Ion electroosmosis equipment

Abstract

Provided is an iontophoresis device capable of reducing skin irritation caused by application of a current while improving skin permeability of a drug. Thus, the iontophoresis device has: a power source; an electrode electrically connected to the power source; a drug disposed between the skin and the electrode; and a control unit that controls the current applied to the skin via the electrode, and the control unit controls the application of a pulse current having a pulse frequency of 0.5 Hz to 50 Hz to the skin.

Description

Technical Field

[0001] The present invention relates to iontophoresis devices. Background Art

[0002] Iontophoresis is a technique known in the art in which a current or voltage is applied to the skin via electrodes to deliver a drug placed between the electrodes and the skin into the body through the skin. Iontophoresis equipment is used to perform iontophoresis.

[0003] Patent Document 1 discloses an iontophoresis device that uses a pulse current with a pulse width of 50 μs to 100 ms, a pulse frequency of 1 Hz to 200 Hz, and a duty cycle of 1% to 90% to improve drug skin permeability. Patent Document 2 discloses an electrical delivery device for an iontophoresis agent that uses a pulse current with a pulse width of 5 ms or greater, a pulse frequency of less than 10 Hz, and a duty cycle of 30% to 90% to improve drug skin permeability. Patent Document 3 discloses a transmucosal drug delivery device that combines pulsed depolarization and pulsed currents to provide excellent drug skin permeability and skin irritation resistance.

[0004] Patent Document 1: Japanese Patent Application No. 2020-503349

[0005] Patent Document 2: Japanese Patent Publication No. 11-507280

[0006] Patent Document 3: International Publication No. 1999 / 000157

[0007] When an electric current is applied to the skin in an iontophoresis device, skin irritation such as erythema may occur in the area of the skin where the current is applied. However, Patent Documents 1 and 2 do not disclose such skin irritation caused by current application. The structure described in Patent Document 3 may not reduce skin irritation. Summary of the Invention

[0008] The present invention aims to improve the skin permeability of drugs while reducing the skin irritation caused by the application of electric current.

[0009] An iontophoresis device according to one embodiment of the present invention comprises: a power source; electrodes electrically connected to the power source; a drug disposed between the skin and the electrodes; and a control unit that controls the current applied to the skin via the electrodes, wherein the control unit controls the application of a pulse current having a pulse frequency of greater than 0.5 Hz and less than 50 Hz to the skin.

[0010] For example, skin irritation can be reduced by the following iontophoresis device.

[0011] [1] An iontophoresis device comprising:

[0012] Electrodes, which are worn on the skin over the medication; and

[0013] The control unit is connected to the electrodes and generates a pulse current having a frequency of 0.5 Hz to 50 Hz.

[0014] [2] An iontophoresis device comprising:

[0015] power supply;

[0016] an electrode, electrically connected to the power supply;

[0017] a drug disposed between the skin and the electrodes; and

[0018] a control unit that controls the current applied to the skin via the electrodes,

[0019] The control unit controls so as to apply a pulse current having a pulse frequency of 0.5 Hz to 50 Hz to the skin.

[0020] [3] The iontophoresis device according to item [1], wherein:

[0021] The pulse current has a pulse width of 10 ms to 1000 ms.

[0022] [4] The iontophoresis device according to item [2], wherein:

[0023] The pulse current has a pulse width of 10 ms to 1000 ms.

[0024] [5] An iontophoresis device comprising:

[0025] Electrodes, which are worn on the skin over the medication; and

[0026] The control unit is connected to the electrodes and generates a pulse current having a pulse width of 10 ms to 1000 ms.

[0027] [6] An iontophoresis device comprising:

[0028] power supply;

[0029] an electrode, electrically connected to the power supply;

[0030] a drug disposed between the skin and the electrodes; and

[0031] a control unit that controls the current applied to the skin via the electrodes,

[0032] The control unit controls so as to apply a pulse current having a pulse width of 10 ms to 1000 ms to the skin.

[0033] [7] The iontophoresis device according to any one of items [1], [3], and [5], wherein:

[0034] The control unit generates the pulse current by applying a pulse voltage subjected to constant voltage control to a constant current element.

[0035] [8] The iontophoresis device according to any one of items [2], [4], and [6], wherein:

[0036] The control unit generates the pulse current by applying a pulse voltage subjected to constant voltage control to a constant current element.

[0037] [9] The iontophoresis device according to any one of items [1], [3], [5], and [7], wherein:

[0038] The electrodes are a pair of electrodes including a first electrode and a second electrode.

[0039] The above-mentioned iontophoresis device has:

[0040] a first storage portion disposed between the skin and the first electrode and storing the drug; and

[0041] The second storage portion is disposed between the skin and the second electrode and stores an electrolyte for transferring ions.

[0042]

[10] The iontophoresis device according to any one of items [2], [4], [6], and [8], wherein:

[0043] The electrodes are a pair of electrodes including a first electrode and a second electrode.

[0044] The above-mentioned iontophoresis device has:

[0045] a first storage portion disposed between the skin and the first electrode and storing the drug; and

[0046] The second storage portion is disposed between the skin and the second electrode and stores electrolyte for ion movement.

[0047] The control unit controls the current applied to the skin via the first electrode.

[0048] According to the present invention, the skin permeability of a drug can be improved while reducing skin irritation caused by application of electric current. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1A It is a diagram showing a state of application to the skin in a first example of iontophoresis according to an embodiment.

[0050] Figure 1B It is a diagram showing a second example of iontophoresis according to the embodiment in a state of being attached to the skin.

[0051] Figure 2 It is schematically represented Figure 1A and Figure 1B Magnified view of region II.

[0052] Figure 3 It is an exploded perspective view schematically showing an example of the overall configuration of an iontophoresis device according to an embodiment.

[0053] Figure 4A It is a plan view schematically showing a first example of the overall structure of the iontophoresis device according to the embodiment.

[0054] Figure 4B It is a plan view schematically showing a second example of the overall structure of the iontophoresis device according to the embodiment.

[0055] Figure 5A yes Figure 4A Schematic cross-sectional view of the VA-VA line in FIG.

[0056] Figure 5B yes Figure 4B Schematic cross-sectional view of the VB-VB line in FIG.

[0057] Figure 6 This is a block diagram showing a configuration example of a control unit according to the embodiment.

[0058] Figure 7 This is a diagram illustrating an example of a pulse current according to the embodiment.

[0059] Figure 8 This is a graph showing an example of the cumulative permeation amount of a drug.

[0060] Figure 9 This is a graph showing an example of drug permeation rate.

[0061] Figure 10 This is a diagram showing an example of the relationship between the cumulative permeation amount of the drug and the electrical charge. DETAILED DESCRIPTION

[0062] Hereinafter, the embodiment of the present invention will be described with reference to the accompanying drawings. In each of the drawings, the same components are denoted by the same reference numerals, and duplicate descriptions are omitted as appropriate.

[0063] The following embodiments illustrate iontophoresis devices for embodying the technical concepts of the present invention and are not intended to limit the present invention to the following embodiments. Unless otherwise specified, the dimensions, materials, shapes, and relative arrangements of the components described below are not intended to limit the scope of the present invention to these dimensions but are provided for illustrative purposes. Furthermore, the dimensions and positional relationships of the components shown in the drawings may be exaggerated for clarity of description.

[0064] In some of the drawings shown below, orthogonal coordinates having an X-axis, a Y-axis, and a Z-axis are used as direction expressions. The X-axis, the Y-axis, and the Z-axis are approximately orthogonal to each other. The Z direction along the Z-axis is set as the direction along the normal direction of the skin on which the iontophoresis device involved in the embodiment is installed. The direction close to the skin is set as the -Z direction, and the direction away from the skin is set as the +Z direction. In this specification, the -Z direction is set as "down" and the +Z direction is set as "up". In addition, looking down means observing the object from the +Z direction side. However, these directional expressions do not limit the directions of the embodiment, and the orientation of the iontophoresis device involved in the embodiment when used is arbitrary. In addition, in this specification, the term "along" can be replaced by "approximately parallel". In this specification, "approximately parallel" means that a deviation of less than ±10 degrees can be included relative to parallel. In addition, in this specification, "approximately orthogonal" means that a deviation of less than ±10 degrees can be included relative to orthogonal.

[0065] In this specification and the scope of claims of this application, the term "drug" includes the following: a "drug" including a dosage form; and a "drug solution" in which a drug is dissolved and formed into a liquid.

[0066] <Example of How to Use the Iontophoresis Device 100>

[0067] First, refer to Figure 1A 、 Figure 1B and Figure 2 A method of using the iontophoresis device 100 according to the embodiment will be described. Figure 1A and Figure 1B FIG. 1 is a diagram showing a state where the iontophoresis device 100 is attached to the skin 300 of a living body 200 . Figure 1A This shows the situation where the power supply and control unit are built into the device. Figure 1B The case where the power supply and the control unit are provided externally is shown. Figure 2 It is schematically represented Figure 1A and Figure 1B Magnified view of region II.

[0068] Iontophoresis is a technology that uses electrodes to apply current or voltage to the skin. This technology allows drugs placed between the electrodes and the skin to be delivered into the body through the skin, leveraging the electrical repulsion and convective movement of water, such as electroosmosis, caused by the applied current or voltage. Drugs that can be delivered transdermally via iontophoresis include low-molecular-weight ionic drugs, high-molecular-weight drugs such as peptides, proteins, and oligonucleotides, as well as antibody drugs and nucleic acid drugs.

[0069] The iontophoresis device 100 is a device used for iontophoresis. Figure 1A and Figure 1B As shown, the iontophoresis device 100 is used in a state of being attached to the surface of the skin 300 of a living body 200 . Figure 1B The figure shows an example of a state in which the components of the iontophoresis device 100 other than the power supply 10 and the control unit 50 are attached to the skin 300 of the living body 200, and the power supply 10 and the control unit 50 of the iontophoresis device 100 are arranged at a position other than the skin 300. The components of the iontophoresis device 100 other than the power supply 10 and the control unit 50 are electrically connected to the power supply 10 and the control unit 50 of the iontophoresis device 100 via the wiring 60. Figure 2 As shown, the skin 300 is composed of keratin 301, epidermis 302, and dermis 303 in order from the surface. Inside the dermis 303, there is subcutaneous tissue 310.

[0070] The iontophoresis device 100 applies an electric current to the skin 300 via the anode 21 serving as an electrode using a power source 10. A drug 31 stored in a first storage portion 30 is disposed between the anode 21 and the skin 300. The drug 31 reaches the subcutaneous tissue 310 through the skin 300 due to the electrical repulsion and convective movement of water in response to the applied current E. The drug 31 is supplied to various parts of the body through the subcutaneous tissue 310. Figure 2 In FIG, the drug 31 is indicated by a black circle. The circle indicated by dotted hatching is the counterion CI of the drug 31.

[0071] As described above, the iontophoresis device 100 can supply the drug 31 into the body of a living being.

[0072] <Configuration Example of the Iontophoresis Device 100>

[0073] Reference Figures 3 to 6 The structure of the iontophoresis device 100 will be described in detail.

[0074] (Overall structure)

[0075] Figures 3 to 5B 1 is a diagram schematically showing an example of the overall structure of the iontophoresis device 100 . Figure 3 It is an exploded three-dimensional diagram. Figure 4A This is a top view of the first example. Figure 4B This is a top view of the second example. Figure 5A yes Figure 4A Cross-sectional view of the VA-VA line in FIG. Figure 5B yes Figure 4B Cross-sectional view of the VB-VB line in FIG. Figure 4A and Figure 5A This shows the situation where the power supply and control unit are built into the device. Figure 4B and Figure 5B The case where the power supply and the control unit are provided externally is shown.

[0076] like Figures 3 to 5B As shown, the iontophoresis device 100 includes a power source 10, a pair of electrodes 20, a drug 31, a first storage unit 30, a second storage unit 40, and a control unit 50. The pair of electrodes 20 includes an anode 21 and a cathode 22. Figure 3 As shown, the anode 21 is electrically connected to the positive electrode of the power supply 10 via the control unit 50 via a wiring 60, and the cathode 22 is electrically connected to the negative electrode of the power supply 10 via the wiring 60. However, the electrical connection method between the power supply 10, the anode 21, and the cathode 22 is not limited to the wiring 60 and can be modified appropriately depending on the usage. Furthermore, the shape of the wiring 60 can be a film, a plate, a cable, or the like. Film-shaped wiring can be, for example, printed wiring produced by screen printing or etching, plate-shaped wiring can be, for example, a metal plate, and cable-shaped wiring can be, for example, a coated metal wire. Furthermore, the control unit 50 does not necessarily need to be connected between the anode 21 and the positive electrode of the power supply 10; it can also be located between the cathode 22 and the negative electrode of the power supply 10. Furthermore, the electrical connection method between the power supply 10, the control unit 50, the anode 21, and the cathode 22 is not limited to a wired connection; wireless connections using radio waves or the like are also possible. For example, at least one of the power supply 10 and the control unit 50 in the iontophoresis device 100 may be positioned outside the skin 300 of the living body 200, while the components of the iontophoresis device 100 other than at least one of the power supply 10 and the control unit 50 may be positioned on the skin. At least one of the power supply 10 and the control unit 50 and the components other than at least one of the power supply 10 and the control unit 50 may be wirelessly connected to each other so as to be able to communicate with each other. In other words, the iontophoresis device 100 may have an integrated structure in which all components are attached to the surface of the skin 300. Alternatively, the iontophoresis device 100 may have a separate structure in which a portion of the components of the iontophoresis device 100 are positioned on the skin 300 of the living body 200, while the remaining components of the iontophoresis device 100 are positioned away from the living body 200.

[0077] like Figures 4A to 5BAs shown, the substrate 2 supports at least the anode 21 and the cathode 22. The substrate 2 is a plate-shaped member having a substantially rectangular outer shape when viewed from above. The substrate 2 supports the anode 21 and the cathode 22 by bonding them to the lower surface with an adhesive member or the like. Figure 4A and Figure 5A In the embodiment, the substrate 2 also supports the power supply 10 and the control unit 50 by bonding them to the upper surface using an adhesive member or the like. The wiring 60 may also be supported by the substrate 2. The substrate 2 may be made of an insulator, such as a resin film, sheet, paper, or cloth. The outer shape of the substrate 2 when viewed from above is not limited to a generally rectangular shape; it may also be generally circular, generally elliptical, generally polygonal, or generally dumbbell-shaped. Furthermore, the iontophoresis device 100 may not necessarily include the substrate 2.

[0078] The anode 21 supports the first reservoir 30 by bonding the first reservoir 30 to the lower surface with an adhesive member or the like. The cathode 22 supports the second reservoir 40 by bonding the second reservoir 40 to the lower surface with an adhesive member or the like. In other words, the substrate 2 supports the first reservoir 30 via the anode 21 and supports the second reservoir 40 via the cathode 22.

[0079] exist Figures 4A to 5B In the embodiment, the skin contact member 3 supports the base material 2 by adhering the base material 2 to the upper surface with an adhesive. Furthermore, the skin contact member 3 secures the iontophoresis device 100 by adhering the iontophoresis device 100 to the surface of the skin 300 with an adhesive on the lower surface. This secures the first and second reservoirs 30, 40 when the iontophoresis device 100 is secured to the surface of the skin 300. The skin contact member 3 has a hole with a diameter equal to or larger than that of the first and second reservoirs 30, 40. The first and second reservoirs 30, 40 are positioned in the hole to secure the first and second reservoirs 30, 40. The hole can have a shape such as a generally rectangular, generally circular, generally elliptical, or generally polygonal. The skin contact member 3 can be made of an insulator, and preferably, a material having sufficient thickness and good conformability to the skin, such as a resin or rubber foam, sheet, paper, or cloth, can be used. Furthermore, the iontophoresis device 100 does not necessarily need to include the skin contact member 3 .

[0080] Figures 4A to 5B The cover tape 1 is a member having an adhesive lower surface. The cover tape 1 adheres or sticks the power source 10, a pair of electrodes 20, a drug 31, a first reservoir 30, a second reservoir 40, and a control unit 50 supported by the base material 2 and the skin contact member 3 to a portion of the lower surface, while the other portion of the lower surface is in contact with the skin 300 (see FIG. Figure 1A to Figure 2 ) surface. Thus, the cover tape 1 can secure the power source 10, the pair of electrodes 20, the drug 31, the first reservoir 30, the second reservoir 40, and the control unit 50 supported by the base material 2 and the skin contact member 3 to the surface of the skin 300. Alternatively, the iontophoresis device 100 can secure the power source 10, the pair of electrodes 20, the drug 31, the first reservoir 30, the second reservoir 40, and the control unit 50 to the surface of the skin 300 using a mechanism other than the cover tape 1.

[0081] In addition, if Figure 4B 、 Figure 5B As shown, at least a portion of the cover tape 1, base material 2, skin contact member 3, anode 21, cathode 22, first reservoir 30, and second reservoir 40 are adhered to skin 300. The power supply 10 and control unit 50 may be used while being located away from the user via wiring 60 connected to the anode 21 and cathode 22.

[0082] exist Figures 3 to 5B The power source 10 can be a primary battery, a secondary battery, or the like. For example, the power source 10 includes two coin-type lithium batteries directly connected to generate a maximum voltage of 6 V. From the perspective of reducing skin irritation, the current density is preferably 0.4 mA / cm 2 Hereinafter, skin irritation refers to the occurrence of changes in properties such as erythema in the portion of the skin 300 to which the current is applied. Skin irritation refers to the occurrence of skin irritation.

[0083] When the iontophoresis device 100 is used disposable, for cost reduction, it is preferable to use an inexpensive primary battery such as a coin-type lithium battery for the power source 10. A disposable use means that one iontophoresis device 100 is used once to deliver a drug to a living body and then discarded.

[0084] The anode 21 corresponds to an electrode electrically connected to the power source 10 and corresponds to a first electrode. The cathode 22 corresponds to a second electrode. Figures 3 to 5BIn the figure, the reference numerals of the pair of electrodes 20 are enclosed in parentheses along with the reference numerals of the anode 21 and the cathode 22, to indicate that the pair of electrodes 20 includes an anode 21 and a cathode 22. The materials of the anode 21 and the cathode 22 can be appropriately selected based on characteristics such as the ionization state of the drug 31 to be supplied. From the perspective of biocompatibility, the anode 21 is preferably constructed from a material such as silver, zinc, gold, platinum, titanium, or carbon. From the perspective of reducing pH fluctuations, it is more preferably constructed from silver or zinc. From the perspective of biocompatibility, the cathode 22 is preferably constructed from silver / silver chloride, gold, platinum, titanium, or carbon. From the perspective of reducing pH fluctuations, it is more preferably constructed from silver / silver halide. Examples of halide salts constituting silver / silver halide include iodide, bromide, chloride, and fluoride, with chloride being preferred.

[0085] The area of the anode 21 and the cathode 22 is preferably 1 cm 2 Over 50cm 2 Below, more preferably 2cm 2 Over 25cm 2 Below, more preferably 3cm 2 Over and 15cm 2 the following.

[0086] The first reservoir 30 is disposed between the skin 300 and the anode 21 and stores the drug 31. Figures 3 to 5BIn the figure, in the sense that the drug 31 is stored on the inner side of the first storage part 30, the reference numeral of the drug 31 is enclosed in brackets and annotated together with the reference numeral of the first storage part 30. The first storage part 30 is constructed to include a cotton non-woven fabric pad or the like. The first storage part 30 can store the drug 31 by impregnating the drug solution as the drug 31 into the cotton non-woven fabric pad. As solvents used for impregnating the drug solution, buffer solutions and electrolyte solutions can be cited. As buffer solutions, for example, buffer solutions composed of acetic acid, phosphoric acid, citric acid, carbonic acid, etc. are used. As electrolytes, halide salts such as calcium chloride, potassium chloride, sodium chloride, etc. are used. The first storage part 30 is not limited to being constructed to include a cotton non-woven fabric pad, but can also be constructed to include a porous membrane or hydrogel. As porous membranes, sheets, films, paper materials, cloth materials, etc. of foamed or porous polymers are used. Materials for these porous membranes include freon-based polymers such as polytetrafluoroethylene, polyimides, polyolefins such as polyethylene, polyesters such as polyethylene terephthalate, cellulose-based polymers such as hydroxypropyl cellulose, and silicone-based polymers such as polydimethylsiloxane. Hydrogels made of resins derived from natural sources or synthetic resins are used. Resins derived from natural sources include polysaccharides such as alginic acid, hyaluronic acid, and chitosan, and their metal salts, and cellulose-based polymers such as carboxymethyl cellulose and hydroxypropyl cellulose. Synthetic resins include polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyacrylic acid and its metal salts, polyacrylamide and its hydrolyzates, polyethers such as polyethylene glycol, and polymers having both a siloxane structure and an ether or ester structure in their molecular structure. Furthermore, the iontophoresis device 100 does not necessarily need to include the first storage unit 30. For example, the user of the iontophoresis device 100 may prepare the first storage unit 30.

[0087] The second storage portion 40 is disposed between the skin 300 and the cathode 22 below the second storage portion 40 and stores an electrolyte 41 for transferring ions. Figures 3 to 5B In the figure, the reference numeral of the electrolyte 41 is enclosed in parentheses and added to the reference numeral of the second storage portion 40, meaning that the electrolyte 41 is stored inside the second storage portion 40. The second storage portion 40 is configured to include, for example, a cotton non-woven fabric pad. The second storage portion 40 can store the electrolyte 41 by impregnating the cotton non-woven fabric pad with a solution obtained by dissolving the electrolyte 41 in a liquid. The second storage portion 40 is not limited to being configured to include a cotton non-woven fabric pad, but may also be configured to include a conductive gel containing the electrolyte 41. In addition, the iontophoresis device 100 does not necessarily need to include the second storage portion 40. For example, the user of the iontophoresis device 100 may prepare the second storage portion 40.

[0088] The control unit 50 controls the current applied to the skin 300 via the anode 21. In the present embodiment, the control unit 50 controls the application of a pulse current having a pulse frequency of 0.5 Hz or more and 50 Hz or less to the skin 300. Preferably, it is 0.8 Hz or more and 40 Hz or less, more preferably 1 Hz or more and 30 Hz or less, and further preferably 2 Hz or more and 25 Hz or less. In addition, in the present embodiment, the pulse current may also have a pulse width of 10 ms or more and 1000 ms or less. Preferably, it is 20 ms or more and 700 ms or less, more preferably 30 ms or more and 500 ms or less. In this specification and the scope of protection requested by this application, the pulse frequency refers to the number of pulse currents that are continuous at a specified period per second. The pulse current refers to a current applied at a specified period, and a current with a peak value flows during a specified time width within one period. In addition, the pulse width refers to a specified time width (e.g., half-value width) of the pulse current within one period. In addition, with respect to the pulse current obtained by the control unit 50, reference will be made to Figure 7 Describe in detail separately.

[0089] Here, the iontophoresis device 100 is not limited to a configuration in which the drug 31 is disposed between the anode 21 and the skin 300. For example, if the drug 31 is a negatively charged anion, the drug 31 may be disposed between the cathode 22 and the skin 300. With this configuration, the iontophoresis device 100 utilizes the electrical repulsion between the anions of the drug 31 and the cathode 22 to move the drug 31 disposed between the cathode 22 and the skin 300 toward the skin 300. Thus, the iontophoresis device 100 can deliver the drug 31 into the body via the skin 300. Furthermore, in this configuration, the control unit 50 controls the current applied to the skin 300 via the anode 21 and cathode 22. In this configuration, the cathode 22 corresponds to the electrode electrically connected to the power source 10 and corresponds to the first electrode. The anode 21 corresponds to the second electrode. However, in iontophoresis, electroosmotic flow, which is one of the driving forces for the movement of the drug 31 , is the flow of the solvent from the anode 21 to the cathode 22 . Therefore, a structure in which the positively charged cations serving as the drug 31 are disposed between the anode 21 and the skin 300 is advantageous.

[0090] (Structure of Control Unit 50)

[0091] Figure 6 is a block diagram showing an example of the structure of the control unit 50. Figure 6As shown, the control unit 50 includes a pulse generating circuit 51, a constant voltage control circuit 52, and a constant current element 53. The control unit 50 is, for example, a substrate on which these components are mounted. In this embodiment, the control unit 50 generates a pulse current PE by applying a pulse voltage PV, which is constant-voltage controlled by the constant voltage control circuit 52, to the constant current element 53. By applying the constant-voltage-controlled pulse voltage PV to the constant current element 53, the control unit 50 can generate a pulse current PE with a nearly constant current density during the on-period using a simple circuit configuration.

[0092] The pulse generating circuit 51 generates a pulse signal PS that is continuous at a predetermined cycle and serves as the basis for generating a pulse current. A pulse signal is a signal that is on only for a predetermined time width, i.e., a pulse width, within one cycle and off during periods other than the pulse width within one cycle.

[0093] The constant voltage control circuit 52 controls the input voltage so that it outputs a substantially constant voltage. Here, the constant voltage control circuit 52 controls the pulse signal PS generated by the pulse generator 51 so that the voltage during the on-period is substantially constant. The result of this control by the constant voltage control circuit 52 is the application of a pulse voltage PV to the constant current element 53.

[0094] The constant current element 53 is an element capable of always flowing a substantially constant current. A Zener diode can be used as the constant current element 53, for example. The pulse current PE is applied from the constant current element 53 to the skin 300 via the anode 21.

[0095] For example, if the power source 10 such as a coin-type lithium battery is mounted on the iontophoresis device 100 , the iontophoresis device 100 generates a pulse signal PS via the pulse generating circuit 51 .

[0096] Next, the iontophoresis device 100 applies a pulse voltage PV to the constant current element 53 through the constant voltage control circuit 52 so as to maintain a substantially constant voltage during the on-period of the pulse signal PS input from the pulse generating circuit 51 .

[0097] Next, the iontophoresis device 100 applies a pulse current PE from the constant current element 53 to the skin 300 via the anode 21. As described above, the iontophoresis device 100 can apply the pulse current PE to the skin 300.

[0098] The control unit 50 includes Figure 6 In addition to the components shown, a switch may be included for switching the start and stop of the iontophoresis device 100 by switching on and off the power supply from the power source 10 to the control unit 50 according to an operator's operation. By including a switch in the control unit 50, power can be used only when necessary, thereby reducing the power consumption of the iontophoresis device 100.

[0099] The control unit 50 does not necessarily need to include the constant voltage control circuit 52 and the constant current element 53. Instead, a pulse current PE obtained by pulse-modulating the current input from the power supply 10 using the pulse generating circuit 51 may be applied to the skin 300. However, the current density of the pulse current PE obtained by this configuration may fluctuate due to changes in the voltage input from the power supply 10, the load resistance, and the like. Therefore, in order to apply a pulse current PE with a substantially constant current density to the skin 300, it is preferable to use Figure 6 The structure shown.

[0100] Alternatively, the control unit 50 may include a constant current control circuit instead of the constant voltage control circuit 52 and the constant current element 53, and apply the pulse current PE obtained by the constant current control circuit to the skin 300. However, the pulse current PE obtained by this configuration may not be able to obtain a substantially constant current density due to control delays, etc. Therefore, from the perspective of applying a pulse current PE with a substantially constant current density to the skin 300, it is preferable to use Figure 6 The structure shown.

[0101] The functions of the pulse generating circuit 51 and the constant voltage control circuit 52 in the control unit 50 may be implemented by a processor, an ASIC (Application Specific Integrated Circuit), a DSP (Digital Signal Processor), an FPGA (Field Programmable Gate Array) implemented in an electronic circuit, or a combination thereof.

[0102] <An example of pulse current PE>

[0103] Figure 7 This is a diagram for explaining an example of the pulse current PE applied from the control unit 50 to the skin 300 via the anode 21 . Figure 7 The change in current density I according to time t is shown.

[0104] exist Figure 7 In the embodiment, the pulse current PE has a roughly rectangular waveform. In the present embodiment, the pulse current PE has a pulse frequency f of not less than 0.5 Hz and not more than 50 Hz. In addition, in the present embodiment, the pulse current PE may also have a pulse width W of not less than 10 ms and not more than 1000 ms. The period T is the period of the pulse current PE. The current density I0 is the current density of the pulse current PE during the pulse width W. In addition, the duty cycle D of the pulse current PE can be calculated by D=W / T×100. In addition, the waveform of the pulse current PE is not limited to a roughly rectangular shape, and may also be a roughly sine wave, a roughly triangular wave, etc.

[0105] <Examples, Comparative Examples>

[0106] Examples 1 to 4 and Comparative Examples 1 to 7 are described below. However, the present invention is not limited to these examples. In the Examples and Comparative Examples, an electric current was applied to the target object from the iontophoresis device 100 under the conditions described in each example. After the current application, the skin irritation and drug permeability of the target object were evaluated. Furthermore, Comparative Example 3 met the conditions disclosed in Patent Document 2. Comparative Examples 4 and 5 met the conditions disclosed in Patent Documents 1 and 3.

[0107] (Skin irritation evaluation)

[0108] (1) Evaluation method

[0109] Paste Object

[0110] A test was conducted by attaching a device having the following structure to the skin on the inner side of the left or right forearm of a subject as an iontophoresis device 100. Prior to attaching the iontophoresis device 100, the area of the skin where the iontophoresis device 100 was to be attached was wiped with absorbent cotton moistened with physiological saline.

[0111] Structure of the electrode, the first storage unit 30, and the second storage unit 40

[0112] Osaki Medical's gauze cotton nonwoven fabric cut into a roughly square shape of 2 cm x 2 cm was used as the first storage portion 30 and the second storage portion 40. On top of it, a gauze cotton nonwoven fabric with a shape of about 3 cm x 2 cm and a current-carrying area of 2 cm x 2 cm = 4 cm was used. 2 3M Japan-made electrocardiogram Red Dot 2360 electrodes were used as electrodes. These electrodes corresponded to the anode 21 and cathode 22. 0.3 mL of physiological saline was added to each of the first and second reservoirs 30 and 40 as electrolyte 41. Furthermore, in the skin irritation test, the first and second reservoirs 30 and 40 were used without the drug 31 added.

[0113] Power supply 10 and control unit 50

[0114] A potentiogalvanostat PocketSTAT II manufactured by IVIUM was used.

[0115] Current application conditions

[0116] The constant current element 53 was connected in series between the anode 21, the power supply 10, and the control unit 50, and the anode 21 was brought into contact with the skin. The cathode 22 was connected to the power supply 10 and the control unit 50, and the cathode 22 was brought into contact with the skin. The voltage from the power supply 10 and the control unit 50 was set to 10 V, and the current applied to the skin from the constant current element 53 was controlled to about 1 mA, thereby achieving a current density of about 0.25 mA / cm 2 To maintain a consistent total charge, the current application time was 10 minutes in Examples 1-3 and Comparative Examples 2-5, where pulsed current was applied, and 5 minutes in Comparative Example 1, where a non-pulsed current, i.e., a substantially constant current, was applied. The pulse current waveforms in Examples 1-3 and Comparative Examples 2-5 were rectangular waves.

[0117] Evaluation benchmark

[0118] After the current application was completed, the electrodes, first reservoir 30, and second reservoir 40 were peeled off the skin, and skin irritation was visually evaluated after 5 minutes based on the evaluation criteria shown in Table 1 below.

[0119] [Table 1]

[0120]

[0121] (2) Evaluation results

[0122] Table 2 shows a list of current application conditions and evaluation results in each example.

[0123]

[0124] In Table 2, erythema was observed in more than 50% of the electrode attachment sites in Comparative Examples 1 to 5. In Comparative Example 1, in addition to erythema occurring throughout the electrode attachment site on the cathode 22 side, papules were also observed. Furthermore, in Comparative Example 2, severe erythema was observed throughout the electrode attachment sites on both the anode 21 and cathode 22 sides. In contrast, in Examples 1 to 3, the severity of the erythema was suppressed and the area of the erythema was reduced compared to Comparative Examples 1 to 5, indicating a reduction in skin irritation. In particular, in Example 2, skin erythema was minimally observed, and the "Skin Irritation Rating" was "1.5," midway between "1" and "2," representing the lowest value in this test.

[0125] (Drug Skin Permeation Evaluation)

[0126] (1) Evaluation method

[0127] Test equipment

[0128] The abdominal skin of hairless male rats (HWY / Slc, SPF, 5 weeks old) was removed and cut into a 3.2 cm diameter circle and placed in a vertical Franz diffusion cell. 1.5 mL of a 0.5 wt% lanreotide acetate solution was added to the donor chamber of the Franz diffusion cell as the drug 31, and a zinc plate (0.5 cm × 2 cm × 0.5 mm) was immersed therein to serve as the anode 21. PBS was used as the receptor solution in the receptor chamber, and a silver / silver chloride rod (11 cm long, 1 mm diameter) was inserted from the sampling port to serve as the cathode 22. The zinc plate and silver / silver chloride rod were connected to the same power supply 10 and control unit 50 as those used in the above-mentioned skin irritation evaluation.

[0129] Current application conditions

[0130] Example 4: A rectangular wave with a frequency of 5 Hz, a period of 100 ms, a duty cycle of 50%, and a current density of 0.35 mA / cm was applied. 2 Pulse current.

[0131] Comparative Example 6: A current density of 0.35 mA / cm was applied at a nearly constant current value. 2 current, not pulse current.

[0132] Comparative Example 7: No current was applied.

[0133] In order to make the total time of current application (the total amount of applied current) uniform, the current was applied for 6 hours in Example 4 and for 3 hours in Comparative Example 6. In addition, Example 4 and Comparative Examples 6 and 7 were all implemented with n=3.

[0134] Evaluation items

[0135] The three items of evaluation were the cumulative amount of drug permeated, the permeation rate, and the relationship between the cumulative amount of drug permeated and the charge.

[0136] Data sampling

[0137] The receptor fluid was sampled every hour, and the amount of drug permeated through the skin was quantified using high-performance liquid chromatography (HPLC), evaluating the above three parameters over time. Furthermore, in Comparative Example 6, sampling continued after the end of current application, similar to Example 4 and Comparative Example 7, until six hours had passed from the start of the test. The HPLC measurement conditions are shown below.

[0138] <HPLC measurement conditions>

[0139] HPLC system: High performance liquid chromatograph (LC2010C) manufactured by Shimadzu Corporation

[0140] Column: ODS, 4.6mmφ×15cm, 5μm

[0141] Column temperature: 40°C

[0142] Mobile phase: A: 0.1% TFA aqueous solution, B: acetonitrile

[0143] Time program: shown in Table 3 below.

[0144] [Table 3]

[0145]

[0146] Detection wavelength: 220nm

[0147] Flow rate: 1.0 mL / min

[0148] Lanreotide detection time: 7.5 minutes

[0149] (2) Evaluation results

[0150] Reference Figures 8-10 The results of the drug skin permeation evaluation are described. Figure 8 It is a graph showing the cumulative permeation amount of the drug. Figure 9 It is a graph showing the penetration rate of drugs. Figure 10 This is a graph showing the relationship between the cumulative permeation amount of the drug and the charge. Figures 8 to 10 In the graph, the curve of “●” represents the data of Example 4, the curve of “■” represents the data of Comparative Example 6, and the curve of “▲” represents the data of Comparative Example 7.

[0151] like Figures 8 and 9 As shown, the drug skin permeability is the highest in Example 4, followed by Comparative Example 6, and the lowest in Comparative Example 7. Figure 8 In Example 4 and Comparative Example 6, skin penetration of the drug was observed approximately 2 hours after the start of the test. On the other hand, in Comparative Example 7, no skin penetration of the drug was observed until 4 hours after the start of the test. Furthermore, the cumulative drug penetration in Example 4 was greater than that in Comparative Example 6 at all times after 2 hours from the start of the test, when skin penetration was first observed. The difference became larger as time went by. Figure 9 As shown, after 2 hours from the start of the test, when skin penetration was first observed, the drug permeation rate of Example 4 was higher than that of Comparative Examples 6 and 7 at all times. Furthermore, the drug permeation rate of Example 4 was maintained from 3 hours to 6 hours from the start of the test, but in Comparative Example 6, the drug permeation rate decreased after 4 hours from the start of the test.

[0152] like Figure 8As shown in FIG. 3 , the cumulative permeation amount in Example 4 after 3 hours from the start of the test was greater than that in Comparative Example 6, although the amount of current applied was about half that in Comparative Example 6. Figure 10 As shown, if the cumulative permeation amounts under the same electrical charge are compared, the cumulative permeation amount of Example 4 is significantly greater than that of Comparative Example 6, and is ultimately more than 5 times.

[0153] These results indicate that the drug permeability in Example 4 and Comparative Example 6 is higher than that in Comparative Example 7, and that drug permeation is promoted by the application of current. Furthermore, in Example 4 and Comparative Example 6, it is found that the drug permeability in Example 4 is higher than that in Comparative Example 6, and that the application of pulsed current promotes drug permeation more than the application of constant current.

[0154] The results of the skin irritation evaluation and the drug skin permeation evaluation shown above indicate that the application of pulse current can improve the drug skin permeation and reduce skin irritation.

[0155] <Main Effects of the Iontophoresis Device 100>

[0156] As described above, in this embodiment, the control unit 50 controls the application of a pulse current PE having a pulse frequency f of 0.5 Hz or higher and 50 Hz or lower to the skin 300. Thus, the iontophoresis device 100 can improve the skin permeability of the drug 31 while reducing skin irritation caused by the application of the current. Furthermore, in this embodiment, the pulse current PE applied to the skin 300 can also have a pulse width W of 10 ms or higher and 1000 ms or lower. Thus, the iontophoresis device 100 can also improve the skin permeability of the drug 31 while reducing skin irritation caused by the application of the current.

[0157] In this embodiment, the iontophoresis device 100 includes a first reservoir 30, positioned between the skin 300 and the anode 21, for storing a drug 31; and a second reservoir 40, positioned between the skin 300 and the cathode 22, for storing an electrolyte 41. A control unit 50 controls the current applied to the skin 300 via the anode 21. This configuration promotes the electrical repulsion and convective movement of water in response to the applied current E, thereby enhancing the skin permeability of the drug.

[0158] While preferred embodiments of the present invention have been described in detail above, the present invention is not limited to these embodiments, and various modifications and changes can be made within the scope of the gist of the present invention as described in the scope of claims of the present application.

[0159] The numbers, such as serial numbers and quantities, used in the description of the embodiments are all illustrative for the purpose of specifically describing the technology of the present invention, and the present invention is not limited by the illustrative numbers. In addition, the connection relationships between the constituent elements are illustrative for the purpose of specifically describing the technology of the present invention, and do not limit the connection relationships that realize the functions of the present invention.

[0160] The embodiments of the present invention are as follows, for example.

[0161] <1> An iontophoresis device comprising: a power source; electrodes electrically connected to the power source; a drug disposed between the skin and the electrodes; and a control unit for controlling an electric current applied to the skin via the electrodes, the control unit controlling the application of a pulsed current having a pulse frequency of not less than 0.5 Hz and not more than 50 Hz to the skin.

[0162] <2> The iontophoresis device according to <1> above, wherein

[0163] The pulse current has a pulse width of 10 ms to 1000 ms.

[0164] <3> An iontophoresis device comprising: a power source; electrodes electrically connected to the power source; a drug disposed between the skin and the electrodes; and a control unit for controlling an electric current applied to the skin via the electrodes, wherein the control unit controls the application of a pulse current having a pulse width of not less than 10 ms and not more than 1000 ms to the skin.

[0165] <4> The iontophoresis device according to any one of <1> to <3>, wherein

[0166] The control unit generates the pulse current by applying a pulse voltage subjected to constant voltage control to a constant current element.

[0167] <5> The iontophoresis device according to any one of <1> to <4>, wherein

[0168] The above-mentioned electrode is a pair of electrodes including a first electrode and a second electrode. The above-mentioned ion electroperfusion device has: a first storage part, arranged between the above-mentioned skin and the above-mentioned first electrode, storing the above-mentioned drug; and a second storage part, arranged between the above-mentioned skin and the above-mentioned second electrode, storing electrolytes for moving ions. The above-mentioned control part controls the current applied to the above-mentioned skin via the above-mentioned first electrode.

[0169] This application claims the benefit of priority based on Japanese Patent Application No. 2023-055104, filed on March 30, 2023. The entire contents of the specification of Japanese Patent Application No. 2023-055104, filed on March 30, 2023, are incorporated herein by reference.

[0170] Description of Reference Numerals

[0171] 1…cover tape; 2…base material; 3…skin contact member; 10…power supply; 20…a pair of electrodes; 21…anode (an example of an electrode, an example of a first electrode); 22…cathode (an example of a second electrode); 30…first storage portion; 31…drug; 40…second storage portion; 41…electrolyte; 50…control portion; 51…pulse generating circuit; 52…constant voltage control circuit; 53…constant current element; 60…wiring; 100…iontophoresis device; 200…biological body; 300…skin; 301…keratin; 302…epidermis; 303…dermis; 310…subcutaneous tissue; II…region; CI…counter ion; D…duty ratio; E…applied current; f…pulse frequency; I, I0…current density; PE…pulse current; PS…pulse signal; PV…pulse voltage; t…time; T…period; W…pulse width.

Claims

1. An iontophoresis device, characterized in that have: Electrodes, which are worn on the skin over the medication; and The control unit is connected to the electrodes and generates a pulse current with a frequency of 0.5 Hz to 50 Hz.

2. An iontophoresis device, characterized in that: have: power supply; an electrode, electrically connected to the power supply; a drug disposed between the skin and the electrode; and a control unit that controls the current applied to the skin via the electrodes, The control unit controls to apply a pulse current having a pulse frequency of 0.5 Hz to 50 Hz to the skin.

3. The iontophoresis device according to claim 1, wherein The pulse current has a pulse width of 10 ms or more and 1000 ms or less.

4. The iontophoresis device according to claim 2, wherein The pulse current has a pulse width of 10 ms or more and 1000 ms or less.

5. An iontophoresis device, characterized in that: have: Electrodes, which are worn on the skin over the medication; and The control unit is connected to the electrodes and generates a pulse current having a pulse width of 10 ms to 1000 ms.

6. An iontophoresis device, characterized in that have: power supply; an electrode, electrically connected to the power supply; a drug disposed between the skin and the electrode; and a control unit that controls the current applied to the skin via the electrodes, The control unit controls to apply a pulse current having a pulse width of 10 ms to 1000 ms to the skin.

7. The iontophoresis device according to any one of claims 1, 3 and 5, characterized in that The control unit generates the pulse current by applying a pulse voltage subjected to constant voltage control to a constant current element.

8. The iontophoresis device according to any one of claims 2, 4 and 6, characterized in that The control unit generates the pulse current by applying a pulse voltage subjected to constant voltage control to a constant current element.

9. The iontophoresis device according to any one of claims 1, 3 and 5, characterized in that The electrodes are a pair of electrodes including a first electrode and a second electrode, The iontophoresis device has: a first storage portion disposed between the skin and the first electrode and storing the drug; and The second storage portion is disposed between the skin and the second electrode and stores electrolyte for transferring ions.

10. The iontophoresis device according to claim 2 or 6, characterized in that The electrodes are a pair of electrodes including a first electrode and a second electrode, The iontophoresis device has: a first storage portion disposed between the skin and the first electrode and storing the drug; and The second storage portion is disposed between the skin and the second electrode and stores electrolyte for transferring ions. The control unit controls the current applied to the skin via the first electrode.

11. The iontophoresis device according to claim 4, wherein The electrodes are a pair of electrodes including a first electrode and a second electrode, The iontophoresis device has: a first storage portion disposed between the skin and the first electrode and storing the drug; and The second storage portion is disposed between the skin and the second electrode and stores electrolyte for transferring ions. The control unit controls the current applied to the skin via the first electrode.

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