System comprising orally ingestible device and sensor including magnetoresistive element

Abstract

Provided is a system comprising an orally ingestible device that can be reduced in size and a sensor for detecting a signal generated by the orally ingestible device. This system comprises: the orally ingestible device provided with a pair of electrodes, the pair of electrodes coming into contact with a body fluid, thereby causing a current to flow between the pair of electrodes through the body fluid; and the sensor including a magnetoresistive element that detects, outside the body, a magnetic field generated from the current flowing through the body fluid.

Description

A system including an orally ingestible device and a sensor including a magnetoresistive element

[0001] The present disclosure relates to a system including an orally ingestible device and a sensor including a magnetoresistive element.

[0002] Physiological communication receivers that can be detachably fixed to the skin of a test subject are known (for example, Patent Document 1). This receiver is configured to receive in-body conductive signals emitted by devices such as an Ingestible Event Marker (IEM) or a smart parenteral device. Furthermore, signals that can be generated by an IEM are exemplified in Patent Document 2, one of which is a magnetic field signal generated by an IEM provided with a coil.

[0003] Japanese Patent No. 5143290 Japanese Unexamined Patent Publication No. 2015-107342

[0004] To improve the ease of taking pharmaceuticals containing orally ingestible devices such as IEMs, miniaturization of orally ingestible devices is required. Accordingly, an object of an embodiment of the present invention is to provide a system including an orally ingestible device that can be miniaturized, and a sensor for detecting a signal generated by the orally ingestible device.

[0005] Aspect 1 of the present invention is a system including: an orally ingestible device including a pair of electrodes, wherein when the pair of electrodes comes into contact with a bodily fluid, a current flows between the pair of electrodes through the bodily fluid; and a sensor including a magnetoresistive element that detects, outside the body, a magnetic field generated from the current flowing through the bodily fluid.

[0006] Aspect 2 of the present invention is the system according to Aspect 1, wherein the sensor is a three-axis magnetic sensor capable of detecting magnetic field components in each of three mutually orthogonal directions, and includes at least one of the three-axis magnetic sensors.

[0007] Aspect 3 of the present invention is the system according to Aspect 1 or 2, wherein the device further includes a non-conductive member for partially changing a current path flowing between the pair of electrodes.

[0008] A fourth aspect of the present invention is the system according to aspect 3, wherein the pair of electrodes face each other in a first direction, the nonconductive member extends outward beyond the outer shape of the pair of electrodes when viewed from the first direction, and the current flows radially outward from the pair of electrodes in a plane perpendicular to the first direction between the pair of electrodes in the bodily fluid.

[0009] Aspect 5 of the present invention is a system according to any one of aspects 1 to 4, wherein the device generates a current with a frequency of 10 kHz to 100 kHz.

[0010] Aspect 6 of the present invention is the system according to aspect 5, wherein the sensor has a lower limit of detectable magnetic field at a frequency of 1 Hz that is lower than 1 nT / √Hz, and its sensitivity in the frequency band of 10 kHz to 100 kHz is greater than or equal to the sensitivity at the frequency of 1 Hz.

[0011] Aspect 7 of the present invention is a system according to any one of aspects 1 to 6, wherein the sensor operates under an environmental magnetic field of ±50 μT or greater.

[0012] Embodiment 8 of the present invention is a system according to any one of embodiments 1 to 7, wherein the distance between the sensor and the device is 50 mm or more.

[0013] Aspect 9 of the present invention is a system comprising an orally ingestible device and a magnetoresistive element for receiving signals from inside the body of the orally ingestible device outside the body, wherein the orally ingestible device comprises a first electrode, a second electrode provided so as to face the first electrode in a first direction, and a non-conductive member provided between the first electrode and the second electrode, the area of ​​which, as viewed from the first direction, is larger than that of the first electrode and the second electrode, and the system is configured such that a current flows radially outward from the first electrode in a plane perpendicular to the first direction between the first electrode and the second electrode in a conductive fluid, and the magnetoresistive element detects a magnetic field generated from the current.

[0014] Aspect 10 of the present invention is the system according to aspect 9, wherein the first electrode and the second electrode are formed of different materials so as to generate a potential difference in the conductive fluid.

[0015] Aspect 11 of the present invention is a system according to aspect 9 or 10, wherein a current flows radially in a 360-degree direction in a plane perpendicular to the first direction between the first electrode and the second electrode in a conductive fluid.

[0016] Aspect 12 of the present invention is a system according to any one of aspects 9 to 11, wherein the magnetoresistive element detects the magnetic field at a position away from the body surface.

[0017] According to one embodiment of the present invention, a system can be provided that includes a miniaturizable, orally ingestible device and a sensor for detecting signals generated by the orally ingestible device.

[0018] Figure 1 is a schematic top view of the system according to Embodiment 1 of the present invention. Figure 2 is a schematic cross-sectional view along line A-A of the orally ingestible device shown in Figure 1. Figure 3 is a schematic perspective view showing an example of a three-axis sensor. Figure 4 is a schematic top view showing an example of an orally ingestible device included in the system according to Embodiment 1 of the present invention. Figure 5 is a schematic top view of the system according to Embodiment 2 of the present invention. Figure 6 is a schematic cross-sectional view along line B-B of the orally ingestible device shown in Figure 5. Figure 7 is a schematic front view of the experimental apparatus used in the example. Figure 8A is a graph showing the results of magnetic field signal measurement in the example, showing the distance dependence of the magnetic field signal spectral density detected by the magnetoresistive element. Figure 8B is a graph showing the results of magnetic field signal measurement in the example, showing the distance dependence of the signal / noise.

[0019] The inventors investigated how to miniaturize an orally ingestible device (e.g., an IEM) in a system comprising an orally ingestible device and a sensor placed outside the body. They focused on using a magnetic field as the signal generated by the orally ingestible device, and the fact that a magnetic field can already be generated from the device without the use of a coil, leading them to the realization that miniaturization of the orally ingestible device is possible. An orally ingestible device having a pair of electrodes is used, and the device is configured such that when the pair of electrodes come into contact with bodily fluids and a voltage is generated, a current flows through the bodily fluids between the pair of electrodes. A magnetic field is generated by the current flowing through the bodily fluids.

[0020] In engineering, magnetic field generation typically utilizes "currents that form explicitly defined paths" using coils, wires, etc. Even without coils, diffusive conduction occurs around orally ingestible devices into the body fluids that spread volumewise. However, the current element in such conduction is extremely weak, and because it conducts diffusively in all directions, the current is averaged out in a large system like the human body, and it is generally expected that the magnetic field will be canceled out, making detection difficult. For this reason, Patent Document 2 describes that when an IEM generates a magnetic field signal, an oscillating current passing through a coil generates the magnetic field signal.

[0021] However, after the inventors conducted thorough research from various perspectives, they focused on the fact that asymmetry can occur in the orally ingestible device itself, and that after the device is orally ingested, local symmetry breaking occurs due to the presence of the stomach wall inside the stomach, the heterogeneity of biological tissue, and the presence of stomach contents. This led them to the idea that a finite magnetic field could be generated, and thus the present invention was completed.

[0022] To arrive at this idea, it is necessary to utilize all of the specific and detailed information about the products in Patent Documents 1 and 2, the embodiments, knowledge about biological tissues, knowledge about electrical conductivity and magnetism in living organisms, and specialized knowledge about high-sensitivity magnetic sensors. It is difficult to conceive the present invention based solely on Patent Documents 1 and 2.

[0023] The systems according to Embodiments 1 and 2 of the present invention will be described below with reference to the drawings.

[0024] (Embodiment 1) Figure 1 is a schematic top view of system 1 according to Embodiment 1 of the present invention, and Figure 2 is a schematic cross-sectional view of the orally ingestible device 10 shown in Figure 1 along line A-A. System 1 includes an orally ingestible device (hereinafter sometimes simply referred to as "device") 10 and a sensor 30.

[0025] Device 10 is used by being enclosed in or attached to orally ingested medication. Device 10 is equipped with a pair of electrodes 11 and 12. Device 10 is configured to conduct an electric current I between the pair of electrodes 11 and 12 through the body fluid BF when it is orally ingested together with the medication and the pair of electrodes 11 and 12 come into contact with body fluid BF such as gastric juice. In Figures 1 and 2, the electric current I is shown flowing from the first electrode 11 through the body fluid BF to the second electrode 12. When Device 10 comes into contact with body fluid BF, it functions as a battery and generates an electric current I that flows through the body fluid BF. The electric current I generates a magnetic field MF, and by detecting the magnetic field MF with the sensor 30, it can be confirmed that the patient has orally ingested the medication.

[0026] The device 10 may include a substrate 15 between the first electrode 11 and the second electrode 12. Within the substrate 15, current can flow from the second electrode 12 towards the first electrode 11. The substrate 15 can function as a support base for the thin film-like first electrode 11 and second electrode 12.

[0027] The device 10 may further include a non-conductive member 19 for blocking a portion of the current I flowing through the body fluid BF and changing the current path. The non-conductive member 19 is formed, for example, in the shape of a sheet. The non-conductive member 19 may extend outward from the side surface of the substrate 15, as shown in Figure 2. That is, if the opposing direction of the pair of electrodes 11 and 12 is defined as the first direction D1, the non-conductive member 19 extends outward beyond the outer shape of the pair of electrodes 11 and 12 when viewed from this first direction D1. Since the non-conductive member 19 does not conduct current, the current I passing near the side surface of the substrate 15 is blocked, and the current path flowing through the body fluid BF, such as gastric juice, can be expanded. Then, in the body fluid BF, the current I can flow radially outward from the pair of electrodes 11 and 12 in a 360-degree direction within a plane perpendicular to the first direction D1.

[0028] By expanding the current path, the magnetic field generation range can be broadened, making it easier to detect with the sensor 30 installed outside the body. Therefore, even if the sensor 30 is installed in a location other than the body surface near the stomach, such as on the arm or beside the bed, it becomes easier to detect the magnetic field MF from the device 101, increasing the flexibility of the installation location of the sensor 30.

[0029] The non-conductive member 19 may have an external shape that is symmetrical when viewed from above, and in the example shown in Figure 1, it has a circular external shape. However, as will be described later, the non-conductive member 19 may have an external shape that is asymmetrical when viewed from above.

[0030] The sensor 30 is installed in the patient's extracorporeal cell (EC). The magnetoresistive element 31 included in the sensor 30 allows the extracorporeal EC to detect the magnetic field (MF) generated inside the body. The sensor 30 may be fixed to the patient's body surface, for example, to a body surface close to the stomach. The sensor 30 may include a casing to protect the magnetoresistive element 31, a circuit for signal amplification and driving / control, a power supply or battery, an adhesive sheet 35 for fixing the magnetoresistive element 31 to the body surface, etc.

[0031] As described above, System 1 generates an electric current I through the bodily fluid BF using device 10, and detects the magnetic field MF generated by the electric current I using sensor 30. The device 10 according to Embodiment 1 of the present invention is smaller than conventional IEMs because it does not require magnetic field generating components such as coils, and is therefore easier to take orally.

[0032] In IEMs equipped with coils, the direction of the current flowing through the coil is constant, and the direction of the generated magnetic field is also constant. Therefore, if the direction of the magnetic field deviates significantly from the sensitivity axis of the sensor, it becomes difficult to detect the magnetic field. Since the orientation of the device cannot be controlled within the body, it is difficult to reliably detect the magnetic field generated by an internal device with an external sensor, and ingenuity is required in the position and direction in which the sensor is installed. In contrast, in the device 10 according to Embodiment 1 of the present invention, when viewed from above, current I flows in all 360 degrees around the device 10, so the magnetic field MF generated by the current I is oriented in various directions. Therefore, the magnetic field MF generated by the device 10 is easier to detect with an external sensor 30 compared to conventional devices.

[0033] The sensor 30 is preferably a three-axis magnetic sensor capable of detecting magnetic field components in each of three mutually orthogonal directions. As shown in Figure 3, the three-axis magnetic sensor 33 includes a magnetoresistive element 31x for detecting a magnetic field in the x-axis direction, a magnetoresistive element 31y for detecting a magnetic field in the y-axis direction, and a magnetoresistive element 31z for detecting a magnetic field in the z-axis direction. The three-axis magnetic sensor 33 may also include substrates 341 and 342 for holding the magnetoresistive elements 31x, 31y, and 31z in appropriate orientations. The first substrate 341 and the second substrate 342 are fixed to each other so that their main surfaces are orthogonal. In the example shown in Figure 3, two magnetoresistive elements 31x and 31y are fixed to the main surface of the first substrate 341, and one magnetoresistive element 31z is fixed to the main surface of the second substrate 342. The three magnetoresistive elements 31x, 31y, and 31z are oriented so that their sensitivity axes are orthogonal to each other.

[0034] The sensor 30 may include at least one three-axis magnetic sensor 33. In particular, it is preferable to include two or more three-axis magnetic sensors 33, which allows for the three-dimensional determination and identification of the position and orientation of the device 10 within the body.

[0035] In the orally ingestible device (hereinafter simply referred to as "device") 101 shown in Figure 4, the external shape of the non-conductive member 190, which is made of a non-conductive material, is asymmetrical, as if a part of the circular shape (for convenience, this will be referred to as the "cut-off portion 19x") has been removed. By removing the cut-off portion 19x, an electric current Ix flows through that portion, and a magnetic field MFx is generated by the electric current Ix. Since the non-conductive member 19 maintains a circular shape except for the cut-off portion 19x, the flow of currents I and Ix is asymmetrical overall. As a result, the magnetic fields MF and MFx generated from currents I and Ix are also asymmetrical. This results in an even more pronounced asymmetry than that of device 10 shown in Figure 1.

[0036] As shown in Figure 4, by providing a cut portion 19x in the non-conductive member 190 to significantly increase the asymmetry, the asymmetry of the current I can be made more pronounced, making it less likely for the magnetic field MF to be canceled out. This makes it possible to increase the strength of the magnetic field generated from the device 101 (the sum of the individual magnetic fields MF and MFx generated by each current), and makes it possible to detect the magnetic field even when the distance between the device 10 and the sensor 30 is increased.

[0037] Devices 10 and 101 preferably generate a current with a frequency of 10 kHz to 100 kHz. This frequency band is hardly used in Japan, and in foreign countries such as the United States, it is used only for special purposes (e.g., in maritime communications). In other words, in countries around the world, including Japan, this frequency band is not used in homes, medical facilities, or office environments. Therefore, by setting the frequency of the current flowing through devices 10 and 101 to 100 kHz, noise in the magnetic field signal corresponding to this frequency band can be reduced in the operating environment of System 1, and the signal-to-noise ratio of the magnetic field signal can be increased, making it possible to detect information such as the position of devices 10 and 101 with high accuracy. By acquiring only the magnetic field signal corresponding to the above frequency from the output of sensor 30 using a filter or the like, specific signal components can be extracted from the overall signal including noise.

[0038] Furthermore, IEMs equipped with coils may experience limitations in coil impedance when flowing currents in the 10kHz to 100kHz frequency range. In contrast, devices 10 and 101 according to Embodiment 1 do not include coils, and therefore there are no circuit design constraints when using them with high-frequency (10kHz to 100kHz) currents, resulting in greater design flexibility for the equipment.

[0039] Preferably, the sensor 30 has a lower limit of detectable magnetic field at a frequency of 1 Hz that is lower than 1 nT / √Hz, and its sensitivity in the frequency band of 10 kHz to 100 kHz is greater than or equal to its sensitivity at a frequency of 1 Hz. This makes it possible to detect information such as the position of devices 10 and 101 with even greater accuracy.

[0040] The sensor 30 preferably operates under an environmental magnetic field of ±50 μT or higher. Since the Earth's magnetic field is approximately ±50 μT, malfunctions caused by the Earth's magnetic field can be suppressed.

[0041] Considering the body shape of Japanese people, the distance between the sensor 30 and devices 10 and 101 can be 50 mm or more when using System 1. For the average Japanese person, the abdominal thickness in the lateral view (the thickness of the abdomen when observed from the side) is 10 cm (100 mm). When devices 10 and 101 are in the stomach area, the position of devices 10 and 101 in the direction of abdominal thickness can be estimated to be near the center of the abdominal thickness. Therefore, by making System 1 usable with a distance of 50 mm or more between the sensor 30 and devices 10 and 101, a System 1 suitable for many Japanese patients can be obtained. To relax the body shape limitations and obtain a System 1 suitable for multiple races, the distance between the sensor 30 and devices 10 and 101 may be, for example, 70 mm or more, 90 mm or more, or 100 mm or more.

[0042] (Embodiment 2) System 2 according to Embodiment 2 differs from System 1 according to Embodiment 1 in some configurations. System 2 according to Embodiment 2 will be described focusing on the differences from System 1 according to Embodiment 1, and configurations, features, and effects similar to those of System 1 according to Embodiment 1 may be omitted from the description.

[0043] Figure 5 is a schematic top view of system 2 according to embodiment 2 of the present invention, and Figure 6 is a schematic cross-sectional view of the orally ingestible device 20 shown in Figure 5 along the line B-B. System 2 includes an orally ingestible device (hereinafter sometimes simply referred to as "device") 20 and a magnetoresistive element 31 that receives signals from inside the body of the device 20 via an extracorporeal EC.

[0044] As shown in FIG. 6, the device 20 includes a first electrode 21, a second electrode 22 provided to face the first electrode 21 in a first direction D1, and a non-conductive member 19 provided between the first electrode 21 and the second electrode 22, the non-conductive member 19 extending outward beyond the outer contours of the first electrode 21 and the second electrode 22 when viewed from the first direction D1. Since the non-conductive member 19 does not conduct current, when the non-conductive member 19 extends outward beyond the outer contours of the first electrode 21 and the second electrode 22, the current path flowing through a conductive fluid CF such as gastric juice can be expanded. In the present embodiment, the area of the non-conductive member 19 as viewed from the first direction D1 is larger than that of the first electrode 21 and the second electrode 22.

[0045] A part of the non-conductive member 19 and a substrate 25 may be disposed between the first electrode 21 and the second electrode 22. The non-conductive member 19 may be provided with a hole capable of accommodating the substrate 25. As shown in FIGS. 5 and 6, the device 20 is configured such that in the conductive fluid CF, a current I radiates outward from the first electrode 21 in a plane perpendicular to the first direction D1 between the first electrode 21 and the second electrode 22. In FIGS. 5 and 6, the current I flows from the first electrode 21 through the conductive fluid CF to the second electrode 22.

[0046] The magnetoresistive element 31 detects a magnetic field MF generated from the current I. Since the device 20 is used by being encapsulated in or attached to an orally ingested drug, detection of the magnetic field MF by the magnetoresistive element 31 makes it possible to confirm that the patient has orally ingested the drug.

[0047] In the conductive fluid CF, a current radiates 360 degrees in a plane perpendicular to the first direction D1 between the first electrode 21 and the second electrode 22. Since the magnetic field MF generated by the current I is oriented in various directions, the magnetic field MF generated by the device 20 can be detected more easily by the external magnetoresistive element 31 than that of a conventional device.

[0048] In the systems 1 and 2 of Embodiments 1 and 2, the magnetoresistive element 31 is preferably capable of detecting the magnetic field MF at a position distant from the body surface. Since the magnetoresistive element 31 can be installed at a position distant from the body surface, such as beside a bed, to detect the magnetic field from the devices 10, 101 and 20, the degree of freedom in the installation location of the magnetoresistive element 31 can be increased. Furthermore, it is also possible to mount the magnetoresistive element 31 as a magnetic sensor in a mobile device such as a smartphone or a smart watch to detect the magnetic field MF from the devices 10, 101 and 20.

[0049] Note that in Patent Document 1, a signal from an IEM is detected electrically, that is, by measuring a voltage on the body surface. Therefore, it is an essential requirement that a physiological communication receiver has an electrical contact mechanism to the skin. However, the quality of electrical contact depends on the condition of the contact surface (such as the presence or absence of body hair), which is a factor that causes individual differences. It also becomes a factor that causes a decrease in quality of life, such as rough skin and restrictions on bathing. From this point of view as well, it is preferable that the magnetoresistive element 31 is capable of detecting a signal in a non-contact manner.

[0050] Next, suitable members and materials for each member constituting the systems 1 and 2 of Embodiments 1 and 2 will be described.

[0051] (First electrodes 11, 21, Second electrodes 12, 22) The first electrodes 11, 21 and the second electrodes 12, 22 can be formed from films or thin plates made of conductive materials such as metals and alloys. In particular, the electrodes are preferably formed of different materials so as to generate a potential difference in the body fluid BF and the conductive fluid CF, and a battery can be configured using the body fluid BF or the conductive liquid as an electrolytic solution. For example, the first electrodes 11, 21 can be formed of Mg, Zn, or the like, and the second electrodes 12, 22 can be formed of Cu, CuI, CuCl, or the like.

[0052] (Substrates 15, 25) The substrates 15, 25 are provided as supporting substrates for the first electrodes 11, 21 and the second electrodes 12, 22 between the first electrodes 11, 21 and the second electrodes 12, 22. The substrates 15, 25 can be formed of, for example, a silicon plate.

[0053] (Non-conductive member 19) The non-conductive member 19 is a member formed from a non-conductive material, for example, in the form of a sheet. In one embodiment, the non-conductive member 19 can also function as a storage container for the active ingredient of a pharmaceutical. For example, the non-conductive member 19 may be an integral part of a capsule. Alternatively, the non-conductive member 19 may be a laminate consisting of several layers, one or more of which may be a controlled-release film that releases the active ingredient. The surface of the non-conductive member 19 may include an anti-adhesion film to prevent it from adhering to the stomach wall or becoming clogged with food residue in the digestive tract. The anti-adhesion film may be used to prevent two or more orally ingestible devices from adhering to each other and blocking signals.

[0054] In various embodiments, the nonconductive member 19 can be made from various materials, categories of materials, or combinations thereof. Categories of materials include, but are not limited to, film-forming agents or binders / adhesives, fillers, soluble materials or disintegrants, plasticizers, coatings, and wetting agents.

[0055] Film-forming agents or binders / adhesives include, but are not limited to, agar; carrageenan; cellulose acetate; chitosan; copovidone; ethylcellulose; gelatin; gums such as acacia, xanthan gum, and guar; sugars such as lactose, mannitol, and xylitol; hydrogels such as hydroxyethylcellulose, sodium alginate, and urethane; acrylic acid polymers, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methacrylic acid copolymers, methylhydroxyethylcellulose, polyethylene glycol, polyvinyl acetate phthalates, polyvinyl alcohol, povidone, starch, carbomer, dextrin, hypromellose, poly(methylvinyl ether / maleic anhydride), glyceryl monooleate, and polyethylene It contains phenyl oxide, polycarbophil, celetonia, powdered sugar, cottonseed oil, dextrose, glucose, glyceryl behenate, hydrogenated vegetable oil, hydroxypropyl starch, inulin, glucose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polydextrose, polymethacrylate, stearic acid, sucrose, sunflower oil, zein, aluminum stearate, calcium silicate, colloidal silicon dioxide, glyceryl palmitostearate, pectin, polyethylene alkyl ether, propylene carbonate, sodium ascorbate, zinc acetate, ammonium alginate, chlorpheniramine maleate, dibutylphthalic acid, dibutyl sebacate, diethylphthalic acid, dimethylphthalic acid, ethyl lactate, vanillin, shellac, etc.

[0056] Fillers include, but are not limited to, oxides such as titanium dioxide and magnesium oxide; silicates such as magnesium silicate; phosphates such as dicalcium phosphate; carbonates and bicarbonates; starches; cellulosic materials such as microcrystalline cellulose; acacia, agar, alginic acid, carbomer, carboxymethylcellulose, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, powdered sugar, copovidone, cottonseed oil, dextrose, dextrin, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, hypromellose, inulin, lactose, glucose, and aluminum silicate. It contains magnesium, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylate, povidone, sodium alginate, starch, stearic acid, sucrose, sunflower oil, zein, bentonite, calcium stearate, cellulose, colloidal silicon dioxide, kaolin, maltitol, sesame oil, sodium starch glycolate, sorbitan ester, tragacanth, xanthan gum, mannitol, ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, fumaric acid, glyceryl palmitostearate, isomalt, lactitol, magnesium carbonate, simethicone, trehalose, xylitol, and more.

[0057] Soluble materials or disintegrants include, but are not limited to, alginates such as sodium alginate or calcium alginate; croscarmellose sodium, carboxymethylcellulose sodium, crospovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, lactose, mannitol, polyvinyl alcohol, and sodium or potassium salts (e.g., sodium chloride or potassium chloride), alginic acid, carboxymethylcellulose, cellulose, chitosan, colloidal silicon dioxide, doxate sodium, guar gum, aluminum magnesium silicate, methylcellulose, microcrystalline cellulose, polaclein potassium, povidone, sodium starch glycolate, starch, and the like.

[0058] Plasticizers include, but are not limited to, dibutyl sebacate, triethyl citrate, triacetin, acetyl tributyl citrate, acetyl triethyl citrate, benzyl benzoate, cellulose acetate phthalate, chlorbutanol, dextrin, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, glycerin, glyceryl monostearate, hypromellose phthalate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polymethacrylate, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, tributyl citrate, and triethanolamine.

[0059] Coating agents include, but are not limited to, polymethacrylate (pH sensitive), polyvinyl acetate phthalate (pH sensitive), hydroxypropyl methylcellulose (moisture-resistant), acetyl tributyl citrate, acetyl triethyl citrate, calcium carbonate, sodium carboxymethylcellulose, carnauba wax, cellulose acetate, cellulose acetate phthalate, cetyl alcohol, chitosan, ethylcellulose, fructose, gelatin, glycerin, glyceryl behenate, glyceryl palmitostearate, hydroxyethylcellulose, hydroxyethylcellulose. It contains methylcellulose, hydroxypropylcellulose, hypromellose, hypromellose phthalate, isomalt, glucose, maltitol, maltodextrin, methylcellulose, microcrystalline wax, paraffin, poloxamer, polydextrose, polyethylene glycol, polyvinyl acetate phthalate, polyvinyl alcohol, povidone, shellac, sucrose, titanium dioxide, tributyl citrate, triethyl citrate, vanillin, xylitol, zein, talc, triethanolamine, ammonium alginate, chlorpheniramine maleate, copovidone, ethyl lactate, and others.

[0060] Wetting agents include, but are not limited to, polyethylene glycol, sodium doxate, sodium lauryl sulfate, polyethylene oxide, lecithin, poloxamer, povidone, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, hypromellose, polyethylene alkyl ether, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sorbitan ester, benzyl alcohol, benzyl benzoate, cyclodextrin, glyceryl monostearate, meglumine, sodium bicarbonate, stearic acid, sulfobutyl ether β-cyclodextrin, and others.

[0061] (Sensor 30) The sensor 30 includes at least a magnetoresistive element 31 and may optionally include a base material 341, 342 for fixing the magnetoresistive element 31, a casing for protecting the magnetoresistive element 31, a circuit for signal amplification and driving / control, a power supply or battery, an adhesive sheet 35 for fixing the magnetoresistive element 31 to the body surface, etc. In this embodiment, a magnetoresistive element 31 with high detection sensitivity is used as a signal receiver, but it is also possible to use an optical pumping magnetometer, a sensor using a diamond nitrogen vacancy center, a flux gate sensor, a superconducting quantum interference magnetometer, etc. instead of the magnetoresistive element 31.

[0062] The base materials 341, 342 and the casing are made of materials that do not interfere with the detection of the magnetic field MF by the magnetoresistive element 31. For example, they can be made of plastic or other resins, non-magnetic metals such as aluminum, gold, silver, copper, and titanium, or their alloys, or non-conductive materials such as glass and ceramics. However, considering the risk of signal attenuation due to eddy currents induced on the casing surface by the AC magnetic field signal, it is desirable that the casing be made of a non-conductive material.

[0063] A circuit for signal amplification and driving / controlling is a circuit that amplifies the signal received by a sensor and drives and controls the sensor, and may include, for example, an operational amplifier, a power supply control integrated circuit, integrated circuit elements that constitute a frequency band limiting circuit, and passive elements such as resistors, capacitors, and coils.

[0064] For the power source, commercial AC power can be used, which is converted to DC by an AC / DC converter before being supplied to the sensor. Batteries may be used instead of commercial AC power, and dry cell batteries or rechargeable batteries can be used. Rechargeable batteries that can be used include lead-acid batteries, nickel-cadmium secondary batteries, lithium-hydrogen secondary batteries, lithium polymer batteries, and lithium-ion batteries.

[0065] The adhesive sheet 35 can be a known adhesive sheet used in the medical field for fixation to the body surface.

[0066] (Magnetoresistance elements 31, 31x, 31y, 31z) Magnetoresistance elements such as tunnel magnetoresistance (TMR), anisotropic magnetoresistance (AMR), and giant magnetoresistance (GMR) elements can be used as magnetoresistance elements 31, 31x, 31y, and 31z. TMR elements are particularly suitable, as they can detect weak magnetic fields with high sensitivity.

[0067] The detectable distance when detecting a magnetic field signal from an orally ingestible device inside the body using an external magnetoresistive element was verified. Figure 7 is a schematic front view of the experimental apparatus, where a resin petri dish 40 with a diameter of 130 mm was filled with physiological saline as the conductive fluid CF to represent the inside of the body, and the outside of the petri dish 40 was considered the outside of the body. An acrylic piece 45 was placed inside the bottom surface of the petri dish 40, and the orally ingestible device 10 was fixed thereto. The orally ingestible device 10 consisted of an integrated circuit with sides of 1.0 mm, a first electrode 21 placed on its upper surface, a second electrode 22 placed on its lower surface, and a non-conductive member 19 surrounding the integrated circuit and extending outward. The first electrode 21 had a laminated structure including a titanium-tungsten layer, a gold layer, and a copper chloride layer, and the second electrode 22 had a laminated electrode structure including a magnesium layer and a titanium layer. The non-conductive member 19 was a disc-shaped member formed from a non-conductive material whose main component was cellulose. The overall dimensions of the orally ingestible device 10 were a thickness of 330–360 μm and an outer diameter of 3.5 mm.

[0068] The magnetic field signal generated by immersing device 10 in physiological saline was detected by a magnetoresistive element 31 placed on the outside of the bottom surface of petri dish 40. One prototype TMR element from Spin Sensing Factory was used as the magnetoresistive element 31. The sensitivity of the TMR element was 5000 μV / μT. While changing the horizontal distance between device 10 and magnetoresistive element 31, detection tests of the magnetic field signal were performed to investigate the relationship between the horizontal distance y between the center of device 10 and the center of magnetoresistive element 31 and the magnitude of the magnetic field signal measured by magnetoresistive element 31. In addition, electrodes 51 and 52 were placed on the inner surface of container 40, and a voltmeter 50 was connected between them.

[0069] In the magnetic field signal measurement, the output of the magnetoresistive element 31 that received the magnetic field signal was converted into a digital signal by an analog-to-digital converter (AD converter) and recorded on a laptop computer. The magnetic signal is emitted by an electrochemical reaction between electrodes 11 and 12 and physiological saline solution. A magnetic signal detection test was performed with a fixed horizontal distance y from the start to the end of magnetic signal emission by one orally ingestible device. When performing detection tests at different horizontal distances y, a new orally ingestible device 10 was used. In other words, one orally ingestible device 10 was consumed to perform a detection test in order to obtain data for a single point at a specific horizontal distance y. The AD converter used was an AD Instruments PowerLab 16 / 35 (PL3516), with AD conversion conditions of 16-bit bit resolution, an input voltage range of ±10V, and a sampling frequency of 200kHz. The recorded signal was converted into a frequency spectrum using the Fast Fourier Transform (FFT) with LabChart, the software included with the A / D converter. The spectral density at the signal frequency during signal acquisition was defined as the signal magnitude. Similarly, the spectral density at the signal frequency when there was no signal was defined as the noise magnitude.

[0070] Figures 8A and 8B are graphs showing the results of the magnetic field signal detection test. Figure 8A is a graph plotting the spectral density of the magnetic field signal detected by the magnetoresistive element 31 against the horizontal distance y between the device 10 and the magnetoresistive element 31, showing the distance dependence of the spectral density. Figure 8B is a graph of the signal-to-noise ratio (S / N ratio) against the horizontal distance y between the device 10 and the magnetoresistive element 31, showing the distance dependence of the signal-to-noise ratio.

[0071] These graphs confirm that the magnetic field signal generated by the device 10 inside the body can be detected by a magnetoresistive element placed outside the body, even when it is 100 mm away from the device 10.

[0072] This application claims priority under Japanese Patent Application No. 2025-056510, filed in Japan on 28 March 2025, the entirety of which is incorporated herein by reference.

[0073] 1, 2 System 10, 101, 20 Orally ingestible device 11, 21 First electrode 12, 22 Second electrode 15, 25 Substrate 19 Non-conductive material 30 Sensor 31, 31x, 31y, 31z Magnetoresistive element 33 Three-axis magnetic sensor 40 Petri dish made of resin 45 Acrylic piece 50 Voltmeter 51, 52 Electrodes BF Body fluid CF Conductive fluid EC Out of the body D1 First direction D2 Second direction I, Ix Current MF Magnetic field

Claims

1. An orally ingestible device having a pair of electrodes, wherein the pair of electrodes come into contact with a bodily fluid, thereby allowing an electric current to flow between the pair of electrodes through the bodily fluid; and a system comprising a sensor including a magnetoresistive element that detects a magnetic field generated from the electric current flowing through the bodily fluid outside the body.

2. The system according to claim 1, wherein the sensor is a three-axis magnetic sensor capable of detecting magnetic field components in each of three mutually orthogonal directions, and the system includes at least one of the three-axis magnetic sensors.

3. The system according to claim 1 or 2, wherein the orally ingestible device further includes a non-conductive member for modifying a portion of the current path flowing between the pair of electrodes.

4. The system according to claim 3, wherein the pair of electrodes face each other in a first direction, the nonconductive member extends outward beyond the outer shape of the pair of electrodes when viewed from the first direction, and the current flows radially outward from the pair of electrodes in a plane perpendicular to the first direction between the pair of electrodes in the bodily fluid.

5. The orally ingestible device is the system according to any one of claims 1 to 4, which generates a current with a frequency of 10 kHz to 100 kHz.

6. The system according to claim 5, wherein the sensor has a lower limit of detectable magnetic field at a frequency of 1 Hz that is lower than 1 nT / √Hz, and its sensitivity in the frequency band of 10 kHz to 100 kHz is greater than or equal to the sensitivity at the frequency of 1 Hz.

7. The system according to any one of claims 1 to 6, wherein the sensor operates under an environmental magnetic field of ±50 μT or greater.

8. The system according to any one of claims 1 to 7, wherein the distance between the sensor and the device is 50 mm or more.

9. A system comprising an orally ingestible device and a magnetoresistive element for receiving signals from inside the body of the orally ingestible device outside the body, wherein the orally ingestible device includes a first electrode, a second electrode provided so as to face the first electrode in a first direction, and a non-conductive member provided between the first electrode and the second electrode, the area of ​​which, as viewed from the first direction, is larger than that of the first electrode and the second electrode, and the system is configured such that a current flows radially outward from the first electrode in a plane perpendicular to the first direction between the first electrode and the second electrode in a conductive fluid, and the magnetoresistive element detects a magnetic field generated from the current.

10. The system according to claim 9, wherein the first electrode and the second electrode are formed of different materials so as to generate a potential difference in the conductive fluid.

11. The system according to claim 9 or 10, wherein a current flows radially between the first electrode and the second electrode in a conductive fluid in a 360-degree direction in a plane perpendicular to the first direction.

12. The system according to any one of claims 9 to 11, wherein the magnetoresistive element detects the magnetic field at a position away from the body surface.

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