the working electrode 4 contains a large amount of vancomycin that is detectable by the working electrode 4, as well as a large amount of inactivated interfering drugs that are not detected by the working electrode 4 (i.e., there are almost no interfering drugs that are detectable by the working electrode 4). In this way, the sensor 1 of this embodiment ensures the selectivity of vancomycin when detecting drugs.

[0048] A predetermined voltage is applied between the reference electrode 6 and the working electrode 4 of the sensor 1 (i.e., a predetermined voltage is applied between the third terminal 65 and the first terminal 45). In this state, a current corresponding to a predetermined amount of vancomycin contained in the liquid sample flows between the working electrode 4 and the counter electrode 5 (i.e., between the first terminal 45 and the second terminal 55). By detecting this current, vancomycin in the liquid sample can be selectively detected.

[0049] As described above, the sensor 1 of this embodiment can easily and selectively detect vancomycin contained in a liquid sample with a simple configuration.

[0050] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to these examples in any way.

[0051] Example 1 As Example 1, a sensor having the configuration shown in the above-mentioned embodiment 1 was prepared. The catalyst layer was prepared under the following conditions. 100 parts by mass of carbon powder, 13 parts by mass of 2-hydroxy-2-azaadamantane (alcohol oxidation catalyst), and an appropriate amount of solvent (isopropanol) were mixed to prepare a paste-like composition. The obtained composition was filled in the electrode hole for the working electrode in a form of being layered on the working electrode, and then the composition was dried to obtain a catalyst layer.

[0052] [Examples 2 to 4] The catalyst layers and sensors of Examples 2 to 4 were prepared in the same manner as in Example 1, except that the amount (catalyst amount) of 2-hydroxy-2-azaadamantane (alcohol oxidation catalyst) used in the catalyst layer was changed to each amount shown in the table of FIG.

[0053] Comparative Example 1 A sensor was produced in the same manner as in Example 1, except that a carbon layer made of a carbon paste not containing an alcohol oxidation catalyst was used instead of the catalyst layer.

[0054] [Detection of vancomycin] Physiological saline R1 containing vancomycin (molecular weight: 1449.3) at a concentration of 300 μg / mL was prepared. For the sensors of Examples 1 to 4 and Comparative Example 1, the sensor output (sensitivity) to vancomycin contained in the physiological saline R1 was measured by the method described below.

[0055] FIG. 5 is an explanatory diagram that shows a schematic diagram of a verification method using the sensor 1 of Example 1. Here, the verification method using the sensor 1 of Example 1 will be described with reference to FIG. 5. As shown in FIG. 5, an electrochemical analysis device (potentiostat) 100 that is electrically connected to the sensor 1 was prepared. This electrochemical analysis device 100 includes a voltage application unit 110 and a current detection unit 120. The voltage application unit 110 applies a predetermined voltage between the reference electrode 6 of the sensor 1 and the working electrode 4 on which the catalyst layer 7 is laminated (between the third terminal 65 and the first terminal 45). The current detection unit 120 detected the value of a current flowing between the working electrode 4 and the counter electrode 5 (the value of a current flowing between the first terminal 45 and the second terminal 55) in a state in which the voltage is applied.

[0056] The results of the sensor output (sensitivity) to vancomycin in the sensors of Examples 1 to 4 and Comparative Example 1 are shown in the graph of FIG.

[0057] [Detection of interfering drugs] Physiological saline R2 containing amikacin (an example of an interfering drug, molecular weight: 585.6) at a concentration of 300 μg / mL was prepared. For the sensors of Examples 1 to 4 and Comparative Example 1, the sensor output (sensitivity) to amikacin contained in physiological saline R2 was measured by the same method as in the above-mentioned "Detection of vancomycin". The results are shown in the graph of FIG. 6.

[0058] 〔result〕 Fig. 6 is a graph showing the relationship between the sensor output (sensitivity) and the catalyst content (mass%) for vancomycin, and the relationship between the sensor output (sensitivity) and the catalyst content (mass%) for amikacin. The horizontal axis of the graph in Fig. 6 represents the content (catalyst content) (mass%) of the alcohol oxidation catalyst in the catalyst layer (carbon layer), and the vertical axis of the graph in Fig. 6 represents the sensor output (sensitivity).

[0059] In each Example, the sensor output (sensitivity) of vancomycin was divided by the sensor output (sensitivity) of amikacin to obtain the S / N ratio. The obtained S / N ratios of each Example are summarized in the graph of Figure 7. Figure 7 is a graph showing the relationship between S / N and catalyst content (mass%).

[0060] As shown in Figures 6 and 7, it was confirmed that in the range of catalyst content of 17.4% by mass or less, as the catalyst content increases, the amikacin sensor output (sensitivity) decreases and the S / N value improves. Note that when the catalyst content is 40% by mass or less (preferably 35% by mass or less), an S / N value capable of selectively detecting vancomycin is obtained. In particular, it was confirmed that when the catalyst content is in the range of 11.1% by mass or more and 29.6% by mass or less, a good S / N value for selectively detecting vancomycin is obtained.

[0061] <Other embodiments> The present invention is not limited to the embodiments described above and illustrated in the drawings, and the following embodiments, for example, are also included within the technical scope of the present invention.

[0062] (1) The liquid sample may be a body fluid such as blood or saliva, or an aqueous solution such as physiological saline, seawater, river water, or well water. The sensor of this embodiment may also be used to detect components in food or components produced during chemical synthesis.

[0063] (2) There are no particular limitations on the size, material, arrangement, etc. of the electrodes in the sensor, so long as they do not impair the object of the present invention.

[0064] (3) As long as the object of the present invention is not impaired, a co-oxidant may be used in combination with the alcohol oxidation catalyst. [Explanation of symbols]

[0065] REFERENCE SIGNS LIST 1...sensor, 2...main body, 3...container, 4...working electrode, 5...counter electrode, 6...reference electrode, 7...catalyst layer, 8...alcohol oxidation catalyst, 9...base material, 45...first terminal portion, 55...second terminal portion, 65...third terminal portion

Claims

1. A sensor having an electrode for detecting vancomycin in contact with a liquid sample containing said vancomycin, The sensor includes an alcohol oxidation catalyst disposed on the electrode.

2. a catalyst layer that has the alcohol oxidation catalyst and a base material that supports the alcohol oxidation catalyst and is disposed on the electrode; 2. The sensor according to claim 1, wherein a content of the alcohol oxidation catalyst in the catalyst layer is 11.1% by mass or more and 29.6% by mass or less.

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