JPH09276416A - Iontophoresis electrode device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To reduce electric stimuli to the skin and a mucous membrance, to make a stabilized current flow for a long period and to efficiently transmit medication to a living body by providing two conductors provided with an electrode part electrically connected to the switching means of a power unit and the electrode part for reproduction and the conductor provided with the electrode part. SOLUTION: At the time of medication administration, the electrode part of a reference side conductor 2 and the donor electrode part 3a of a donor side conductor 3 are energized. Then, switching parts 4d and 4e are switched by the control signals of a control part 4a, and by the depolarization pulse output means of a current pulse output means 4b for treatments and a current output means 4c for reproduction, at the time of depolarization, a donor electrode part 3a is connected to a negative pole, an electrode part 3b for the reproduction is connected to a positive pole and the donor electrode part 3a is reproduced. Also, the donor electrode part 3a and the reference electrode part of the reference side conductor 2 are depolarized by short-circuit. Thus, electrode reproduction is simultaneously performed at the time of the depolarization.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an iontophoresis electrode device in which an electrode containing a drug is brought into contact with the skin or mucous membrane and a voltage is applied between the electrodes to absorb the drug into the body through the skin or mucous membrane. Regarding More specifically, the present invention relates to an iontophoresis electrode device that includes a depolarizing means and an electrode regenerating means and improves the drug delivery efficiency.

[0002]

2. Description of the Related Art In recent years, iontophoresis electrode devices that absorb drugs from the skin and mucous membranes are easier to administer, maintain blood levels, and digest as compared with oral administration, which is known as a general drug administration method. Since it has features such as avoiding side effects of drugs on the tube, it is under intensive development. The iontophoresis electrode device is a method in which each of the anode and cathode electrode devices is attached to the skin or mucous membrane, the drug is contained in either or both electrodes, and the drug is delivered from the power supply device into the living body. Is.

The energizing methods are mainly direct current type, pulse type,
There is a pulse depolarization type. Among them, the pulse depolarization type energization causes less irritation to the skin and mucous membranes even when a higher current is applied than the DC type or the pulse type.

As the electrode device, an electrode based on polarizable platinum, gold, carbon, titanium or non-polarizable silver or copper is used on the anode side, and based on silver chloride or copper chloride on the cathode side. Electrodes are used. When a polarizable electrode is used, polarization occurs on the surface of the electrode and current cannot be passed efficiently when applied. On the other hand, the non-polarizable electrode has an advantage that it is difficult to polarize because the change in pH is small even when electricity is applied. However, the non-polarizable electrode has a drawback in that the electrode itself undergoes a chemical change due to energization. Therefore, when applied for a long time, there is a problem that the electrode components react and are consumed and a stable current cannot be supplied. In addition, substances generated by chemical changes, for example, silver ions when the electrode part is silver and chloride ions when silver chloride is used, are sufficient to reduce the drug transport number by drastically reducing the contribution of iontophoresis to the drug. However, there have been problems such as the inability to deliver the drug into the living body.

Therefore, as a solution to these problems, Japanese Patent Publication No. 63-50240 (hereinafter referred to as "A") discloses an iontophoresis electrode device having an ion exchange membrane in the electrode portion. Has been done.

Further, as a means for electrically preventing the elution of ions without using an ion exchange membrane, the positive and negative of the electrode part are reversed at the time of energization and a current is passed in the opposite direction so that the eluted ion of the original electrode part is removed. An iontophoresis electrode device that restores the components and prevents the elution of the electrode components from the electrode portion is disclosed in Japanese Patent Application Laid-Open No. 4-313471 (hereinafter referred to as “B”). Further, WO95 / 00200 (hereinafter referred to as "C") discloses an iontophoresis electrode device in which a reproducing electrode is arranged on one conductor.

[0007]

However, the conventional iontophoresis electrode device described above has the following problems. (1) When an ion-exchange membrane is used as in Japanese Patent Publication (A) Publication No. 3, not only productivity is lacked because the structure of the preparation is complicated because an electrolyte solution layer is provided between the electrode part and the ion-exchange membrane. However, there is a problem in that a small amount of electrolyte permeates the ion exchange membrane, which reduces the drug transport number. (2) In the method of simply inverting the positive and negative of the electrode portion when applied as in Japanese Patent No. 2), in the case of high-frequency pulsed iontophoresis, the polarity is inverted every pulse, so the eluted ions are the original electrode components. Returning to step 2, although the electrode part is regenerated, the polarity of the current applied to the drug is instantaneously reversed, which causes a problem that the delivery amount of the drug important in iontophoresis is reduced. On the contrary, when the pulse interval is lengthened and a reverse current for regeneration is passed for a certain period of time after energization for a certain period of time, the ions generated by the reaction of the electrode part have already passed through the skin or mucous membranes. However, it has been found that it is difficult to effectively regenerate the electrode portion, and further there is a problem that it is not preferable in terms of safety. Further, there is a problem in that, when electricity is applied for drug administration, the eluted ions and the drug compete with each other for the current, and the drug transport number is reduced. (3) In the iontophoresis electrode device disclosed in Japanese Patent Publication No. H-Gazette, since there is no means for performing depolarization, there is a risk that electrical stimulation will be great against the skin and mucous membranes during administration and may cause burns. Had.

The present invention solves the above-mentioned conventional problems, and can significantly reduce electric stimulation to the skin and mucous membranes, and further allows a stable current to flow for a long time, thereby contributing the iontophoresis current to the drug. An object of the present invention is to provide an iontophoresis electrode device capable of delivering a drug into a living body without reducing the amount of the drug, remarkably improving the life of the electrode portion and excellent in durability.

[0009]

In order to solve this problem, the iontophoresis electrode device of the present invention has at least one conductor (electrode device) provided with a reproducing electrode portion, and a therapeutic current pulse output means. During the drug delivery pulse quiescent period, it is provided with a regeneration current output means for energizing the electrode portion to be regenerated at the same time as the depolarization and the regeneration electrode portion, and is configured to simultaneously perform the depolarization and the regeneration of the electrode portion. With this configuration,
The ions generated by the electrode reaction can be returned to the original electrode components, the life of the electrode part can be significantly improved, the competition between ions and drugs can be prevented, the transport number of drugs can be improved, and electrical stimulation can be achieved by depolarization. It can prevent giving to the adapted person.
Each claim will be specifically described below. The iontophoresis electrode device according to claim 1 of the present invention comprises:
(A) a control unit, a therapeutic current pulse output unit that outputs a drug delivery pulse and a depolarization pulse, a regeneration current output unit, and a switching unit that performs an on / off operation according to a control signal from the control unit, A direct current power source for supplying a current to the power source device; (b) a conductor having an electrode part and a reproducing electrode part electrically connected to the switching means of the power source device; And a conductor having the electrode portion electrically connected to the switching means of the power supply device. With this configuration, when a drug is administered, the donor electrode part of the donor-side conductor and the reference electrode part of the reference-side conductor are energized to deliver the drug as in the conventional iontophoresis electrode device, and the power supply is used during depolarization. The polarity is reversed in the device,
The donor electrode portion and the reproducing electrode portion are connected to each other to regenerate the donor electrode portion. Further, the reference electrode portion and the donor electrode portion have a function of being able to perform depolarization by a short circuit.

The iontophoresis electrode device according to claim 2 of the present invention is the same as that according to claim 1,
Treatment current pulse output means for performing drug delivery pulse output / depolarization pulse output, regeneration current output means, switching means for performing on / off operation according to the control signal of the control section, and DC power supply for supplying current to these A power supply device having a portion, and two conductors each electrically connected to the switching means of the power supply device and each having an electrode portion and a reproducing electrode portion. With this configuration, the switching unit turns on the drug delivery pulse output unit of the treatment current pulse output unit and turns off the depolarization pulse unit and the regeneration current output unit according to the control signal of the control unit to deliver the drug. Then, the polarity is inverted by the on / off operation of the switching means, so that the depolarization between the electrode portions and the regeneration of each electrode portion can be performed. Further, since the depolarization is repeated every short time, it has an effect that it is possible to prevent the electrical stimulation from being applied and further prevent the electrode portion from being consumed.

An iontophoresis electrode device according to a third aspect of the present invention is the iontophoresis electrode device according to the second aspect, wherein the reproduction current output section is further provided with a reproduction current control means. . With this configuration, since the reproduction current equal to the treatment current is supplied, the life of the electrode portion can be remarkably improved.

Here, the energization pattern of the iontophoresis electrode device is a pulse depolarization type. As a result, electrical stimulation can be prevented, safety can be improved, and long-term administration can be realized. 0.01 as the current value
˜50 mA, preferably 0.05 to 10 mA. The voltage value is 1 to 30V, preferably 3 to 15V. Frequency is 1 to 1000 kHz, preferably 10 to 1
It is 00 kHz. Pulse duty is 1 to 90%,
Preferably it is 10 to 50%. The reproduction current output means outputs a direct current or a pulse output current. As the current value, an amount of current necessary for returning the changed electrode component to the original electrode component may be excessive or insufficient, but the current value is, for example, 0.01 to 50 mA, preferably 0.05 to 10 mA. It is preferable to energize. The therapeutic current pulse output means has a mechanism for connecting the output terminals to the depolarization pulse output means when the drug delivery pulse output means is turned off. As the control unit, a microcomputer that outputs a control signal based on an algorithm, a gate array, an analog circuit composed of other discrete components, a digital circuit, a hybrid circuit of these, or the like is used. As switching means, analog switches, relays, transistors, FE
T, a rectifying element, etc. are used. Electrochemically stable materials such as platinum, gold, carbon, titanium, and
Aluminum or the like is used. Among them, carbon is preferably used because it is highly safe for the human body and has excellent workability.

The electrode part of the donor-side conductor is an electrode for iontophoretic administration of a drug, and a non-polarizable electrode is used. An electrode material based on silver or copper may be mentioned on the side which becomes the anode during drug delivery, but a silver based one is preferable. As the electrode material on the cathode side, those based on silver chloride or copper chloride can be mentioned, but those based on silver chloride are preferred. The electrolyte layer is for supplying a stable electric current between the electrode portions during drug delivery, and for supplying a current between the electrode portion and the regeneration electrode portion during electrode regeneration. Since a polarizable electrode is used for the reproducing electrode section, p
H changes. For this reason, buffer solutions such as acetic acid, phosphoric acid, citric acid, and carbonic acid, and strong electrolyte solutions such as sodium chloride, sodium sulfate, and potassium chloride are used in this electrolyte layer. ,
Gauze, absorbent cotton, polyethylene with continuous foaming, polypropylene, vinyl acetate, polyolefin foam, polyamide foam, xanthan gum, starch, gum arabic, echo gum, locust bean gum, gelatin, agar, pectin, polyvinyl alcohol and its saponification product, polyvinyl formal, Polyvinyl methyl ether and its copolymer, polyvinyl pyrrolidone and its copolymer, polyhemes and its cross-linked product (etc.) are used.

The drug is not particularly limited, and any drug applicable to iontophoresis can be used.
Preferably, central analgesics such as morphine, fentanyl, pethidine, codeine, buprenorphine, butorphanol, eptazocine, pentazocine, insulin, calcitonin, calcitonin-related gene peptide, vasopressin, desmopressin, prothrelin (TRH),
Corticotropin (ACTH), luteinizing hormone-releasing factor (LH-RH), growth hormone-releasing hormone (GRH), nerve growth factor (NGF) and other releasing factors, angiotensin (angiotensin), parathyroid hormone (PTH) , Thyroid-stimulating hormone (TSH,
Thyrotropin), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, serum gonadotropin, placental gonadotropin (HCG), pituitary gonadotropin (HMG), growth hormone , Somatostatin, somatomedin, glucagon, oxytocin,
Gastrin, secretin, endorphin, enkephalin, endothelin, cholestokinin, neurotensin, interferon, interleukin, transferrin, erythropoietin, superoxide desmutase (SOD), granulocyte stimulating factor (G-CSF), intestinal vasodilator (VIP) , Muramyl dipeptide,
Peptides such as corticotropin, urogastrone, human atrial diuretic peptide (h-ANP), tranquilizers such as carmazepine, chlorpromazine, diazepam, nitrazepam, bleomycin, adreamycin, 5-
Antineoplastic drugs such as fluorouracil and mitomycin,
Angina drugs such as digitalis, digoxin, digitoxin,
Sex hormones such as estradiol and testosterone, and antihypertensive agents such as reserpine and clonidine can be used.

[0015]

Embodiments of the present invention will be described below in detail with reference to the drawings. In order to make the explanation easy to understand, as an example of the regeneration electrode part of the present invention, a case where a drug charged with + is administered by iontophoresis will be described. (Embodiment 1) FIG. 1 is an apparatus block diagram showing a structure of an iontophoresis electrode device according to Embodiment 1, and FIG. 2 is a state during drug delivery of the iontophoresis electrode device according to Embodiment 1. FIG. 3 is a schematic diagram showing the state during depolarization / electrode regeneration, and FIG. 4 is a schematic diagram showing the structure of the donor-side conductor. 1 to 3, 1 is an iontophoresis electrode device according to the first embodiment, 2 is a reference side conductor formed of an electrode material such as silver chloride, and 3 is a donor formed of an electrode material such as silver. Donor side conductors provided with an electrode portion 3a and a reproducing electrode portion 3b made of carbon or the like, 2'and 3'denotes backing members of the respective conductors, 4 a reference side conductor 2 and a donor side conductor 3 It is a power supply device that supplies a current to. The power supply device 4 includes a control unit 4a, a therapeutic current pulse output unit 4b and a regeneration current output unit 4c that perform drug delivery pulse output and depolarization pulse output controlled by a control signal of the control unit 4a, and a control unit. It is provided with a circuit having switching means 4d and 4e for performing on / off operation according to the control signal of 4a and a DC power supply section (not shown) for energizing these. At the time of application, the power supply device 4 has a function of passing a current, which is reversed from that at the time of drug delivery, to the donor electrode portion 3a and the regeneration electrode portion 3b. 5, 6 and 7 are output terminals A of the power supply device 4,
It is a lead wire for connecting B and C and the electrode portions 2, 3a and 3b. The output end C is not connected to the control of the switching means and is always connected at a reference potential (ground in the circuit). Reference numeral 8 denotes a human or animal application site to which the iontophoresis electrode device 1 is applied. In FIG. 4, 3a is a donor electrode part, 3b is a regeneration electrode part, 3c is a stable and high-rate current flowing through each electrode part 3a of the donor-side conductor 3 during drug delivery, and iontophoresis is carried out during electrode regeneration. An electrolyte layer 3d that allows a current to flow at a high rate between the electrode portion 3a and the reproducing electrode portion 3b is laminated on the electrolyte layer 3c, or the electrolyte layer 3c when the iontophoresis electrode device 1 is applied to the application site. Is a drug holding layer (FIG. 4 shows the drug holding layer 3d laminated on the electrolyte layer 3c).

The operation of the iontophoresis electrode device according to the first embodiment configured as described above will be described below. FIG. 5 is a diagram showing an energization pattern of the iontophoresis electrode device and polarities of electrode portions in the first embodiment. First, as shown in FIGS. 2 and 5, during drug administration, the electrode portion of the reference side conductor 2 and the donor electrode portion 3a of the donor side conductor 3 are energized in the same manner as in the conventional iontophoresis electrode device. Then, the switching parts 4d and 4e are switched by the control signal of the control part 4a, and as shown in FIGS. 3 and 5, the depolarization pulse output means of the therapeutic current pulse output means 4b and the regeneration current output means 4c are used to remove the depolarization pulse. During polarization, the donor electrode portion 3a is connected to the negative electrode and the reproducing electrode portion 3b is connected to the positive electrode so that the donor electrode portion 3a is reproduced. In addition, the donor electrode portion 3a and the reference electrode portion of the reference side conductor 2 are depolarized by a short circuit. In FIG. 5, the reference-side conductor 2 has a negative polarity, but in terms of current, it acts as + due to the depolarizing current from the load, and is therefore represented as ± for convenience.

As described above, according to the iontophoresis electrode device of the present embodiment, electrode regeneration can be simultaneously performed during depolarization. In particular, by performing depolarization / electrode regeneration every pulse, it is possible to prevent the ions generated from the electrode from competing with each other for the drug, and it is possible to significantly reduce the amount of the electrode material such as silver used for the electrode.

(Second Embodiment) FIG. 6 is a schematic view showing the mechanism of the iontophoresis electrode device according to the second embodiment. 11a is the iontophoresis electrode device according to the second embodiment, 12 is the reference-side conductor,
Reference numeral 12a is a reference electrode portion formed of silver chloride or the like, 1
Reference numeral 2b is a reference side reproducing electrode section, 13 is a donor side conductor, 13a is a donor electrode section formed of silver or the like, 13b is a donor side reproducing electrode section, and 14a is an iontophoresis electrode device according to the second embodiment. 11a is a power supply device.
The power supply device 14a performs a treatment current pulse output means for performing drug delivery pulse output / depolarization pulse output, a reproduction current output means, a control section for controlling these, and an on / off operation by a control signal of the control section. Switching means,
A DC power supply unit 14a 'for supplying current to these is provided. Reference numerals 15, 16, 17, and 18 are lead wires connecting the switching means of the power supply device 14a and each electrode portion, 19 is an application site of skin or mucous membrane, and SW1, SW2, SW3 and SW4 are switching means for switching each connection portion. Switches, which are schematic representations of circuits, are terminals.

The operation of the iontophoresis electrode device having the above-described structure according to the second embodiment will be described below with reference to the drawings. FIG. 7 is a schematic diagram showing the state of the iontophoresis electrode device during drug delivery in the second embodiment, and FIG. 8 is a schematic diagram showing the state during depolarization and electrode regeneration. First, FIG.
At the time of drug delivery, SW1 is connected to the side and SW2 is connected to the side to form an electrically closed circuit.
4, is opened and is in the cutoff state. As a result, a current flows between the reference electrode portion 12a and the donor electrode portion 13a to administer the drug. Next, referring to FIG. 8, the control signal from the control unit causes the switching means to be turned on and off.
During depolarization and electrode regeneration, SW1 is connected to the side and SW2 is connected to the side to form an electrically closed circuit, and SW3 and SW4 are connected and short-circuited. As a result, the polarities of the reference electrode portion 12a and the donor electrode portion 13a are opposite to those at the time of drug delivery, and depolarization is performed. Further, in the reference side conductor 12, chloride ions generated from silver chloride of the reference electrode portion 12a can be fixed to silver chloride, and silver ions generated from silver of the donor electrode portion 13a can be fixed to silver.

As described above, according to the iontophoresis electrode device of the present embodiment, since both the donor-side conductor and the reference-side conductor are provided with the regenerating electrode portion, the ion which is an electrode reactant. Can be prevented from entering the body of the person being applied. In addition, since the donor electrode portion and the reference electrode portion are constantly regenerated, the electrodes are not consumed and a constant current can always be stably applied.

(Third Embodiment) FIG. 9 is a schematic view showing the mechanism of the iontophoresis electrode device according to the third embodiment. The iontophoresis electrode device 11b of the third embodiment is different from that of the second embodiment in that the number of SWs in the power supply device 14b is reduced to one and, instead, two rectifying elements 17a and 18a are provided in the circuit. Capacitor 15
This is a point provided with a, 16a and one resistor 18b. 1
Reference numeral 4b 'denotes a DC power supply section provided in a circuit in the power supply apparatus 14b, 17a denotes a rectifying element arranged between the reference side reproducing electrode section 12b and the DC power supply section 14b' with a polarity opposite to that of the rectifying element 18a, and 15a. Is a capacitor arranged between the reference electrode 12a and the DC power supply unit 14b 'in the same manner as the capacitor 16a, 18b is a resistor arranged between the DC power supply unit 14b' and the rectifying element 18a, and one SW5 is arranged in the system. The installed switches, and are terminals.

The operation of the iontophoresis electrode device according to the third embodiment configured as described above will be described below. First, at the time of drug delivery, SW
5 is connected to the terminal, and the terminal is open. As a result, a therapeutic current flows between the donor electrode portion 13a and the reference electrode portion 12a. After that, the SW5 is connected to the terminal and the terminal is opened, so that the donor electrode portion 13
The polarity of a is reversed, and as a result, the donor electrode portion 13a and the reference electrode portion 12a are depolarized and simultaneously regenerated by the respective reproduction electrode portions 12b and 13b. As described above, according to the present embodiment, it is possible to efficiently perform reproduction with a small amount of switching means and with a current equal to the therapeutic current.

[0023]

【Example】

(Examples 1 to 3) FIG. 10 is a conduction circuit diagram of the iontophoresis electrode device in Examples 1 to 3. In the figure, 21 is an iontophoresis electrode device, 22 is a reference side conductor, 23 is a donor side conductor, 23a is a donor electrode part, 23b is a regeneration electrode part, 24a is a drug delivery / depolarization pulse power source, and 24b. Is a power source for electrode regeneration, 25,
Reference numeral 26 is a lead wire, and 27 is a synthetic resin cylindrical cell.
Next, a method for manufacturing the iontophoresis electrode device 21 will be described. First, effective transmission area 2.5c
m ^2, the half to the donor electrode portion on 23a and the donor electrode portion 23a and the same plane made of a non-polarizable electrode one end of an area 1.2 cm ² of semi-circular cylindrical cell 27 consisting of width 1.4 cm (silver electrode) The donor-side conductor 23 was provided with a backing member in which circular reproducing electrode portions 23b made of carbon having an area of 1.2 cm ² were arranged so as not to contact each other. After injecting 3.6 ml of a 0.01 mol / l acetic acid / sodium acetate buffer solution having a pH of 6 into the cylindrical cell 27,
An iontophoresis electrode device 21 was prepared by attaching a backing member having a circular silver chloride electrode having an area of 2.5 cm ² to the other end of the cylindrical cell 27 as a reference side conductor 22. Using the iontophoresis electrode device manufactured as described above, the weight change of the electrode part was measured. FIG. 12 shows the result. As for the measuring method, the circuit system as shown in FIG. 10 was energized under the following conditions for 3 hours, and the weight of the silver electrode before and after energization was measured to examine the change. Drug delivery / depolarization pulse power supply voltage (24a): voltage is 5
V constant voltage, frequency was 30 kHz and duty was 30%. DC power supply voltage (24b): a voltage value (2.4 to 2.6 V) adjusted to be equal to the transmission current immediately after the start of energization flowing through the resistor R2 of the circuit of Comparative Example 1 (FIG. 11).

(Comparative Examples 1 to 3) FIG. 11 is a conduction circuit diagram of the iontophoresis electrode device in Comparative Example 1. Reference numeral 31 is an iontophoresis electrode device of Comparative Examples 1 to 3, 32 is a reference side conductor, 33 is a donor side conductor, 34 is a drug delivery / depolarization pulse power source, and 35 is a synthetic resin cylindrical cell. Next, a method for manufacturing the iontophoresis electrode device of Comparative Example 1 will be described. A backing member having a semi-circular nonpolarizable (silver electrode) having an area of 1.2 cm ² is attached to one end of a cylindrical cell 35 having an effective permeation area of 2.5 cm ² and a width of 1.4 cm, and a donor-side conductor is attached. 33. 0.0 of pH 6 in the cylindrical cell 35
1 mol / l acetic acid / sodium acetate buffer solution 3.6 m
After injecting l, the area at the other end of the cylindrical cell 35 is 2.5
An iontophoresis electrode device 31 was prepared by using a backing member 32 provided with a circular silver chloride electrode of cm ² as a reference side conductor 32. Then, using the obtained iontophoresis electrode device, the weight change of the electrode part was measured. FIG. 12 shows the result. The measurement method is 3 under the following conditions in the circuit system as shown in FIG.
The electricity was applied for a period of time, and the weight of the silver electrode before and after the electricity was applied was measured to examine the change. Drug delivery / depolarization pulse power supply voltage: constant at 5 V, frequency was 30 kHz, and duty was 30%. FIG. 12 is a diagram showing changes in the weight of the silver electrode. This figure 1
As is clear from 2, the weights of the silver electrodes in Examples 1 to 3 hardly changed before and after energization.
In the case where the electrode was not regenerated as in No. 3, silver was reduced in an approximately equimolar amount (7.25 ± 0.11 mg (mean ± standard deviation of 3 cases)) with respect to the amount of current flowing. It was found that the iontophoresis electrode device of the example enables stable drug administration during the energization period while regenerating the electrode part, and significantly improves the durability of the electrode part. The circuit in which the capacitor in FIG. 10 was removed was energized in the same manner as in Examples 1 to 3, but in this case as well, there was almost no change in the weight of the silver electrode before and after energization.

(Embodiment 4) 2.5 cm ² area Donor electrode part composed of circular non-polarizable electrode (silver electrode), and outer diameter of 1.25 cm and inner diameter of 1 cm on the same plane and concentric circles.
The ring-shaped reproducing electrode portions made of carbon and having an area of 1.77 cm ² were mounted on a backing member made of a film so as not to contact each other. Next, the donor electrode portion contains 200 μl of a 10 mM acetic acid / sodium acetate buffer aqueous solution having a pH of 3.14 cm ² and a thickness of 0.5 mm.
1 round non-woven fabric (Japan Vilene WP-2085)
Sheet, further immersed in purified water, area 5.3 cm ² , thickness 0.1.
5mm circular non-woven fabric (Japan Vilene LMW-900
Two pieces of 7) were layered to form a purified water layer. On top of that, the area 4.1
A circular biodyne film having a cm ² and a thickness of 5 μm (Pall) was stacked to form a drug holding layer, and 4 μg of salmon calcitonin (NOVA) was dropped on the drug holding layer, which was used as a donor-side conductor. This donor-side conductor was applied on the abdominal skin of a rat (7-week-old SD rat). Also sodium chloride 12
% Polyvinyl alcohol gel (Unitika UF-
A non-polarizable electrode made of silver chloride having 250 G) laminated thereon was prepared and applied as a reference side conductor onto the abdominal skin of the rat described above. With the donor-side conductor as the anode and the reference-side conductor as the cathode, energize the iontophoresis electrode device for 45 minutes under the following conditions, and observe the non-woven fabric of the donor-side conductor and the skin of the rat application site after energization. did. Drug delivery / depolarization pulse power supply voltage: 10 V constant voltage, frequency was 30 kHz, and duty was 30%. DC power supply voltage: 0.3 mA was constant.

(Comparative Example 4) A donor electrode portion composed of a circular nonpolarizable electrode (silver electrode) having an area of 2.5 cm ² was mounted on a backing member composed of a film. Next, the donor electrode portion contains 200 μl of a 10 mM acetic acid / sodium acetate buffer solution having a pH of 6, an area of 3.14 cm ² , and a thickness of 0.5 mm.
1 round non-woven fabric (Japan Vilene WP-2085)
Sheet, further immersed in purified water, area 5.3 cm ² , thickness 0.1.
5mm circular non-woven fabric (Japan Vilene LMW-900
Two pieces of 7) were layered to form a purified water layer. On top of that, the area 4.1
A circular biodyne film having a cm ² and a thickness of 5 μm (Pall) was stacked to form a drug holding layer, and 4 μg of salmon calcitonin (NOVA) was dropped on the drug holding layer, which was used as a donor-side conductor. Then, the donor-side conductor was used as a rat (SD rat 7
(Week old) abdominal skin. Further, a non-polarizing electrode made of silver chloride in which 12% polyvinyl alcohol gel containing 0.9% sodium chloride (Unitika UF-250G) was laminated was prepared, and this was applied as a reference side element to the abdominal skin of a rat. . Using the donor-side conductor as an anode and the reference-side conductor as a cathode, the iontophoresis electrode device was energized for 45 minutes under the following conditions, and the non-woven fabric of the donor-side conductor and rat skin after the energization were observed. Drug delivery / depolarization pulse power supply voltage: 10 V constant voltage, frequency was 30 kHz, and duty was 30%. DC power supply voltage: 0.3 mA was constant. As a result of the above Examples and Comparative Examples, in Example 2 in which the donor electrode portion was regenerated, no coloring that could be attributed to the elution of silver ions was observed in the non-woven fabric or rat skin, whereas the electrode portion was regenerated. In Comparative Example 2, which was not performed, black coloring that was considered to be silver ions was confirmed on the nonwoven fabric and rat skin. From the above, it was found that the iontophoresis electrode device of the present example regenerates the donor electrode portion, prevents the reactant of the electrode from entering the living body, and is extremely excellent in safety.

(Embodiment 5) FIG. 13A is a schematic exploded side view of a donor-side conductor in Embodiment 5, and FIG.
(B) is a principal part schematic plan view showing the structure of the electrode part of the donor side conductor. In FIG. 13 (a), 43 is the donor-side conductor of Example 3, 44 is an electrolyte layer made of a non-woven fabric containing a citrate buffer, and 45 is a biodyne membrane (manufactured by Pall) containing 10 IU of salmon calcitonin. It is a drug holding layer. In FIG. 13B, 43a is a donor electrode part made of a silver electrode, and 43b is a reproduction electrode part made of a carbon electrode. The reference side conductor (not shown) is
It was prepared by laminating silver / silver chloride (2.5 cm ² ) on a 12% polyvinyl alcohol gel containing 0.9% sodium chloride. Using the obtained iontophoresis electrode device, it was attached to the abdomen of an SD rat, and 1 mA was passed as a permeation current to the donor-side conductor and the reference-side conductor. Here, the permeation current refers to the current that actually flows between the skin and the mucous membrane via the donor electrode portion and the reference electrode portion during energization of pulse depolarized iontophoresis. This will be specifically described with reference to FIG. FIG. 14 is a diagram showing a current waveform during pulse depolarization energization in Example 3. The transmission current is shown in Fig. 1.
It is represented by a value obtained by subtracting the area of β from the area of α of 3 and dividing it by the time t. Blood was collected from the rat jugular vein over time, and the salmon calcitonin concentration in the blood was measured using a commercially available radioimmunoassay kit (Peninsler).
The result is shown in FIG.

(Comparative Example 5) A silver electrode was used as a donor side electrode, a non-woven fabric containing a citrate buffer solution was superposed as an electrolyte layer, and then salmon calcitonin 1 was used as a drug.
A drug holding layer composed of a biodyne film, which was dropped by 0 IU, was overlaid to prepare a donor-side conductor. What was described in Example 3 was produced as a reference side conductor. The obtained iontophoresis electrode device was used to attach to the abdomen of an SD rat. Next, when iontophoresis was applied, a permeation current of 1 mA was applied between silver and silver chloride. Blood was collected from the rat jugular vein over time, and the salmon calcitonin concentration in the blood was measured using a commercially available radioimmunoassay kit (Peninsler). The result is shown in FIG. FIG. 15 is a diagram showing changes in salmon calcitonin concentration in serum over time. As is clear from FIG. 15, the maximum serum concentration of salmon calcitonin in this example was 602.
1 ± 2978.8 ng / ml (mean ± standard error, 4 cases)
Met. On the other hand, the maximum serum concentration of the comparative example is 152.3.
It was ± 18.6 ng / ml (mean ± standard error, 4 cases). From the above, it was found that the present invention can increase the absorption of salmon calcitonin by about 4 times. In this example, since the silver ion generated from the electrode is regenerated to silver, the transport number to salmon calcitonin is not reduced, but when the electrode is not regenerated like the comparative example, the silver ion generated from the electrode competes with salmon calcitonin and salmon. It is thought that this is because the transport number of calcitonin is reduced.

[0029]

As described above, according to the iontophoresis electrode device of the present invention, the following excellent effects can be realized. It is possible to reduce electrical stimulation to the skin and mucous membranes, pass a stable electric current for a long time, and efficiently deliver a drug into a living body. There is almost no consumption of electrode material, the amount of electrode material used can be significantly reduced, and mass productivity can be improved at low cost. Since the ions of the electrode material do not enter the body, the safety can be significantly improved.

[Brief description of drawings]

FIG. 1 is an apparatus block diagram showing a structure of an iontophoresis electrode device according to a first embodiment.

FIG. 2 is a schematic diagram showing a state during drug delivery of the iontophoresis electrode device according to the first embodiment.

FIG. 3 is a schematic diagram showing a state during depolarization / electrode regeneration of the iontophoresis electrode device according to the first embodiment.

FIG. 4 is a schematic diagram showing the structure of a reference side conductor in the first embodiment.

FIG. 5 is a diagram showing the energization pattern and the polarity of the electrode part of the iontophoresis electrode device according to the first embodiment.

FIG. 6 is a schematic diagram showing the mechanism of the iontophoresis electrode device according to the second embodiment.

FIG. 7 is a schematic diagram showing a state of the iontophoresis electrode device according to the second embodiment during drug delivery.

FIG. 8 is a schematic diagram showing a state during depolarization / electrode regeneration of the iontophoresis electrode device according to the second embodiment.

FIG. 9 is a schematic diagram showing the mechanism of the iontophoresis electrode device according to the third embodiment.

FIG. 10 is a conduction circuit diagram of the iontophoresis electrode device in Examples 1 to 3.

FIG. 11 is a conduction circuit diagram of iontophoresis electrode devices in Comparative Examples 1 to 3.

FIG. 12 is a diagram showing a change in weight of a silver electrode.

13A is a schematic exploded side view of the iontophoresis electrode device in Example 5, and FIG. 13B is a schematic plan view of essential parts showing the structure of the electrode part of the donor-side conductor.

FIG. 14 is a diagram showing a current waveform at the time of energizing pulse depolarization in Example 5.

FIG. 15 is a graph showing the time course of salmon calcitonin concentration in serum.

[Explanation of symbols]

1, 11 Iontophoresis electrode device of Embodiment 1 2, 12 Reference side conductor 2'Backing member 3,13 Donor side conductor 3a Donor electrode part 3'Backing member 3b Regeneration electrode part 3c Electrolyte layer 3d Drug Contained layer 4 Power supply device 4a Control part 4b Treatment current pulse output means 4c Regeneration current output means 4d, 4e Switching means 5, 6, 7 Lead wire 8 Application site 11a Iontophoresis electrode device of Embodiment 2 12 Reference Side conductor 12a Reference electrode part 12b Reference side reproduction electrode part 13 Donor side conductor 13a Donor electrode part 13b Donor side reproduction electrode part 14a Power supply device for iontophoresis electrode device of Embodiment 2 14a 'DC power supply part 14b Iontophoresis electrode of the third embodiment Vice power supply device 14b 'DC power supply part 15, 16, 17, 18 Lead wire 15a, 16a Capacitor 17a, 18a Rectifying element 18b Resistance 19 Switch 21,31 Iontophoresis electrode device 22,32 Reference side conductor 23,33 , 43 Donor side conductor 23a Donor electrode part 23b Regeneration electrode part 24a Drug delivery / depolarization pulse power source 24b Electrode regeneration power source 25, 26 Lead wire 27 Cylindrical cell 31 Iontophoresis electrode device 43a Donor electrode part 43b Regeneration electrode Part 44 Electrolyte layer 45 Drug retention layer

Front page continued (72) Inventor Kazutaka Inoue 1-25-11 Kannondai Tsukuba, Ibaraki Prefecture Hisamitsu Pharmaceutical Co., Ltd. Tsukuba Research Center

Claims (3)

[Claims] 1. A control unit and a drug delivery pulse output
It has a treatment current pulse output means for outputting a depolarization pulse, a reproduction current output means, a switching means for performing an on / off operation according to a control signal of the control section, and a DC power supply section for supplying a current to these. A power supply device; (b) two conductors having an electrode part and a reproducing electrode part electrically connected to the switching means of the power supply device; and (c) electrically connected to the switching means of the power supply device. An iontophoresis electrode device, comprising: a conductor having an electrode portion connected thereto; 2. A control unit, a treatment current pulse output unit for performing drug delivery pulse output / depolarization pulse output, a reproduction current output unit, and a switching unit for performing on / off operation according to a control signal of the control unit. A power supply device having a direct current power supply part for supplying a current to these, and two conductors each electrically connected to the switching means of the power supply device and each having an electrode part and a reproducing electrode part. The iontophoresis electrode device according to claim 1, wherein the iontophoresis electrode device is provided. 3. The reproducing current output means is further provided with reproducing current control means.
Or the iontophoresis electrode device according to 2.