JP2000288098A - Iontophorese apparatus - Google Patents

Abstract

PROBLEM TO BE SOLVED: To make it possible to efficiently transport an electrifying medicine component to the skin by an iontophorese electrode section which has the opposite ions of the electrifying ions of the ionic medicine and the ions of the same kind as these ions and a ground electrode which has respective ion exchange membranes for selecting the opposite ions, both of which electrodes forwardly shift the ion exchange membranes. SOLUTION: The iontophorese apparatus X has the mechanism which integrates the outer cylindrical body (a), inner cylindrical body (b) and intermediate cylindrical body (c) of the iontophorese electrode section 1 via the threaded parts formed to their each other's abutment surfaces by means of screwing and brings the iontophorese electrode section directly or indirectly into tight contact with the skin side by the relative movement of the outer cylindrical body (a) and the middle cylindrical body (c). The middle cylindrical body (c) of a cylindrical shape comprises the cylindrical body having a supporting part c1 for the ion exchange membrane 13 which fixes and supports the cation exchange membrane 13 cooperatively with a pressing part b1 for the cation exchange membrane 13 of the cylindrical body (b), a housing part c2 for the ionic medicine which houses the ionic medicine 14 and a skin pressing part c3 which displaces the anion exchange membrane 15 to the skin side by the relative movement with the outer cylindrical body (a).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a device used for percutaneously administering various ionic drugs (transdermal drug delivery) by iontophoresis (hereinafter referred to as an iontophoresis device). ).

More specifically, according to the present invention, a stable energized state (constant current and / or constant voltage) is ensured for a long time in the iontophoresis electrode section (working side electrode section) and the ground electrode section (non-working side electrode section). Therefore, the positive (+) or negative (−) charged drug component of the ionic drug can be efficiently transported (driven) to the skin (or mucous membrane) side at the iontophoresis electrode portion, and The toforese electrode portion (working side electrode portion) and the ground electrode portion (non-working side electrode portion) contribute to the maintenance of the above-mentioned stable energized state and can eliminate the adverse effect on the skin due to the electrode reaction. And an iontophoresis device having improved characteristics.

[0003] Further, the present invention comprises a plurality of ion exchange membranes having different ion selectivities arranged on an iontophoresis electrode section and a ground electrode section. The present invention relates to an iontophoresis device in which the efficiency of administration of an ionic drug is improved by improving the adhesiveness of the ion exchange membrane that comes into contact with the ion exchange membrane.

[0004]

2. Description of the Related Art An electromotive force for driving an ionic drug (ionic chemical substance) placed on the skin or mucous membrane (hereinafter simply referred to as skin) at a desired site is applied to the skin. A method of introducing (penetrating) these ionic drugs into the body through the skin is called iontophoresis (iontophoresis, iontophoresis, iontophoresis, iontophoresis) (the iontophoresis of the iontophoresis). For the definition, see, for example, JP-A-63-352.
No. 66 is helpful).

As described above, iontophoresis (io)
In ntophoresis, an ionizable ionic drug placed on the skin is driven (transported) under a predetermined electromotive force to penetrate the skin. For example, positively charged ions are driven (transported) into the skin on the anode side of the electrical system of the iontophoresis device. On the other hand, negatively charged ions are driven (transported) into the skin on the cathode side of the electrical system of the iontophoresis device.

[0006] Examples of the ionic drugs applied to the above-mentioned iontophoresis include the following. (1). Positively charged ionic drugs: anesthetics (procaine hydrochloride, lidocaine hydrochloride, etc.), drugs for gastrointestinal diseases (carnitine chloride, etc.), skeletal muscle relaxants (banklonium bromide, etc.), antibiotics (tetracycline preparations) , Kanamycin-based preparations, gentamicin-based preparations). (2). Negatively charged ionic drugs: vitamin (hereinafter abbreviated as V) agents (VB ₂ , VB ₁₂ , VC, VE, folic acid, etc.), adrenocortical hormones (hydrocortisone-based water-soluble preparations, dexamethasone-based water-soluble agents) Preparations, prednisolone-based water-soluble preparations, etc.), antibiotics (penicillin-based water-soluble preparations,
Chromium phenicol-based water-soluble preparation).

[0007] A method of administering an ionic drug by iontophoresis and a device for applying the same have been studied and developed for a long time, and various types have been proposed. As a conventional technique relating to this type of iontophoresis, there is a technique using an ion exchange membrane. As will be described later in detail, the present invention also belongs to a category using an ion exchange membrane. Therefore, in order to help understand the difference between the present invention using an ion exchange membrane and the prior art,
Hereinafter, a conventional technique using an ion exchange membrane will be described in detail.

[0008] 1. Patent Application Publication No. 3-504343 (hereinafter referred to as Conventional Technique 1) (1). This Conventional Technique 1 is used as an iontophoresis electrode for (i) an electrode plate, and (ii) ionic properties to be permeated. A reservoir containing (or ionizable) drug; (iii) an ion exchange disposed outside the reservoir (on the side in contact with the skin) and having an ion of the same polarity as the ionic drug. And a membrane. (2). According to the prior art 1, when the function of the ion exchange membrane is transferred (driven) to the skin side of the ionic drug, the ion exchange membrane moves to the electrode side beyond the interface between the electrode and the skin by the ion exchange membrane. Constraining the movement of oppositely charged ions that are to migrate,
For example, it describes reducing the movement of sodium, chlorine, and other ionic species that may be present in the skin and create ionic current paths different from ionic drugs. (3) Also, in the prior art 1, since the ion exchange membrane can reduce the amount of other mobile charged carriers in the reservoir containing the ionic drug, the administration efficiency of the ionic drug can be reduced. It can be increased.

[0009] 2. U.S. Pat. No. 4,722,726 (hereinafter referred to as "prior art 2") (1). This prior art 2 is described as a related art in the above-mentioned prior art 1 publication. The iontophoresis electrode is divided into (i) an upper chamber filled with a buffer solution (buffer solution) and a lower chamber filled with an ionic drug, and (ii) the upper chamber is a lower chamber by an ion exchange membrane. An electrode having a structure isolated from the electrode is disclosed. (2) This prior art 2 explains that the upper chamber filled with a buffer solution (buffer solution) mitigates the adverse effect of water hydrolysis, and that the ion exchange membrane separates the ionic drug from the contents of the upper chamber. are doing. However, the technique using the buffer solution disclosed in the prior art 2 clearly increases the concentration of additional ionic species in the system, and thus obviously lowers the transport efficiency of charged ions of the active drug component of the ionic drug. It also has undesirable aspects. Therefore, attention should be paid to the technique of simply using a buffer solution.

[0010] 3. JP-A-3-94771 (hereinafter, referred to as "
This is referred to as Conventional Technology 3. (1). This prior art 3 is (i) a moisture holding portion surrounded by a flexible supporting member and having an electrode plate therein, and (ii) disposed on the front surface (skin side) of the moisture holding portion. Ion exchange membrane,
And (iii) an electrode for iontophoresis comprising a drug layer (ionic drug layer) disposed on the front surface (skin side) of the ion exchange membrane. (2) The prior art 3 attempts to administer the ionic drug at a high concentration while preventing the ionic drug from being diluted by water when administering the ionic drug. (3) For this reason, the prior art 3 uses a water-permeable ion-exchange membrane that is substantially impermeable to a drug, and spray-drys the drug on the living body (skin) contact surface. An electrode for iontophoresis is formed by using a material adhered or adhered by spraying or the like.

4. JP-A-4-297277 (hereinafter referred to as prior art 4) (1). This prior art 4 relates to an earlier application filed by the present applicant, and for example, in FIG. (Working electrode section) (In the case of FIG. 2, the cathode is the working electrode section in relation to the polarity of ions of the ionic drug to be used.) The cathode plate / gauze / cation containing the ionic drug Disclosed is a multilayer structure comprising an exchange membrane / a gauze containing an ionic drug / anion exchange membrane. (2). The iontophoresis technology disclosed in the prior art 4 is a subject of improvement of the present invention, and the limitations of the prior art 4 will be described in detail in the description of the present invention described later. .

In the above-mentioned prior art, the prior art 4
When attention is paid to the number of ion exchange membranes used (arranged), the conventional techniques 1 to 3 have a single-layer structure using one ion exchange membrane, whereas the conventional techniques 1 to 3 use two ion exchange membranes. This is different from the others in that a multi-layer structure is disclosed. Focusing on the number of used ion-exchange membranes, the present invention belongs to a multi-layer structure as in the above-mentioned prior art 4. However, the present invention is based on a technical idea completely different from that of the prior art 4, which will be described in detail later, and the ion is applied not only to the working side electrode section but also to the ground side electrode section (ground side electrode section, neutral electrode section). There is a great feature in adopting a three-layer or four-layer structure in which exchange membranes are provided.

[0013]

As described above, in a method of transdermally administering an ionic drug by iontophoresis, there is a technique using an ion exchange membrane. However, the above-described iontophoresis technology using the conventional ion exchange membrane involves electrochemical reaction on the electrode plate surface in the iontophoresis electrode section (working side electrode section) and / or the ground electrode section (non-working side electrode section). It lacks the initiative and creativity to prevent and eliminate various drawbacks based on reactions. In other words, the conventional iontophoresis technology using an ion-exchange membrane is based on the total overall electrochemical reaction between the iontophoresis electrode (working electrode) and the ground electrode (non-working electrode). And lacks an attitude to eliminate the drawbacks induced thereby and to establish high value-added iontophoresis technology.

For this reason, the iontophoresis technology using the conventional ion exchange membrane, more specifically, the ion exchange membrane is used in the working-side electrode portion as shown in the above-described conventional technology, but the ground electrode is used. The conventional iontophoresis technology, which is not used in some parts, has the following disadvantages.

(I) It is difficult to administer an ionic drug (drug delivery) under a stable energized state for a long period of time (operating under conditions of constant voltage or current stable for a long period of time) Is difficult to do). For example, the polarity of the working electrode portion differs depending on the polarity of the charged ions of the active ingredient of the ionic drug, but in the positive (+) working electrode portion, a physiological medium, which is a conductive medium, is applied at the electrode plate interface. The gas is decomposed to generate bubbles (oxygen gas, chlorine gas, etc.), which increases the current-carrying resistance and rapidly reduces the iontophoresis effect (ion transport efficiency) with time. The above is also caused by bubbles (such as hydrogen gas) generated in the negative (-) pole ground electrode portion.

(Ii) At the contact surface between the working electrode and / or the ground electrode and the skin, burns, inflammations (current burns induced by the current itself, H ⁺ generated by electrolysis)
Or OH ^- and the like pH-induced burns due to sudden change in pH. ) Etc. occur.

(Iii) The electrode plate (for example, +
At the contact surface between the skin and the skin, hypochlorous acid based on harmful substances generated by sweat on the skin surface or electrolysis of saline as a conductive medium, for example, Cl ⁻ (chlorine ion) (Known as a suitable oxidizing agent), causing skin damage and the like.

(Iv) At the contact surface of the skin with the electrode plate (eg, one pole) of the ground electrode portion, harmful substances generated by sweat on the skin surface or electrolysis of physiological saline as a conductive medium, for example, Skin damage and the like due to highly alkaline substances (NaOH) occur.

The present invention has been made in view of the disadvantages and limitations of the conventional iontophoresis technology using the above-mentioned ion exchange membrane. The present inventors have intensively studied a conventional iontophoresis technique using an ion exchange membrane in order to increase the added value.

As a result, the present inventor has proposed that the configuration of the iontophoresis electrode section (working side electrode section) of the iontophoresis apparatus be based on the effectiveness of the ionic drug disclosed in, for example, Japanese Patent Application Publication No. 3-504343. An iontophoresis electrode material (working-side electrode material) connected to a power source of the same type as the charged ions of the drug component, an ionic drug disposed on the front surface of the iontophoresis electrode material, and a front surface of the ionic drug An ion-exchange membrane that selects the same type of ions as the charged ions of the active drug component of the ionic drug disposed on the side of the part that contacts the skin. The configuration between the iontophoresis electrode material and the ionic drug is viewed from the iontophoresis electrode material side, and (i) at least the iontophoresis electrode material Along with disposing a conductive medium such as physiological saline on the front part, (ii) an ion exchange membrane for selecting an ion opposite to the charged ion of the active drug component of the ionic drug is provided on the front part of the conductive medium. It has been found that when arranged and configured, the above-mentioned drawbacks in the iontophoresis electrode section are eliminated.

Further, the present inventor has never known that an ion exchange membrane is provided on the side of a ground electrode portion (non-working side electrode portion) in a conventional iontophoresis apparatus using an ion exchange membrane. However, when the configuration of the ground electrode portion (the non-working side electrode portion) is viewed from the electrode material side of the ground electrode portion, (iii). A conductive medium such as saline is disposed at least on the front surface of the ground electrode material. And (iv). When an ion exchange membrane for selecting an ion opposite to the charged ion of the active drug component of the ionic drug is arranged on the front surface of the conductive medium, the above-mentioned drawbacks in the ground electrode portion are disadvantageous. Found that it will be resolved.

Further, the inventor of the present invention has a configuration in which the ground electrode portion is configured by disposing an ion exchange membrane having a different ion selective permeability in addition to the ion exchange membrane of (v) and (iv). At this time, it has been found that biosafety in the ground electrode portion can be maintained at a high level.

Further, the present inventor has proposed that, in the iontophoresis electrode section and the ground electrode section, each of the conductive media is (vi) a substance having a redox potential lower than the electrolysis potential of water (a substance having a redox potential lower than that of water). It has been found that, when it is made of a conductive medium such as a physiological saline solution containing a substance that is easily oxidized and reduced), it is possible to greatly improve the current-carrying characteristics particularly at both electrode portions.

Further, the present inventor has proposed that when an ionic drug is transdermally administered via an ion exchange membrane of an iontophoresis electrode section (working side electrode section), (vii). It has been found that it is extremely important that the ion exchange membrane is configured to be directly or indirectly adhered to the skin surface in order to improve the transdermal transport efficiency of the drug.

The present invention is based on the above-mentioned knowledge, and an iontophoresis electrode portion (working-side electrode portion) and a ground electrode portion (non-working electrode portion) which integrate (incorporate) a configuration based on the above-described knowledge. The present invention provides an iontophoresis device having a side electrode portion). ADVANTAGE OF THE INVENTION According to this invention, the administration efficiency of an ionic drug is high under the stable electricity supply state (state of constant current and / or constant voltage) for a long time, and the biosafety which prevented the burn and inflammation of the skin surface was improved. A novel iontophoresis device capable of realizing administration of an ionic drug (drug delivery) with high iontophoresis is provided.

[0026]

SUMMARY OF THE INVENTION In summary of the present invention, an iontophoresis electrode (working electrode) and a ground electrode are connected to a power source used to administer an ionic drug by iontophoresis. (Non-working electrode)
In the iontophoresis apparatus having (1), the iontophoresis electrode section, (1) -1.electrode material connected to a power source of the same polarity as the charged ions of the ionic drug, (1) -2 .
A conductive medium disposed on at least the front surface of the electrode material,
(1) -3. An ion exchange membrane for selecting an ion opposite to the charged ion of the ionic drug disposed on the front surface of the conductive medium,
(1) -4. An ionic drug disposed on the front of an ion exchange membrane for selecting an ion opposite to the charged ion of the ionic drug, and (1) -5. Disposed on the front of the ionic drug. An ion exchange membrane for selecting the same type of ions as the charged ions of the ionic agent, and (2) the ground electrode section, (2) -1. Of the iontophoresis electrode section. An electrode material having a polarity opposite to that of the electrode material, (2) -2.a conductive medium disposed at least on the front surface of the electrode material, and (2) -3.ionicity disposed on the front surface of the conductive medium. An ion-exchange membrane for selecting an ion opposite to the charged ion of the drug, and (3) the iontophoretic electrode section and / or the ground electrode section are disposed at the forefront thereof. Characterized in that the exchange membrane is configured to be displaced forward. On zero equipment.

Further, the present invention provides a method for improving the performance of an iontophoresis device having the above-mentioned iontophoresis electrode section (working side electrode section) and a ground side electrode section (non-working side electrode section). The conductive medium of the iontophoresis electrode section and the ground electrode section is characterized by being composed of a substance containing a substance which is easily oxidized or reduced, and more specifically, (ii). The conductive medium of the toforase electrode portion and the ground electrode portion is composed of a material containing ferrous sulfate and ferric sulfate, or an organic acid and / or a salt thereof as a substance easily oxidized or reduced. It is a feature.

Further, according to the present invention, in order to improve the performance of the iontophoresis device, the ground electrode portion (non-working side electrode portion) is constituted by using both a cation exchange membrane and an anion exchange membrane. It is characterized by the following. It should be noted that one ion exchange membrane (the ion selectivity of the ion conversion membrane differs depending on the charging polarity of the ionic drug) is used for the above-mentioned ground electrode part, and further, the ion selectivity differs for the ground electrode part. The use of two types of ion exchange membranes is not found at all in the prior art.

Another feature of the iontophoresis device of the present invention is that the iontophoresis electrode portion and the ground electrode portion may be formed separately or integrally. It is. Furthermore,
The present invention is, as described above, the iontophoresis device of the present invention is provided with a plurality of ion exchange membranes having different ion selectivity in the iontophoresis electrode section and the ground electrode section,
The ion exchange membrane is used by changing the arrangement of the ion exchange membrane in relation to the charged ions of the ionic drug. Other components, particularly the ion exchange membrane, can be detachably attached to the electrode material element. An iontophoresis device which is configured so as to be attached and which is excellent in operability and convenience with reduced labor for arranging and replacing the ion exchange membrane is provided.

Hereinafter, the technical structure of the present invention will be described in more detail. First, in order to gain an understanding of the present invention, a conventional method of administering an ionic drug by iontophoresis using the basic configuration diagram of the iontophoresis device of the present invention and its problems, and furthermore, the ionic drug of the present invention The features of the method of administration will be described. Next, a specific configuration of the iontophoresis device of the present invention will be described. Although the drawings are referred to for explaining the technical configuration of the present invention, those shown in the drawings should be interpreted as merely one embodiment, and the present invention is not limited to these drawings. There is no such thing.

FIGS. 1 and 2 show a basic configuration of an iontophoresis device (X) in which an iontophoresis electrode (1) and a ground electrode (2) of the present invention are formed non-integrally. It is. 1 is a perspective view, and FIG. 2 is a sectional view of a main part. 1 and 2 can be said to simultaneously show a method (drug delivery) of administering an ionic drug by a new iontophoresis realized by the iontophoresis device (X) of the present invention.

FIG. 3 is a diagram showing the basic configuration of the iontophoresis device (X) shown in FIG. 2 when the administration of an ionic drug is performed under the following conditions. FIG. (i) As an ionic drug, a sodium (Na) salt of ascorbic acid (vitamin C) (hereinafter sometimes abbreviated as As ⁻ Na ⁺ ) is used. (ii). Physiological saline (Na ⁺ Cl ⁻ aqueous solution) is used as the conductive medium. In the present invention, as the physiological saline, in order to remove defects caused by the electrode reaction,
In some cases, ferrous sulfate and ferric sulfate having a redox potential lower than the electrolytic potential of water or a substance to which a substance which is easily redox-reduced such as an organic acid is added. (iii) The iontophoresis electrode section (working-side electrode section) is used as a cathode (negative pole). (iv). Connect the ground electrode (non-working side electrode) to the anode (+
Pole). (v). The type (selective permeability of ions) of the ion exchange membrane to be used and the arrangement site are as shown in the figure.

FIG. 4 is a basic configuration diagram (a cross-sectional view of a main part) of another iontophoresis device (X) of the present invention in which the performance of the iontophoresis device (X) shown in FIG. 3 is further improved. Show. As shown in FIG. 4, the ion exchange membrane of the ground electrode part (2) is different from that of FIG. 3 in that the cation exchange membrane (23) and the anion exchange membrane (2) are different from those of FIG.
5) is different in that it is configured in combination with 5).

In FIGS. 1 to 4, the reference numerals in the drawings correspond to the reference numerals of the respective components of the iontophoresis device described in the section of "Means for Solving the Problems". For example, "(1) -1" as a component of the iontophoresis device (X) is displayed as "11" in the figure.

FIGS. 5 and 6 show the basic configuration of an iontophoresis device (X) in which an iontophoresis electrode (1) and a ground electrode (2) of the present invention are integrally formed. FIG. 3 is a diagram corresponding to FIGS.

The greatest feature of the iontophoresis device (X) of the present invention is that the purpose of this type of iontophoresis is to apply an ionic drug to the body through the skin (or mucous membrane) under a predetermined electromotive force. It is well known in the prior art that the amount of ions that move with a certain electromotive force (this depends on the ion concentration, the ion mobility, and the valence of the ions). ), The present invention focuses on the electrochemical reaction of each electrode part, and particularly focuses on the disadvantageous factor (negative factor) based on the electrochemical reaction, from which the iontophoresis is performed. The technology is being rebuilt.

In iontophoresis, the electrode portion necessarily undergoes an electrochemical reaction, that is, an oxidation reaction (anode) and a reduction reaction (cathode). Then, by the electrochemical reaction, for example, the generation of harmful substances by the electrolysis of physiological saline as a conductive medium (for example, hypochlorite caused by Cl ⁻ , which is known as a strong oxidant at the anode) Acid formation), rapid pH changes (rapid acidification at the anode, rapid alkalinization at the cathode), or the formation of bubbles (eg, H ₂ gas at the cathode, O ₂ gas or Cl ₂ at the anode). The generation of gas) causes fatal defects in iontophoresis, such as adverse effects on human skin, skin irritation, and inability to conduct electricity (increase in resistance due to gas generation).

The present invention aims at improving the iontophoresis technology and increasing the value of the iontophoresis technology based on the elimination of the drawbacks caused by the electrochemical reaction occurring at the electrode portion in the iontophoresis.

The iontophoresis device (X) of the present invention
FIG. 2 shows a conventional method for administering an ionic drug in order to eliminate the above-mentioned drawbacks.
As shown in FIG. 3, (i). As the configuration of the iontophoresis electrode section (working-side electrode section) (1), the above-described technical components (1) -2 to (1) of the present invention are used. 3 (indicated by reference numerals 12 to 13 in FIGS. 2 to 3), and (ii) a ground electrode portion (non-working side electrode portion).
As the configuration of (2), the technical components of the present invention described above (2)
-2 to (2) to 3 (reference numerals 22 to 23 in FIGS. 2 to 3)
Indicated by ) Has a major feature.

Furthermore, the iontophoresis device (X) of the present invention is different from the conventional one in that, as shown in FIG. 4, (iii) the ground electrode portion (non-working side electrode portion) (2) As a configuration, a cation exchange membrane (2
There is a significant feature in using both 3) and the anion exchange membrane (25).

In short, the iontophoresis device (X) of the present invention is intended to use an ion-exchange membrane in order to eliminate the above-mentioned drawbacks caused by the electrode reaction observed in the conventional ionic drug administration method. It is important to note that two ion-exchange membranes are used for the iontophoresis electrode and at least one ion-exchange membrane is used for the ground electrode in consideration of the permselectivity of ions. .

The iontophoresis device (X) of the present invention further comprises (iv). (I) and (ii) or (i) and (iii). Having the technical configuration (3) described above has a significant feature.

Further, the iontophoresis device (X) of the present invention is provided with a specific ion-exchange membrane as described above in order to eliminate the above-mentioned drawbacks caused by the electrode reaction in the conventional ionic drug administration method. In addition to the arrangement of the above, (v). A material containing a substance which is easily oxidized or reduced as compared with electrolysis of water as a conductive medium for both electrode portions (iontophoresis electrode portion and ground electrode portion) There is a significant feature in adopting

Hereinafter, the iontophoresis device of the present invention will be described.
The above-mentioned features of (X) can be used as ionic drugs.
Sodium scorbate (As^-Na⁺)
Will be explained in the following. In this case, the active drug component of the ionic drug
Charged ions are anions (As ^- )
But it is not. For this reason, it is shown in FIGS.
Thus, the iontophoresis electrode (1) is connected to the cathode (-
Pole) and the ground electrode (2) becomes the anode (+ pole).
You. Needless to say, ionic drugs
Is dissociated into positively charged ions,
Electrode polarity and ion exchange membrane type (selection characteristics of ions)
Gender) are, of course, the opposite.
That is.

1 to 6 showing the basic structure of the iontophoresis device (X) of the present invention, reference numeral 1 denotes an iontophoresis electrode section (working side electrode section), and 2 denotes a ground electrode section (non-working side electrode section). ), 3 indicates a power supply device, and 4 indicates skin (or mucous membrane).

As shown in FIGS. 3 and 4, the iontophoresis electrode section (working side electrode section) (1) has (i).
Negative (-) electrode (11), (ii). Conductive medium (12), specifically, 0.9% NaCl aqueous solution containing ¹ MAs ^- Na ⁺ (iii). Cation exchange membrane (13), (iv) ). An ionic drug (14), specifically, a 1 MAs ^- Na ⁺ aqueous solution, and (v) an anion exchange membrane (15).

In the case of FIG. 3, the ground electrode portion (2) is composed of (i) a positive (+) pole (21), and (ii) a conductive medium (2).
2), specifically, a 0.9% NaCl aqueous solution, and (iii) a cation exchange membrane (23).

In the present invention, as shown in FIG. 4, the ground electrode portion (2) has a positive (+)
From the direction of 1) to the skin (4), (i). Positive (+) pole (21), (ii). Conductive medium (22), specifically 1M
0.9% NaCl aqueous solution containing As ^- Na ⁺ , (iii).
An anion exchange membrane (25), (iv). A conductive medium (24),
Specifically, 0.9% NaCl containing ¹ MAs ^- Na ⁺
An aqueous solution, (v) a cation exchange membrane (23).

In the present invention, the two electrode portions (1, 2)
The conductive medium (12, 22) may be composed of a compound containing a compound which is easily oxidized and reduced as compared with the electrolysis reaction of water (oxidation and reduction reaction of water).
Further, in the present invention, the conductive medium (12, 22) of the two electrode portions (1, 2) has a lower oxidation-reduction potential of the ionic drug (for example, As ^- Na ⁺ ) than water in general. These ionic drugs may be contained as a compound which is easily oxidized and reduced. The same can be said for the conductive medium (24) of the ground electrode section (2) shown in FIG.

Hereinafter, a more specific iontophoresis for implementing a new administration method of an ionic drug will be described with reference to the basic configuration diagram (FIGS. 1 to 6) of the iontophoresis device (X) of the present invention. The configuration of the device (X), that is, the specific configuration of the iontophoresis electrode section (working side electrode section) (1),
Next, the specific configuration of the ground electrode portion (the non-working side electrode portion, the ground electrode portion) (2) will be described in this order.

In the iontophoresis device (X) of the present invention, the iontophoresis electrode section (working side electrode section)
The electrode plate (11) of (1) may be constituted by a desired one. In addition, the electrode material (12) of the ground electrode portion (non-working side electrode portion) (2) may be configured as desired. For example, an inert electrode made of a conductive material such as carbon or platinum may be used.

In the iontophoresis device (X) of the present invention, the electrode material (11, 12) may be an active electrode known in the field of iontophoresis instead of the inactive electrode. Good thing. As an example of the above-mentioned active electrode, when the drug component of the ionic drug is a positive (+) ion, specifically, morphine hydrochloride or lithium chloride (in this case, morphine ion as a drug component, In the case of using lithium ion as a positive ion and chlorine as a counter ion as a negative ion), there is a silver electrode or the like which reacts with these counter ions as an anode (+) material. In the case of the above-described active electrode, the silver electrode and chlorine ion (Cl ⁻ ) easily react with each other, and Ag + Cl ⁻ → AgC
Insoluble AgCl is produced by l + e ⁻ . The advantage of using the active electrode is that the electrolysis reaction of water can be prevented because the standard potential of the reaction is lower than the standard potential of the electrolysis reaction of water at the anode (+). Accordingly, rapid acidification at the anode (positive electrode) based on H ⁺ ions and rapid alkalinization at the cathode (negative electrode) based on OH ⁻ ions are prevented.

However, in the iontophoresis apparatus (X) of the present invention, as described above, a plurality of ion exchange membranes having different ion selectivities, at least three or more, are used in the iontophoresis system. Insoluble substances (insoluble fine particles) such as silver chloride (AgCl) generated in step (1) may hinder the properties of the ion exchange membrane. From the above, the iontophoresis device (X) of the present invention uses a plurality of ion exchange membranes having different ion selectivities,
It is preferable to use a more economical inactive electrode without using a special electrode material called an active electrode. In addition, in the iontophoresis system, metal ions and the like which are inevitably generated from the electrode material are also transported, and the iontophoresis effect is reduced by that amount, so that the iontophoresis device (X) of the present invention is used as an electrode material. Is preferably a carbon electrode.

In the iontophoresis device (X) of the present invention shown in FIG. 3, the iontophoresis device (1) is disposed so as to be in contact with the negative (-) electrode material (11) of the iontophoresis electrode portion (1). The conductive medium (12) is made of a material containing a compound that is easily reduced. In the iontophoresis device (X) of the present invention shown in FIG.
The conductive medium (22) disposed so as to be in contact with the periphery of the positive (+) electrode material (21) of the ground electrode portion (2) includes:
It is composed of a compound containing a compound that is easily oxidized. The site for disposing the compound that is easily oxidized or reduced,
It goes without saying that the reaction corresponds to the electrochemical reaction in each electrode plate, that is, the reduction reaction at the negative (-) electrode and the oxidation reaction at the positive (+) electrode.

The iontophoresis electrode section (1) of the iontophoresis apparatus (X) of the present invention shown in FIG. 3 comprises a conductive medium (12) containing a compound which is easily reduced as shown in FIG. A cation exchange membrane (13) is provided between (As ^- Na ⁺ ) (14). In the present invention, the conductive medium (12) containing the compound that is easily reduced is disposed so as to be in contact with the negative (-) electrode material (11) in relation to the above-described configuration.
The compound which is easily reduced in the conductive medium (12) is
As will be described later, it plays an important role. This is the same for the easily oxidizable compound in the conductive medium (22) on the ground electrode section (2) side.

In the present invention, the conductive medium (12)
As the compound which is easily oxidized or reduced, those which are excellent in biosafety, economical efficiency (inexpensive and easily available) and the like are preferable. For example, inorganic compounds such as ferrous sulfate and ferric sulfate , Ascorbic acid (vitamin C)
Pharmaceutical agents such as sodium and sodium ascorbate; acidic compounds such as lactic acid present on the skin surface; or organic acids such as oxalic acid, malic acid, succinic acid, and fumaric acid and / or salts thereof.

Among the compounds which are more likely to be oxidized or reduced than the above-described electrolytic reaction of water (oxidation at the positive electrode and reduction at the negative electrode), for example, ferric sulfate is such that ferric ions are easily converted to ferrous iron at the negative electrode. Reduce to ions. In addition, ferrous sulfate easily oxidizes ferrous ions to ferric ions at the positive electrode. As a result, as will be described in detail later, it is possible to eliminate the drawbacks caused by the electrolysis reaction of water, and to provide an iontophoresis device (X) having excellent performance in relation to the specific ion exchange membrane arrangement of the present invention. ) Is provided.

In the present invention, the conductive medium (12)
Are for ensuring electrical conductivity, and a typical example is a saline solution or a physiological saline solution. In the iontophoresis device (X) of the present invention, the configuration for housing or holding the conductive medium (12) may be any desired configuration. Also,
The conductive medium (12) may be, for example, a solution type or a type in which a desired medium (gauze, water-absorbing polymer material, etc.) is impregnated.

Here, as the conductive medium (12),
The advantage of using a compound containing the compound which is easily oxidized or reduced will be described in detail. In the iontophoresis electrode section (1) and the ground electrode section (2), an electrochemical reaction occurs, and decomposition of the electrolyte solution and decomposition of the ionic drug occur. As a result, air bubbles are generated in the electrode chamber, and contact between the electrode part and the electrolytic chamber solution is hindered. For example, H ₂ gas for the negative electrode, Cl ₂ and O _{2 for the} positive electrode
Gas is generated. When such a situation occurs, the resistance increases due to bubbles, and no current flows even if a voltage is applied. In the case of the above-mentioned As ^- Na ⁺ delivery, stable energization becomes impossible for a long time (30 minutes or more). This is a very serious problem from the viewpoint of the practicality of the iontophoresis device.

In order to remove the above-mentioned instability factor and stably perform iontophoresis, it is extremely important to suppress the generation of bubbles. In order to achieve the above-mentioned object, it is useful to put a substance which is susceptible to oxidation or reduction reaction into each electrode chamber without generating bubbles. That is, when water is oxidized or reduced, oxygen or hydrogen is generated. To suppress these reactions, for example, ferrous sulfate, ferric sulfate, ascorbic acid or a sodium salt thereof is added to the electrode chamber solution. (Electrode solution). For example, when sodium ascorbate is used, sodium ascorbate is oxidatively decomposed instead of oxygen at the electrode where the oxidation reaction occurs, and sodium ascorbate is reductively decomposed instead of hydrogen at the electrode where the reduction reaction occurs. However, this can suppress the generation of oxygen or hydrogen bubbles which impair the stability of the current-carrying characteristics.

As described above, a substance which is more easily oxidized or reduced than water in an electrochemical reaction such as sodium ascorbate (a substance having a redox potential lower than the redox potential of water) is sacrificed. By
The generation of gas (gas) in the electrode chamber can be suppressed, and an iontophoresis device (X) capable of more stable operation can be obtained. In the present invention, in addition to the above-described ferrous sulfate, ferric sulfate, and ascorbic acid, any of the sacrificial substances may be used as long as the sacrificial substance undergoes oxidation-reduction to suppress the decomposition of water. It goes without saying that you can do it. In the case of sodium ascorbate as the sacrificial substance, sodium ascorbate is used for (i) an electrode (-electrode) where a reduction reaction occurs, to CO ₂ or H ₂ CO ₃ , and (ii) an oxidation reaction. At the electrode (+ electrode) where occurs, it changes to dehydroascorbic acid, 2,3 diketo 6-gulonic acid, and the like.

In the iontophoresis device (X) of the present invention, a desired cation exchange membrane (13) can be used. As described above, the iontophoresis device (X) of the present invention comprises a cation exchange membrane (13).
In addition, an anion exchange membrane (15) is used. Here, specific examples of both the cation exchange membrane (13) and the anion exchange membrane (15) used in the present invention will be described.

In the present invention, the cation exchange membrane (1)
3) Neosepta (CM) manufactured by Tokuyama Corporation
-1, CM-2, CMX, CMS, CMB, etc.).

In the present invention, the anion exchange membrane (1)
5) includes Neosepta (AM) manufactured by Tokuyama Corporation.
-1, AM-3, AMX, AHA, ACH, ACS, A
CS-3) can be used.

In the iontophoresis device (X) of the present invention, the configuration for containing or holding the ionic drug (As ⁻ Na ⁺ ) (14) may be any configuration. The ionic drug (14) may be, for example, a solution type or a type in which a desired medium (gauze, water-absorbing polymer material, etc.) is impregnated.

In the iontophoresis device (X) of the present invention, the ion-exchange membrane provided on the front side of the ionic drug (As ⁻ Na ⁺ ) (14), that is, on the skin side, component of charged ions (as ^-) anion exchange membrane (15) having an ion selectivity of the same type are used.

With the above-described technical configuration of the iontophoresis electrode section (1) of the iontophoresis device (X) of the present invention, a longer and more stable iontophoresis effect and biosafety can be obtained than in the conventional method. Can be. That is,
The technical configuration of the iontophoresis electrode section (1) makes it possible to obtain a long-term and stable current-carrying characteristic. In other words, the ionic agent can be supplied for a long time and stably via the skin (4). Thus, the drug can be efficiently penetrated into the body (drug delivery), and the generation of harmful substances due to an electrolysis reaction at the electrode portion can be prevented.

Next, the configuration of the ground electrode portion (+ electrode) (2) of the iontophoresis device (X) of the present invention will be described with reference to the basic configuration diagrams (FIGS. 1 to 6).

The prior art relating to iontophoresis is
Regarding the configuration of the ground electrode part (earth electrode part), it is suggested that the simple idea of simply taking the ground (earth) works strongly, and that consideration is given to securing stable current-carrying characteristics and securing biological safety. It has not been done yet. This is described in Japanese Patent Application Laid-Open Publication No. 3-504343 and Japanese Patent Laid-Open Publication No.
No. 4771 and Japanese Unexamined Patent Publication No.
It is justified by looking at 297277.

The present invention provides an iontophoresis device (X)
In addition to the configuration of the iontophoresis electrode section (1), in connection with the overall configuration of the device, it is possible to administer the ionic drug by iontophoresis stably for a long period of time, and to have a high level of biosafety. From the viewpoint of being obtained, a technical configuration different from the conventional one is also adopted for the ground electrode portion (2).

As shown in FIG. 3, the ground electrode portion (2) of the iontophoresis device (X) of the present invention has a polarity opposite to that of the electrode material (11) of the iontophoresis electrode portion (1). An electrode material (21), a conductive medium (22) disposed at least in front of the electrode material (21), and a front part of the conductive medium (22), that is, disposed on the skin (4) side. And an ion exchange membrane (23) for selecting an ion opposite to the charged ion of the ionic drug.

In the iontophoresis device (X) of the present invention, as shown in FIGS. 5 to 6, the ground electrode portion (2) is used to improve operability and convenience. It may be configured integrally with (1).

According to the present invention, in order to further improve the operability and convenience of the iontophoresis device (X), the ground electrode portion (2) is provided with the iontophoresis electrode portion (1).
In the iontophoresis device (X) integrated or non-integrated with at least the iontophoresis electrode part (1), other components can be detachably attached to the electrode material (11). It may be configured as follows. In the present invention, in addition to the iontophoresis electrode section (1), a ground electrode section (2)
It is needless to say that also in this case, other components may be detachably attached to the electrode material (21).

In the iontophoresis device (X) of the present invention, the point that the ion exchange membrane (23) is provided on the ground electrode portion (2) in order to enhance biosafety is a large feature not found in the prior art. It is a feature point. Further, in the iontophoresis device (X) of the present invention, in order to achieve long-term stable operation with biosafety, the ground electrode portion (1) as well as the conductive medium (12) of the iontophoresis electrode portion (1). The conductive medium (22) of 2) may be composed of a material containing a substance having a redox potential lower than the redox potential of water. And disposing an ion exchange membrane (23) on the ground electrode section (2);
A high value-added iontophoresis device (X) by combining the use of the substance that is easily redox-reduced is also a major feature not found in the prior art.

In the iontophoresis device (X) of the present invention, as shown in FIG. 2, the ground electrode portion (2) is a single ion exchange membrane (2) having a predetermined ion selectivity.
3) may be configured. The advantage of disposing the ion exchange membrane (23) on the ground electrode section (2) will be described later with demonstration data. Further, the conductive medium (22) of the ground electrode portion (2)
The advantage of adding a substance which is easily oxidized and reduced is that the conductive medium (1) of the iontophoresis electrode unit (1) has already been added.
As described in 2).

As shown in FIG. 3, the ionic drug is negative (−) such as sodium ascorbate (As ⁻ Na ⁺ ).
When the electrode material (2) is charged in the ground electrode portion (2) of the iontophoresis device (X) of the present invention,
1) is composed of an anode (+), the conductive medium (22) is composed of, for example, physiological saline, and the ion exchange membrane (23) is composed of a cation exchange membrane.

In the present invention, the conductive medium (22) of the ground electrode portion (2) is made of a substance which is easily oxidized and reduced, for example, ferric sulfate or ferric sulfate containing ferrous sulfate (both of them). Molar solution), physiological saline containing ascorbic acid, sodium ascorbate and the like. Further, as shown in FIG. 4, the ground electrode section (2) of the present invention may use two types of ion exchange membranes having different ion selectivities as the ion exchange membrane.

In the method for administering an ionic drug by iontophoresis described with reference to the iontophoresis device (X) shown in FIG. 3, as described above, the active drug component of the ionic drug is negative (-). Charged sodium ascorbate
(As ^- Na ⁺ ). In the present invention, even if the active drug component of the ionic drug is positively (+) charged, it can be similarly administered.

The active drug component of the ionic drug that is positively (+) charged includes, for example, procaine hydrochloride and lidocaine hydrochloride as anesthetics. In this case, the polarity of each electrode material (11, 12) and the ion exchange membrane (13, 1).
It goes without saying that the ion exchange properties of 5, 23, 25) must be completely reversed from the case of administration of Na ascorbate (As ^- Na ⁺ ). When the positively (+) charged ionic drug is used, the features of the present invention can be easily understood by analogizing the administration case of the negatively (−) charged sodium ascorbate.

The power supply unit (3) shown in FIGS.
Can be used as desired. In the present invention, as the power supply device (3), a battery, a constant voltage device, a constant current device, a constant voltage / constant current device (galvano device)
Etc. can be used.

Next, an experimental device equivalent to the basic configuration diagram of the iontophoresis device (X) shown in FIGS.
An experimental example / comparative experimental example in the case where sodium ascorbate (As ⁻ Na ⁺ ) was administered as an ionic drug using an experimental apparatus manufactured by modifying the above experimental apparatus for collecting comparative data was described. . From the experimental examples / comparative experimental examples described below, in the iontophoresis device (X) of the present invention, it is possible to understand particularly the importance of disposing an ion exchange membrane on the ground electrode section (2). .

FIGS. 7 to 10 are schematic diagrams of the experimental apparatus used. 7 and 8 show an apparatus for a comparative experiment. FIG.
FIG. 10 to FIG. 10 show an experimental device equivalent to the iontophoresis device (X) of the present invention. The meanings of the reference symbols of the experimental devices are as follows. (1). Reference numerals 11, 21, 12, 13, 14, 15, 2
2, 23, 24, and 25 are the same as those in FIGS. As the cation exchange membranes (13, 23) and the anion exchange membranes (15, 25), Neoceptor CMX (cation) and AMX (anion) manufactured by Tokuyama Corporation were used, respectively. (2). Reference numeral 4 denotes a virtual skin tank (room) imagining the skin. (3). Reference symbol PP is a porous polypropylene membrane (AN filter, AN manufactured by Nippon Millipore Limited).
06). (Note) PP has no selective permeability for ions. (4) Reference numerals A to E indicate tanks (chambers) partitioned by an ion exchange membrane or PP.

1. Iontophoresis experiment using the experimental apparatus shown in Fig. 7 (a). Experimental conditions (1). Electrode solution in chamber A (iontophoresis electrode chamber, negative electrode chamber) is composed of conductive medium (12) and ionic drug. (14), and 0.9% N in which 1M As ⁻ Na ⁺ is dissolved.
aCl aqueous solution was used. (2). As a medium of room B (virtual skin room simulating skin)
A 0.9% NaCl aqueous solution was used. (3) 0.9% NaCl aqueous solution was used as the conductive medium (22) in the room C (ground electrode room). (4). Energizing conditions: voltage 30V (initial setting value), current 10mA (constant current),
Energizing time 30 minutes. (b). Experimental results: As experimental results, pH of each room (A to C)
The changes are shown in Table 1 below.

[0084]

[Table 1]

[0085] (c) Discussion:. (1) .A chamber reduction reaction, the oxidation reaction occurs in the C chamber, the chamber A As - ^(ascorbate ions) are transported to the B compartment. Obviously, the pH shifts from neutral to alkaline in the room A, and changes from neutral to strongly acidic in the room C. Therefore, the case of the present experiment where the ground electrode (21) in the room C and the skin (4) in the room B are in direct contact is in a very dangerous state. This can be seen from the fact that the chamber B has been shifted to an acidic state, and that the shift to the acidic side is due to the acid (HClO ₃ ) generated in the chamber C. The hypochlorous acid is known as a strong oxidizing agent. (2). Room A, which is an iontophoresis electrode room, and skin (B)
Although the anion exchange membrane (15) is present between the chambers (A), the chamber A is somewhat prevented from becoming alkaline, but the OH ^- ions in the chamber A are not exchanged with the anion exchange membrane (15).
It is thought that the skin surface is locally alkaline because it passes by electrophoresis to the room B side via the. That is, it is considered that in the room B, it is thought that the pH tends to be more acidic, but it stops at pH = 4.20, OH ^- ions reach the skin surface, and the pH is locally shifted to the alkaline side. . (3) From the above, when performing iontophoresis, the mode of using only one ion exchange membrane as in this experiment should be avoided from the viewpoint of biosafety. (4). The amount of As ⁻ (ascorbate ion) administered in this experiment was about 300 μmol (theoretical value: 560 μmo).
1), which substantially corresponds to the decrease amount of the room A and the increase amount of the room B. However, the dose is about 1/2 of the theoretical value.
, And the large amount in the A chamber OH ^- ions are generated, which As ^- to be transported with the As ^- transporting 50%
Obstructing. Also from this point, this experimental apparatus is unsuitable as an iontophoresis apparatus.

2. (A). Experimental conditions: room A and room B of the experimental device shown in FIG.
The configuration of the chamber (skin) was changed as shown in the figure to the cation exchange membrane (1).
3) and an anion exchange membrane (15) were used, and the experimental apparatus reconfigured was used, and the conductive medium (12) and the ionic drug (12) were used as the electrode solution in the room A and the ionic drug solution in the room B, respectively. 0.9) dissolved in 1M As ^- Na ⁺ containing 14)
The experiment was performed in the same manner as in the above “1”, except that a% NaCl aqueous solution was used. (b). Experimental results: As experimental results, pH of each room (A to D)
The changes are shown in Table 2 below.

[0087]

[Table 2]

(C). Discussion (1). An iontophoresis electrode chamber (A chamber) and a solution chamber (B) containing As ⁻ Na ⁺ as an ionic drug as an administration reagent.
By separating the chamber B) with the cation exchange membrane (13), the pH of the chamber B can be kept constant. This prevents the skin surface (C room) from becoming alkaline. Further, the ion permeation amount is improved as compared with the experiment of the above “1”, and a value substantially close to the theoretical value is obtained. (2). However, the pH of the room C (virtual skin tank) (4) is lowered. This suggests the effectiveness of partitioning between the chamber C and the chamber D, that is, between the ground electrode chamber (D) and the virtual skin bath (4) with an ion exchange membrane instead of a simple membrane (pp). . Furthermore, in the ground electrode chamber (D), there is a risk that hypochlorite ions are generated by oxidative decomposition of physiological saline as a conductive medium and diffused into the skin.

3. (A). Experimental conditions: room C and D of the experimental device shown in FIG.
The experiment was carried out in the same manner as in the above "2", except that the PP membrane between the chambers was changed to the cation exchange membrane (23). (b). Experimental results: Table 3 below shows the changes in pH in each room (A to D) as experimental results.

[0090]

[Table 3]

(C). Discussion: This experiment corresponds to the experiment using the iontophoresis device (X) of the present invention.
This experimental apparatus is characterized in that it is configured by arranging one cation exchange membrane (23) on the ground electrode section (2). (1) Although a change in pH was observed in each of the electrode chambers, that is, the chambers A and D, the As ^- Na ⁺ solution chamber (room B) and the skin (C
The change in pH in the chamber is suppressed and is effective. Further, a cation exchange membrane (23) is provided in the ground electrode chamber (D chamber).
The harmful anions such as hypochlorite ions can be kept in the room D without contacting the skin. (2) Since the permeation amount of ascorbate ion shows almost the theoretical value, this experimental apparatus is useful as an iontophoresis apparatus. (3). However, as an improvement of this experimental apparatus, in the ground electrode chamber (D room) in contact with the virtual skin bath (C room), H generated by electrolysis of water on the ground electrode (21) was used.
⁺ Ions migrate through the cation exchange membrane (23) and
This has led to acidification of the chamber, which should be improved. For this reason, it is preferable to employ two types of ion exchange membranes, that is, a cation exchange membrane and an anion exchange membrane, on the ground electrode side as well as on the intzeze electrode side.

[0092] 4. Iontophoresis experiment using the experimental device shown in FIG. 10 (a). Experimental conditions: In the experimental device shown in FIG.
An anion exchange membrane (25) is provided in the ground electrode chamber (D chamber) in addition to the cation exchange membrane (23) in the manner shown in the figure, and 1M is used as an electrode solution for the newly partitioned ground electrode chamber (E chamber). An experiment was performed in the same manner as in the above “3” except that a 0.9% NaCl aqueous solution in which As ⁻ Na ⁺ was dissolved was used. (b). Experimental Results As experimental results, the changes in pH in each room (AE) are shown in Table 4 below.
Shown in

[0093]

[Table 4]

(C). Considerations: (1). Two electrodes were placed on the iontophoresis electrode side shown in FIG.
In an iontophoresis apparatus in which two ion-exchange membranes (13, 15) and two ion-exchange membranes (23, 25) are arranged on the ground electrode side, the iontophoresis electrode side (Rooms A and B) Supplies only As ⁻ to the human body (C room) from the ground electrode portion and supplies only Na ⁺ to the human body (C room) from the ground electrode side (E to D rooms). As a result, sodium ascorbate (As ^- so that the Na ⁺⁾ are injected into the body. Since no substances other than those described above are injected into the body, the present experimental device is an extremely safe and effective means of administering (drug delivery) ionic drugs. (2). PH change is hardly observed in the B, C and D rooms. This is, (i) in the iontophoresis electrode section, B chamber ascorbate ion. (As ^-) moved to a virtual skin chamber (C chamber), and Natoumuion (N
a ⁺ ) has moved to the iontophoresis electrode chamber (chamber A), and (ii) D
The sodium ion (Na ⁺ ) in the room is a virtual skin bath (Room C)
And that the ascorbate ion (As ⁻ ) has moved to the ground electrode chamber (E chamber), whereby no pH change occurred in each chamber.

5. Other iontophoresis experiments using the experimental apparatus shown in FIG. 10 (1). In the iontophoresis experiment shown in FIG. 9, the electrode solution in the chamber D (the positive electrode ground electrode chamber) It is composed of a 0.9% NaCl aqueous solution. In this case, the ground electrode chamber (chamber D) of the positive electrode shows a large drop in pH and the generation of chlorine gas and hydrogen gas due to the energization for 30 minutes, and the energization conditions thereafter start to deteriorate. In the iontophoresis experiment shown in FIG. 9, 1 MAs ⁻ Na ⁺ (which has an oxidation-reduction potential lower than the oxidation-reduction potential of water) was used as the electrode solution of the chamber A (the iontophoresis electrode chamber of the negative electrode). Even if it is composed only of a 0.9% NaCl aqueous solution without adding an oxidation-reduction substance), hydrogen gas is generated at the negative electrode by energizing for 30 minutes, and the energizing conditions thereafter start to deteriorate.

(2) In order to improve the above-mentioned drawbacks, the iontophoresis experiment shown in FIG. 10 was carried out in addition to the provision of the anion exchange membrane (25) in the E chamber (the positive electrode ground electrode chamber). A, 0.9% NaCl aqueous solution in which 1M As ⁻ Na ⁺ is dissolved is used as an electrode solution for the chamber A, the negative electrode iontophoresis electrode chamber, and the chamber E.

(3) In this experiment, ferrous sulfate and ferric sulfate were used as a substance that is easily redox-reduced (a substance having a redox potential lower than the redox potential of water), and an electrode solution was used. The effect of using these equimolar solutions is examined.

(A). Experimental conditions: (1) 0.9% NaCl aqueous solution containing 200 mM ferrous and ferrous sulfates was used as the electrode solution in the A and E chambers. (2). As the ionic drug solution in room B, 100 mM As ⁻
An aqueous solution of Na ⁺ was used. (3) As a solution in room C (virtual skin layer) and room D, 0.9
% NaCl aqueous solution was used. (4). Energizing conditions Voltage: 30 V (initial setting value), current: 10 mA (constant current).

. [0099] (b) Experimental Results (1) by a .30 minutes energization, the B chamber As ^- to C chamber 120
μmol flowed. Further, the B chamber As ^- Na ⁺ initial amount and 3 of
The residual amounts after 0 minute energization were 890 μmol and 65
0 μmol, and the difference was 140 μmol.
The value of 140 μmol substantially matches the amount of 120 μmol actually transferred to the C chamber. The theoretical value of the transfer amount of As ⁻ from the room B to the room C is 186 μmol.
The actual transfer amount of 120 μmol is about 65% of the theoretical value, indicating a high value. This indicates that the iontophoresis method of the present invention is excellent. (2). The pH change in the C room (virtual skin room) is an initial value of 5.8.
It was 7.06 after energization for 2 and 30 minutes, and it was possible to keep it almost neutral. (3) After 90 minutes from the energization, no gas was generated from both electrode chambers (A and E chambers). In addition, it was observed that the energization conditions began to deteriorate after about 35 minutes of energization when an aqueous solution of NaCl was used as the electrode solution instead of the aqueous solutions of the first and second ferrous sulfates. This indicates that the method of the present invention is significantly superior to the conventional iontophoresis method, and that the iontophoresis method of the present invention can stably and safely administer an ionic drug for a long time. Indicates that you can do it.

[0100]

Next, an embodiment of an iontophoresis device (X) used for administering an iontophoretic ionic drug of the present invention will be described in detail with reference to the drawings. In the following description of the embodiments, the above-mentioned constituent requirements (1) of the iontophoresis device of the present invention,
The importance of the constituent requirements (1) and (2) of (2) and (3) has been proved by the experimental examples and the comparative experimental examples. . Further, since the configuration of the ground electrode portion can be easily inferred from the configuration of the iontophoresis electrode portion, detailed description will be omitted.

In the reference drawings, the ion-exchange membranes (13, 15, 23, 25) are indicated by dashed lines for clarity, and some of the constituent elements (members) and constituent elements (members) Is omitted.
However, configurations omitted in the drawings can be easily understood from the description of each embodiment and other attached drawings.

FIGS. 11 to 12 are views for explaining a first embodiment of the iontophoresis device (X) of the present invention.
FIG. 11 is a longitudinal sectional view of the iontophoresis device (X) of the first embodiment. Also, FIG.
And a state where the ion exchange membrane (15) is displaced toward the skin (4) surface side by the relative movement of the outer cylinder (a) and the middle cylinder (c).

As shown in FIG. 11, the iontophoresis device (X) of the first embodiment of the present invention is roughly divided into (i) a cylindrical iontophoresis electrode (1),
(ii) a ground electrode section (2) configured separately from the cylindrical iontophoresis electrode section (1); and (iii) a constant voltage / constant current power supply (3). It is composed of three elements.

In the iontophoresis device (X) shown in FIG. 11 of the present invention, the ground electrode portion (2) is configured separately from the iontophoresis electrode portion (1). The meaning of “configured separately” means that the iontophoresis electrode unit (1
1) and the ground electrode part (2) are non-integral type,
For example, it has a structure in which the iontophoresis patient grasps the ground electrode portion (2) and takes ground (earth). The iontophoresis device (X) of the present invention
May be configured such that the iontophoresis electrode section (1) and the ground electrode section (2) are of an integrated type. In this case, the integrated type is shown in FIGS. Of the embodiment.

The iontophoresis device (X) of the first embodiment of the present invention shown in FIG. 11 administers sodium ascorbate (As ⁻ Na ⁺ ) as an ionic drug (14) by iontophoresis. It is configured on the assumption that. For this reason, in the iontophoresis device (X) shown in FIG. 11, the reference numerals of each component of the iontophoresis electrode unit (1) mean the following. (i) The electrode plate of the iontophoresis electrode part (1) shown in (11) has a (-) electrode, and (ii) the conductive medium of the iontophoresis electrode part (1) shown in (12). Is a saline solution, (iii). The ion exchange membrane of the iontophoresis electrode part (1) shown in (13) is a cation exchange membrane, (i)
v). The ionic drug of the iontophoresis electrode part (1) shown in (14) is sodium ascorbate (As ⁻
Na ⁺ ) and (v). The ion exchange membrane of the iontophoresis electrode section (1) shown by (15) indicates an anion exchange membrane, respectively. Although the specific configuration of the ground electrode section (2) is omitted in FIG. 11, the reference numerals of the components of the ground electrode section (2) in relation to FIGS. vi). The electrode plate of the ground electrode part (2) shown in (21) is a (+) pole, and the conductive medium of the ground electrode part (2) shown in (vii). ,
(Viii) The ion exchange membrane of the ground electrode portion (2) shown in (23) is a cation exchange membrane.

As shown in FIG. 11, in the iontophoresis device (X) of the first embodiment of the present invention, the iontophoresis electrode section (1) is roughly divided into (i).
A non-conductive cylindrical outer cylinder (a); (ii) a non-conductive cylindrical inner cylinder (b); and (iii) a discontinuous cylindrical middle cylinder (c). ), And the above-mentioned reference numerals (11 to 1) are described under these elements (a, b, c).
The element shown in 5) is held or accommodated. The elements (a, b, c) may be made of, for example, non-conductive plastic.

FIG. 11 shows a member (d) for guiding the lead wire (31) from the electrode (3) and supporting the electrode plate (11), in addition to the elements (a, b, c). However, this may also be made of non-conductive plastic. The member (d) may be omitted as described in a second embodiment described later.

As shown in FIG. 1, the iontophoresis electrode section (1) having the above-mentioned structure has a circular plan view. The iontophoresis electrode section (1) is configured to have a desired size (outer diameter and height), for example, because it is gripped by hand and brought into contact with a desired diseased part. Further, as shown in FIG. 11, the outer cylinder (a), the inner cylinder (b) and the middle cylinder (c) are screwed together via screw portions formed on the mutual contact surfaces. It is a screw type that is integrated and can move relative to each other. In the drawing, the above-mentioned threaded portions are indicated by symbols ab and bc. The threaded portion between the inner cylinder (b) and the member (d) is indicated by the symbol bd.

The iontophoresis device (X) of the present invention
As will be described in detail later, the outer cylinder (a) and the middle cylinder (c)
It is essential to have a mechanism for bringing the ion-exchange membrane (15), which directly or indirectly comes into contact with the skin surface, into close contact with the skin surface side by the relative movement of the skin. Therefore, as long as it has the above-mentioned mechanism, the outer cylinder (a), the inner cylinder (b), and the middle cylinder (c) may be integrated by other methods. For example, it may be an engagement type, a locking type, an insertion type, or the like.

As shown in the figure, the cylindrical outer cylinder (a) includes (i) a support (a1) for anion exchange membrane (15) for fixing anion exchange membrane (15), ii). There is a pressing ring (a11) for the anion exchange membrane (15) for fixing the anion exchange membrane (15), and (iii) a fixing pin (a12) for fixing the anion exchange membrane (15). It is composed of things.

As shown in the figure, the cylindrical inner cylinder (b) is composed of (i) a cation exchange membrane (1) of the middle cylinder (c).
3) The cation exchange membrane (1) cooperates with the support (c1) for
(3) Pressing part (b1) for cation exchange membrane (13) for supporting fixation, (ii). Housing part (b2) for conductive medium (12) for housing conductive medium (12), (iii) Guide holes (b) for the electrode plate support (d) for guiding the lead wires (31) from the power supply section (3) and supporting the electrode plates (11).
3) (iv). It has a top disk portion (b4).

As shown in the figure, the cylindrical middle cylinder (c) is composed of (i) a cation exchange membrane (1) of the inner cylinder (b).
3) The cation exchange membrane (1) cooperates with the pressing portion (b1) for
3 (c) for supporting the ion exchange membrane (13) fixedly supporting
1), (ii) an accommodating portion (c2) for accommodating the ionic drug (14) for accommodating the ionic drug (14), and (iii) an anion exchange membrane by relative movement with the outer cylinder (a). It has a skin pressing portion (c3) for displacing (15) toward the skin (4).

The electrode plate support (d) is screwed and fixed to the guide hole (b3) of the inner cylinder (b) as described above. As shown in the figure, the electrode plate support (d) includes (i) a support (d) for the electrode plate (11) supporting the electrode plate (11).
1), (ii) a guide portion (d2) for a lead wire (31) for guiding a lead wire (31) from the power supply portion (3). In FIG. 11, the symbol (d3)
Is a resilient body (b5) interposed between the support part (d1) for the electrode plate (11) and the top part (b5) of the accommodating part (b2) for the conductive medium (12) of the inner cylinder (b). (Spring body).
The spring body (d3) ensures the adhesion between the electrode plate (11) and the conductive medium (electrode solution) (12). In this case, the members (b, d) may have a structure in which the members (b, d) are simply inserted in place of the screws (bd).

In the iontophoresis device (X) of the present invention, the electrode plate support (d) may be omitted as shown in Example 2 to be described later. in this case,
An accommodating portion (b) for the conductive medium (12) of the inner cylinder (b)
The top portion (b5) of 2) has the function of the support portion (d1) for the electrode plate (11).

In the present invention, the ion exchange membrane (13, 1
Various modifications of the arrangement mode 5) are possible. For example, the anion exchange membrane (15) includes the pressing ring (a1).
It goes without saying that, instead of 1) and the method of fixing to the support portion (a1) by the fixing pin (a12), the fixing portion may be directly adhered or fused to the support portion (a1). is there. Alternatively, the cartridge holding the anion exchange membrane (15) may be detachably fixed to the support (a1). Also, a cation exchange membrane (13)
May be fixed to one of the pressing portion (b1) and the supporting portion (c1) by adhesion or fusion instead of the method of sandwiching the pressing portion (b1) and the supporting portion (c1). Things.

Further, in the iontophoresis device (X) of the present invention, in order to improve its operability and convenience,
At least one of the above-mentioned components (13, 14, 15) may be configured using an outer cylinder (a) which is previously arranged or accommodated in the outer cylinder (a).
In the present invention, in the case where the active ingredient of the ionic drug is replaced with the positively (+) charged morphine hydrochloride or the like instead of the negatively (−) charged sodium ascorbate as the ionic drug, the ion exchange membrane may be used. Needless to say, the arrangement order and the polarity of the electrode plates must be changed to the opposite ones.

In the iontophoresis device (X) of the present invention, although not shown, the conductive medium (12, 22) and / or the ionic drug (14) is impregnated with gauze or a water-absorbing polymer material. It may be in a form. Further, the ion exchange membranes (15, 23) disposed on the skin side may be disposed so as to directly or indirectly contact the skin (4). In particular, when a high level of ecological safety is required, for example, for patients with weak skin, a gauze or a water-absorbing polymer material impregnated with a conductive medium is applied to the front surface of the ion exchange membrane, and the ion exchange membrane (15, 23) may indirectly contact the skin (4).

In the iontophoresis device (X) of the present invention, although not shown for the sake of clarity, a conductive medium is connected to the iontophoresis electrode (1) and / or the ground electrode (2). (12, 22, 24) and supply path or discharge path for the ionic drug (14), vent holes for gas generated from the electrode plates (11, 12), or adsorbents for adsorbing the gas It is needless to say that an accommodation section, etc. may be provided.

FIG. 12 shows one of the features of the iontophoresis device (X) according to the first embodiment of the present invention.
As shown in the figure, the middle cylinder (c) is moved by the relative movement of the outer cylinder (a) and the middle cylinder (c), that is, by lowering the middle cylinder (c) in the arrow direction in FIG. The anion exchange membrane (15) by the skin pressing part (c3) of the skin (4)
It can be in close contact with the surface. Thereby, the ionic drug (14) is efficiently delivered transdermally.

FIG. 13 is a view for explaining a second embodiment of the iontophoresis device (X) of the present invention.
FIG. 2 is a diagram corresponding to FIG.

The iontophoresis device (X) of the second embodiment shown in FIG. 13 differs from that of the first embodiment shown in FIGS. 11 to 12 in the following points. (1) A hollow cylindrical body (e) is used instead of the middle cylindrical body (c) of the first embodiment, and the hollow cylindrical body (b) is moved in conjunction with the downward movement of the inner cylindrical body (b) with respect to the outer cylindrical body (a). The cylinder (e) is moved downward, and the anion exchange membrane (15) is brought into close contact with the skin at the lower end of the hollow cylinder (e). (2) The electrode plate support (d) of the first embodiment is omitted, and the function of the electrode plate support (d) is given to the inner cylinder (b).

In the iontophoresis device (X) of the second embodiment shown in FIG. 13, the cation exchange membrane (13) is a pressing portion (b1) for the ion exchange membrane (13) of the inner cylinder (b). And the upper end of the hollow cylindrical body (e). Further, the electrode plate (11) is fixedly supported on the top (b5) of the accommodating portion (b2) for the conductive medium (12) of the inner cylinder (b).

In the iontophoresis device (X) according to the second embodiment, the hollow cylindrical body (e) is an outer cylindrical body (a).
A slide groove is formed on the inner wall surface of the inner cylinder and the inner cylindrical body (b)
During the downward movement, the slide groove may be guided to move downward. In addition, the cation exchange membrane (1
3) and the arrangement of the anion exchange membrane (15) can be variously modified, for example, directly adhered or fused to the pressing portion (b1) of the inner cylinder (b).

[0124]

According to the present invention, an iontophoresis device having the following excellent characteristics is provided. (i) Since the iontophoresis electrode section (working side electrode section) and the ground electrode section (non-working example electrode section) can maintain a stable energized state (constant current and / or constant voltage) for a long period of time, The positively (+) or negatively (-) drug component of the ionic drug can be efficiently transported (drug delivery) to the skin (or mucous membrane) at the toforase electrode portion. (ii). The iontophoresis electrode section (working side electrode section) and the ground electrode section (non-working example electrode section) contribute to the maintenance of the above-mentioned stable energized state, and use (arrangement) of a specific ion exchange membrane. According to the embodiment, adverse effects on the skin (skin irritation, fever, inflammation, etc.) due to the electrode reaction can be eliminated. (iii). Furthermore, in the iontophoresis device of the present invention, in particular, the iontophoresis electrode section (working side electrode section)
Because the ion exchange membrane that directly or indirectly contacts the skin surface on the side can be displaced so as to be in close contact with the skin surface side, iontophoresis can efficiently deliver the ionic drug transdermally. it can. (iv) In addition, the iontophoresis device of the present invention provides a plurality of ion exchange devices having different ion selectivities with respect to the iontophoresis electrode section (working side electrode section) and the ground electrode section (non-working side electrode section). A membrane is used and the arrangement of these ion exchange membranes is changed depending on the charging characteristics (positive ion or negative ion) of the ionic drug. When the arrangement of the ion exchange membrane according to the charging characteristics of the drug is configured to be detachably provided, the handleability (convenience) is improved, and the ionic drug can be efficiently administered. In addition, malfunctions can be avoided without erroneous arrangement of the ion exchange membrane when configuring each electrode portion, and the ionic drug can be safely and efficiently administered. (v). Further, the iontophoresis electrode section (working electrode section)
In the case where the and the ground electrode portion (non-working side electrode portion) are integrated, the work of taking the ground (earth) by the treating person as in the related art is released, and the convenience is improved. In the above-mentioned integrated structure, when a plurality of sets of iontophoresis electrode portions and ground electrode portions are integrated, the degree of penetration of the ionic drug into the skin (depth of penetration from the skin surface)
Can be adjusted as desired.

[Brief description of the drawings]

FIG. 1 is a basic configuration diagram (schematic perspective view) of a first iontophoresis device (X) of the present invention.

FIG. 2 is a basic configuration diagram (schematic sectional view) of the iontophoresis device (X) corresponding to FIG.

FIG. 3 is a basic configuration diagram of an iontophoresis device (X) corresponding to FIG. 2 and used when administering sodium ascorbate (As ⁻ Na ⁺ ) as an ionic drug.

FIG. 4 is a basic configuration diagram of another iontophoresis device (X) corresponding to FIG. 2 which is used when administering sodium ascorbate (As ⁻ Na ⁺ ) as an ionic drug.

FIG. 5 is a basic configuration diagram (schematic perspective view) of a second iontophoresis device (X) of the present invention.

6 is a basic configuration diagram (schematic cross-sectional view) of the iontophoresis device (X) corresponding to FIG.

FIG. 7 is a schematic diagram of a first experimental device (a device to be compared with the present invention) for testing the iontophoresis effect.

FIG. 8 is a schematic diagram of a second experimental device (a device to be compared with the present invention) for testing the iontophoresis effect.

FIG. 9 is a schematic diagram of a third experimental device (the device according to the present invention) for testing the iontophoresis effect.

FIG. 10 is a schematic view of a fourth experimental apparatus (an apparatus according to the present invention) for testing the iontophoresis effect.

FIG. 11 is a diagram illustrating an iontophoresis device (X) according to the first embodiment of the present invention.

FIG. 12 is an enlarged view of a main part of FIG. 11;

FIG. 13 is a diagram illustrating an iontophoresis device (X) according to a second embodiment of the present invention.

[Explanation of symbols]

 X ... Iontophoresis device 1 ... Iontophoresis electrode part 11 ... Electrode material 12 ......... Conductive medium 13 ......... Ion (cation) exchange membrane 14 ... ... Ionic drug 15 ... Ion (anion) exchange membrane 2 ... Ground electrode 21 ... Electrode material 22 ... Conductive medium 23 ... Ion (cation) exchange Membrane 24 ... Conductive medium 25 ... Ion (anion) exchange membrane 3 ... Power supply 31, 32 Lead wire 4 ... Skin a ... Body a1 Support section for ion-exchange membrane (15) a11 Pressing ring for ion-exchange membrane (15) a12 Fixing pin b ... Inner cylinder body b1 ... … Pressing part for ion exchange membrane (13) b2 …………… Housing for conductive medium (12) b3 ... Guide hole for electrode plate support (d) b4 ... Top disk part b5 ... Support for electrode plate (11) c ... ... Middle cylinder body c1 Supporting part for ion exchange membrane (13) c2 ... Housing part for ionic drug (14) c3 ... Skin pressing part d ... Electrode plate Support member d1 Support portion for electrode plate (11) d2 Guide portion for lead wire (31) d3 Spring member ab, bc, ac, bd Screw portion

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Takehiko Matsumura 22-2 Kitamine-cho, Ota-ku, Tokyo (72) Inventor Yoriko Kobayashi 2-38-7 Motomiya, Otsu-shi, Shiga F-term (reference) 4C053 HH02 HH04 4F071 AA01 AH19 FA11 FC13 FD05 FE06

Claims (9)

[Claims] 1. An iontophoresis having an iontophoresis electrode section (working side electrode section) and a ground electrode section (non-working side electrode section) connected to a power supply used for administering an ionic drug by iontophoresis. In the rese apparatus, (1) the electrode portion of the iontophoresis is connected to a power source having the same polarity as the charged ion of the ionic drug, (1) -1. (1) -3. An ion exchange membrane for selecting an ion opposite to the charged ion of the ionic drug disposed on the front surface of the conductive medium, (1) -3. An ionic drug disposed on the front of an ion exchange membrane that selects an ion opposite to the charged ion of the ionic drug, and (1) -5. Electrification of the ionic drug disposed on the front of the ionic drug An ion exchange membrane that selects the same type of ions as the ions, And (2) the ground electrode portion has a polarity opposite to that of the electrode material of the iontophoresis electrode portion, and (2) -2. (2) -3. An ion exchange membrane for selecting ions opposite to charged ions of the ionic drug disposed on the front surface of the conductive medium,
And (3). The iontophoresis electrode section and / or the ground electrode section are configured to displace the ion exchange membrane disposed at the forefront thereof forward. Characterized iontophoresis device. 2. The iontophoresis device according to claim 1, wherein the iontophoresis electrode portion is configured to displace the “ion exchange membrane (1) -5” disposed at the forefront thereof forward. Reese device. 3. The iontophoresis electrode section comprises an outer cylinder (a), an inner cylinder (b) and a middle cylinder (c), and the relative movement between the outer cylinder (a) and the middle cylinder (c). The iontophoresis device according to claim 2, wherein the "ion exchange membrane (1) -5" is configured to be displaced forward. 4. The method according to claim 1, wherein the ground electrode part is provided with the “(2) -2. The conductive medium disposed on the front surface of the electrode material” and “(2) -3. The ions disposed on the front surface of the conductive medium. The iontophoresis device according to claim 1, further comprising an ion exchange membrane for selecting an ion opposite to the ion exchange membrane, between the ion exchange membrane and the ion exchange membrane for selecting an ion opposite to the charged ion of the active agent. . 5. The iontophoresis device according to claim 1, wherein the ground electrode portion is formed non-integrally with the iontophoresis electrode portion. 6. The iontophoresis device according to claim 1, wherein the ground electrode portion is adjacent to and integrally formed with the iontophoresis electrode portion. 7. The iontophoresis device according to claim 1, wherein the conductive medium of the iontophoresis electrode portion and the ground electrode portion is formed of a material containing a substance which is easily oxidized or reduced. 8. The iontophoresis device according to claim 7, wherein the conductive medium is composed of a solution containing ferrous sulfate and ferric sulfate as substances that are easily oxidized or reduced. 9. The iontophoresis device according to claim 7, wherein the conductive medium is composed of a solution containing an organic acid and / or a salt thereof as a substance which is easily oxidized or reduced.