Sensor

Abstract

To provide a sensor capable of easily selectively detecting vancomycin in a liquid sample.SOLUTION: A sensor 1 includes electrodes 4, 5, and 6 to detect vancomycin by contact with a liquid sample containing vancomycin, and a filter 7 including a porous body having micropores of 0.3 μm or more and 0.7 μm or less and mesopores of 2 nm or more and 10 nm or less and disposed overlapping with the electrodes 4, 5, and 6.SELECTED DRAWING: Figure 1

Description

[Technical field]

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

[0002] Sensors that selectively detect specific components (organic substances) contained in body fluids such as blood and saliva, and liquid samples such as water, are known. For example, a sensor that measures the concentration of a specific drug contained in a subject's blood at a predetermined time interval in therapeutic drug monitoring (TDM) is known as this type of sensor (Patent Document 1). This sensor is used together with a laser deionization mass spectrometer, and uses concentration information of nanoparticle-form tungsten disulfide and concentration information of an internal standard substance that has similar physicochemical properties to the target substance to detect a specific drug (target substance). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Special Publication No. 2022-518570 Summary of the Invention [Problem to be solved by the invention]

[0004] In the above-mentioned conventional sensors, several complicated steps must be taken to separate and detect a specific drug contained in blood, which poses a problem.

[0005] Furthermore, in this type of sensor, when a detection target is a component (drug) with a large molecular weight contained in a liquid sample, it has been difficult to detect it preferentially over a component (drug) with a small molecular weight.

[0006] 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]

[0007] The means for solving the above problems are as follows. <1> A sensor having an electrode that comes into contact with a liquid sample containing vancomycin and detects the vancomycin, the sensor comprising a filter that includes a porous body having macropores of 0.3 μm or more and 0.7 μm or less and mesopores of 2 nm or more and 10 nm or less and is arranged so as to overlap the electrode.

[0008] <2> The thickness of the filter is 0.6 mm or more. <1> The sensor according to claim 1 . Effect of the Invention

[0009] 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]

[0010] [Figure 1] 1 is a top view of a sensor according to a first embodiment. [Diagram 2] Top view of the sensor without the filter [Diagram 3] Cross section of line AA in Figure 1 [Figure 4] FIG. 1 is a schematic explanatory diagram showing a verification method using the sensor of the first embodiment. [Diagram 5] Graph showing sensor output for vancomycin and amikacin [Figure 6] Graph showing sensor output versus time for vancomycin and amikacin passing through the filter while each is dripped onto the filter alone. [Figure 7] Graph showing sensor output versus time for vancomycin and amikacin mixed together and dripped onto a filter and passing through the filter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] <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, Fig. 2 is a top view of the sensor 1 with the filter 7 removed, and Fig. 3 is a cross-sectional view taken along line AA in Fig. 1.

[0012] 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 in which vancomycin is used in combination with another drug (e.g., amikacin). In this case, blood corresponds to the liquid sample.

[0013] The sensor 1 is generally in the shape of a plate extending in the left-right direction of Figures 1 and 2. In this specification, the right side of Figures 1 and 2 will be referred to as the front end side of the sensor 1, and the left side of Figures 1 and 2 will be referred to as the rear end side of the sensor 1.

[0014] 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 filter .

[0015] 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."

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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 (the right side in Figs. 1 and 2) of the rectangular upper surface 1a extending in the front-to-rear direction in a plan view. Note that a terminal section is disposed on the rear end side (the left side in Figs. 1 and 2), as described below.

[0020] 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 has an opening 23a provided so as to penetrate 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. 2, the opening 23a has a square shape in a plan view.

[0021] 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.

[0022] 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.

[0023] 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 working electrode 4 described below.

[0024] 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 2 in the thickness direction.

[0025] 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 extending along the thickness direction (vertical direction) of the main body 2, and the upper surface 4a is exposed from the upper side (bottom surface 31 side) of the electrode hole 31a. The upper surface 4a is circular and arranged to be flush with the bottom surface 31. As the electrode material for the working electrode 4, for example, a molecular imprint material having a molecular template or an enzyme is used so that vancomycin can be specifically detected. The molecular imprint material is obtained by copolymerizing a functional monomer having affinity for vancomycin and a crosslinking monomer in the presence of vancomycin (template). Since the redox current at the working electrode 4 depends on the concentration of vancomycin, vancomycin can be quantitatively measured by measuring the current.

[0026] 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.

[0027] 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.

[0028] 2, the working electrode 4, the counter electrode 5, and the reference electrode 6 are arranged to form a triangle while maintaining a distance between each other on the bottom surface 31 of the housing part 3. In the case of this embodiment, the counter electrode 5 is arranged at the most distal end side, and the working electrode 4 and the reference electrode 6 are arranged on the rear end side of the counter electrode 5.

[0029] 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.

[0030] 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. 2, 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.

[0031] 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.

[0032] 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.

[0033] 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 etc., the second terminal portion 55 is formed on the rear end side portion 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).

[0034] 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.

[0035] The filter 7 is made of a layered silica monolith body (an example of a porous body) having a predetermined thickness. The silica monolith body is a bulk body of silica gel having a silica skeleton including three-dimensional mesh-like pores (macropores) of micrometer size and pores (mesopores) of nanometer size. The silica monolith body is manufactured using a known method such as a combination of a sol-gel reaction and spinodal decomposition using silicon alkoxide (e.g., tetraethoxysilane, tetramethoxysilane, methyltrimethoxysilane, methyltriethoxysilane, etc.) as a starting material.

[0036] The filter 7 is made of a monolith body (an example of a porous body) having macropores of 0.3 μm to 0.7 μm and mesopores of 2 nm to 10 nm. The filter 7 is obtained, for example, by pressure molding porous particles filled in a predetermined mold.

[0037] The filter 7 has a square shape that is slightly larger than the storage unit 3 (bottom surface 31) when viewed from the top surface 1a side, and is disposed on the top surface 1a of the main body 2 so as to overlap with the electrodes (working electrode 4, counter electrode 5, and reference electrode 6) of the sensor 1 disposed on the bottom surface 31 of the storage unit 3. In this embodiment, the filter 7 is disposed so as to cover the storage unit 3.

[0038] The thickness of the filter 7 is not particularly limited as long as it does not impair the object of the present invention, but is preferably, for example, 0.6 mm or more. When the thickness of the filter 7 is 0.6 mm or more, vancomycin contained in a liquid sample can be easily and selectively detected.

[0039] The upper limit of the thickness of the filter 7 is not particularly limited as long as it does not impair the object of the present invention, and may be, for example, 10 mm or less.

[0040] 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.

[0041] 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. Finally, 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 except for the filter 7.

[0042] The filter 7 is made of a silica monolith having a predetermined thickness by a known method as described above. In this manner, the sensor 1 of this embodiment is manufactured.

[0043] In the sensor 1 of this embodiment, when drugs such as vancomycin contained in blood pass through the filter 7 made of a monolithic silica body, the passing time differs depending on the size (molecular weight) of the molecule. In this embodiment, vancomycin, which has the largest molecular size (molecular weight), passes through the filter 7 preferentially compared to other drugs.

[0044] Vancomycin has a larger molecular size (molecular weight) than other drugs, and therefore when it passes through the filter 7, it does not enter the nanometer-sized pores (mesopores) in the silica skeleton, but passes only through the three-dimensional network pores (macropores). In other words, vancomycin has a shorter residence time in the filter 7, and passes through the filter 7 preferentially over other drugs.

[0045] In contrast, drugs other than vancomycin pass through the filter 7 while penetrating into nanometer-sized pores (mesopores), and therefore have a longer residence time in the filter 7. Therefore, drugs with smaller molecules than vancomycin pass through the filter 7 later than vancomycin.

[0046] By using such a filter 7, vancomycin in the blood can be supplied into the storage section 3 faster than other drugs.

[0047] For example, when detecting vancomycin in blood (a liquid sample), a predetermined amount of blood is dropped onto the surface of filter 7 placed so as to cover storage unit 3. The blood on the surface of filter 7 passes through filter 7 in the thickness direction, and then falls onto bottom surface 31 of storage unit 3 below filter 7.

[0048] The main body 2 of the sensor 1 is disposed so that the bottom surface of the container 3 is approximately horizontal. The amount of blood (liquid sample) placed on the surface of the filter 7 is set so that, for example, the upper surface 4a of the working electrode 4, the upper surface 5a of the counter electrode 5, and the upper surface 6a of the reference electrode 6, which are disposed on the bottom surface 31, are all sufficiently covered with the blood (liquid sample) and so that the blood (liquid sample) does not overflow from the container 3.

[0049] 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, when blood (liquid sample) that has passed through the filter 7 is gradually supplied into the storage section 3, a current corresponding to a predetermined amount of vancomycin contained in the blood 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 blood can be selectively detected. After such a current corresponding to vancomycin is detected, a current corresponding to drugs other than vancomycin flows between the working electrode 4 and the counter electrode 5.

[0050] As described above, the sensor 1 of this embodiment can easily and selectively detect vancomycin contained in a liquid sample with a simple configuration.

[0051] 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.

[0052] Example 1 (Verification of sensor output for vancomycin and interfering drugs) As Example 1, a sensor 1 having the configuration shown in the above-mentioned embodiment 1 was prepared. In addition, a physiological saline S1 containing vancomycin at a concentration of 300 μg / mL and a physiological saline S2 containing amikacin (an interfering drug) at a concentration of 300 μg / mL were prepared. Then, using the sensor 1 with the filter 7 removed, the sensor output sensitivity to vancomycin contained in the physiological saline S1 and the sensor output sensitivity to amikacin contained in the physiological saline S2 were verified. Here, with reference to FIG. 4, a verification method using the sensor 1 of Example 1 will be described. FIG. 4 is an explanatory diagram that shows a schematic representation of the verification method using the sensor 1 of Example 1. As shown in FIG. 4, an electrochemical analysis device (potentiostat) 100 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 and the working electrode 4 (between the third terminal 65 and the first terminal 45) of the sensor 1. The current detection unit 120 detects 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) while the voltage is applied.

[0053] Then, physiological saline S1 was placed directly into the storage section 3 without using the filter 7, and the sensor output for vancomycin in the physiological saline S1 was measured using the electrochemical analysis device 100. Similarly, physiological saline S2 was placed directly into the storage section 3 without using the filter 7, and the sensor output for amikacin in the physiological saline S2 was measured using the electrochemical analysis device 100. The results are shown in FIG.

[0054] 5 is a graph showing the sensor output for vancomycin and amikacin. As shown in FIG. 5, the sensor 1 of Example 1 is sensitive to each of vancomycin and amikacin. Therefore, the sensor 1 of Example 1 cannot selectively detect vancomycin in a state where vancomycin and amikacin are mixed.

[0055] (Measurement of vancomycin and interfering drug concentrations using filter 7) A filter 7 was prepared that was made of a silica monolith having a thickness of 0.6 mm, macropores of 0.3 μm to 0.5 μm, and mesopores of 3 nm. With this filter 7 arranged so as to overlap with the electrodes (working electrode 4, counter electrode 5, and reference electrode 6) of the sensor 1, a predetermined amount of the physiological saline solution S1 (concentration of vancomycin: 300 μg / mL) was dropped onto the surface of the filter 7 at a constant rate, while the concentration of vancomycin was measured using the electrochemical analysis device 100. The measurement results are shown in FIG. 6.

[0056] Similarly, the saline solution S2 (amikacin concentration: 300 μg / mL) was dropped at a constant speed onto the surface of the filter 7 arranged so as to overlap with the electrodes (working electrode 4, counter electrode 5, and reference electrode 6) of the sensor 1, while the vancomycin concentration was measured using the electrochemical analyzer 100. The measurement results are shown in FIG.

[0057] FIG. 6 is a graph showing the relationship between the sensor output and time for vancomycin and amikacin, which are dropped onto the filter 7 individually and pass through the filter 7. The vertical axis of FIG. 6 is the sensor output (sensitivity), and the horizontal axis is the time (seconds). As shown in FIG. 6, after the saline solution S1 containing vancomycin is dropped onto the surface of the filter 7, detection of vancomycin by the electrodes (working electrode 4, counter electrode 5, and reference electrode 6) of the sensor 1 is observed from about 350 seconds to 420 seconds. In contrast, after the saline solution S2 containing amikacin is dropped onto the surface of the filter 7, detection of amikacin by the electrodes (working electrode 4, counter electrode 5, and reference electrode 6) of the sensor 1 is observed from about 420 seconds. In this way, it was confirmed that vancomycin (molecular weight: 1449.3), which has a larger molecular size, can pass through the filter 7 more quickly than amikacin (molecular weight: 585.6).

[0058] At 400 seconds after the start of dripping, a clear difference was observed between the sensor output (sensitivity) for vancomycin and the sensor output (sensitivity) for amikacin.

[0059] (Concentration measurement of saline S containing vancomycin and amikacin) Next, a physiological saline solution S containing vancomycin and amikacin at a concentration of 300 μg / mL each was prepared. The concentration of vancomycin was measured using the electrochemical analysis device 100 while dropping the physiological saline solution S at a constant speed onto the surface of the filter 7 arranged so as to overlap with the electrodes (working electrode 4, counter electrode 5, and reference electrode 6) of the sensor 1. The measurement results are shown in FIG. 7. FIG. 7 is a graph showing the relationship between the sensor output and time for vancomycin and amikacin that were mixed together and dropped onto the filter 7 and passed through the filter 7. The vertical axis of FIG. 7 is the sensor output (sensitivity), and the horizontal axis is the time (seconds). As shown in FIG. 7, even if vancomycin and amikacin coexist in the physiological saline solution S, it was confirmed that vancomycin and amikacin are separated from each other when the physiological saline solution S passes through the filter 7, and are supplied to the storage section 3 in this order of vancomycin and amikacin.

[0060] In this manner, by using the filter 7 in which the macropores, mesopores, etc. are set to predetermined conditions, vancomycin contained in a liquid sample can be selectively detected using the sensor 1.

[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) Examples of drugs interfering with vancomycin include, in addition to amikacin, drugs having a smaller molecular weight than vancomycin, such as clindamycin, gentamicin, and acetaminophen.

[0063] (2) The liquid sample may be a body fluid such as blood or saliva, or may be an aqueous solution.

[0064] (3) 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. [Explanation of symbols]

[0065] REFERENCE SIGNS LIST 1...sensor, 2...main body, 3...accommodation section, 4...working electrode, 5...counter electrode, 6...reference electrode, 7...filter, 45...first terminal section, 55...second terminal section, 65...third terminal section

Claims

1. A sensor having an electrode for detecting vancomycin in contact with a liquid sample containing said vancomycin, The porous body has macropores of 0.3 μm or more and 0.7 μm or less and mesopores of 2 nm or more and 10 nm or less, The sensor includes a filter positioned to overlap the electrode.

2. 2. The sensor according to claim 1, wherein the filter has a thickness of 0.6 mm or more.

Images