JP2000237329A - Administration method of ionic medicine by iontophoresis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To make it possible to administer (percutaneous drug delivery) various kinds of ionic medicines by iontophoresist with high efficiency and safety. SOLUTION: An iontophoresis electrode section 1 comprises an electrode material 11 which is connected to a power source of the same kind of the polarity as the polarity of the electrification ions of the ionic medicine, a conductive medium 12 which is disposed at the electrode material, an ion exchange membrane 13 which is disposed on the front of the conductive medium and selects the ions opposite to the electrification ion of the ionic medicine, the ionic medicine 14 which is disposed on the front of the ion exchange membrane for selecting the ions opposite to the electrification ion of the ionic medicine and an ion exchange membrane 15 which is disposed at the front of the ionic medicine and selects the ions of the same kind as the electrification ions of the ionic medicine. A ground electrode section 2 comprises an electrode material 21 which has the polarity opposite to the polarity of the electrode material of the iontophoresis electrode section and a conductive medium 22 disposed at the front of the electrode material and an ion exchange membrane 23 which is disposed at the conductive medium and selects the ions opposite to the electrification ions of the ionic medicine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for percutaneously administering various ionic drugs with high efficiency and safety (transdermal drug delivery) by iontophoresis. It is. More specifically, the present invention relates to an iontophoresis device comprising an iontophoresis electrode portion (working electrode portion) and a ground electrode portion (non-working electrode portion) used for iontophoresis. (I) the iontophoresis electrode section and the ground electrode section can maintain a stable energized state (constant current and / or constant voltage) for a long time;
(ii) It is possible to efficiently transport (drive) an ionic drug, that is, a drug component charged positively (+) or negatively (-) to the skin (or mucous membrane) side under the above-mentioned long-term stable energized state. And (iii) a method for administering an ionic drug by iontophoresis, which has a characteristic of being able to eliminate adverse effects on the skin due to electrode reactions at the iontophoresis electrode section and the ground electrode section. . Still further, according to the present invention, the iontophoresis device serving as a tool is provided with a plurality of ion exchange membranes having different ion selectivities in the iontophoresis electrode section and the ground electrode section, and the iontophoresis apparatus is provided with a charged ion of the ionic drug. In this connection, the arrangement of the ion exchange membrane is changed and used.However, since the work of arranging and replacing the ion exchange membrane is labor-saving, the efficiency is excellent and the administration mistake is prevented. The present invention relates to a method for administering an ionic drug by iontophoresis.

[0002]

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 mentioned 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.

[0004] 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).

A method of administering an ionic drug by iontophoresis and a device to be applied to the method 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.

[0006] 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.

[0007] 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.

[0008] 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 drug at a high concentration while preventing dilution with 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 It discloses a multilayer structure composed of 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. The ground electrode (ground electrode,
There is a significant feature in that a three- or four-layer structure in which an ion-exchange membrane is provided also for the neutral electrode portion).

[0011]

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). Lack of initiative or creativity to prevent or eliminate various disadvantages 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 seen in the above-mentioned 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 power supply state for a long period of time (operation 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 between the electrode plate (eg, one pole) of the ground electrode portion and the skin, harmful substances generated by electrolysis of sweat on the skin surface or saline as a conductive medium, for example, High alkalinity (NaOH) causes skin damage and the like.

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 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.

Furthermore, the present inventor has never known that an ion exchange membrane is provided on the side of a ground electrode (non-working electrode) 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 an oxidation-reduction potential lower than the electrolysis potential of water (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.

The present invention is based on the above-mentioned findings, and the configurations (i) to (iv) and the configurations (v) and / or (vi) are integrated (embedded). Efficient administration of ionic drugs using an iontophoresis device having an iontophoresis electrode section (working electrode section) and a ground electrode section (non-working electrode section) (drug delivery)
What you want to do.

In particular, the present invention provides the above-mentioned constitutions (i) to (iv),
Furthermore, while integrating (incorporating) the configurations of the above (v) and / or (vi), errors in changing the combination of the electrode material and the ion exchange membrane in relation to the ionic properties of the ionic drug are eliminated. It uses a new structure of iontophoresis device that takes measures to prevent and efficiently administer the ionic drug, and maintains a stable current state (constant current and / or constant voltage state) for a long period of time. It is an object of the present invention to provide a method of administering an ionic drug by iontophoresis, which has high administration efficiency of the ionic drug and has high biosafety by preventing skin burns and inflammation.

[0024]

SUMMARY OF THE INVENTION In general, the present invention relates to a method of administering an ionic drug by iontophoresis, comprising the steps of: Of an iontophoretic device having an iontophoretic device having an iontophoretic device and a ground electrode portion (non-working side electrode portion). About the law. (1) .The iontophoresis electrode section is (1) -1. An electrode material connected to a power source having the same polarity as the charged ions of the ionic drug, (1) -2. (1) -3. An ion exchange membrane for selecting an ion opposite to a charged ion of the ionic drug disposed on the front surface of the conductive medium, (1) -4. An ionic drug disposed on the front surface of the ion-exchange membrane to select an ion opposite to the charged ion, and (1) -5. Of the same type as the charged ions of the ionic drug disposed on the front surface of the ionic drug. An ion exchange membrane for selecting ions, and
(2) .The ground electrode portion is (2) -1.An electrode material having a polarity opposite to that of the electrode material of the iontophoresis electrode portion, and (2) -2.Conductivity disposed at least in front of the electrode material And (2) -3. An ion-exchange membrane for selecting ions opposite to the charged ions of the ionic drug disposed on the front surface of the conductive medium, and (3) An iontophoresis device in which at least the iontophoresis electrode portion of the iontophoresis electrode portion and the ground electrode portion is configured such that another component is detachably attached to an electrode material element.

The present invention further provides (i) a ground electrode in addition to the technical constitution of the first invention in order to improve the method of administering an ionic drug by the iontophorase of the first invention. A method of disposing two kinds of ion exchange membranes (cation exchange membrane and anion exchange membrane) having different ion selective permeability in the section to administer an ionic drug, and (ii) an iontophoresis electrode section and a ground. As a conductive medium for each of the electrode portions, a substance having a redox potential lower than the redox potential of water, that is, a conductive medium such as physiological saline containing a substance which is more easily redox reduced than water, A method of administering a sex drug.

As described above, in order to safely and efficiently administer the ionic drug by the iontophoresis, the present invention provides not only the iontophoresis electrode section (working side electrode section) but also the ground electrode section ( Non-working electrode)
In this method, an iontophoresis apparatus using at least one kind of ion exchange membrane or two kinds of ion exchange membranes having different ion selective permeability is carried out. 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.

The present invention also provides an iontophoretic device comprising the iontophoretic device according to the present invention. A plurality of ion-exchange membranes having different properties are arranged, and the arrangement of the ion-exchange membrane is changed in relation to charged ions of the ionic drug to use an iontophoresis device. It is a feature of the present invention to provide a new method of administering an ionic drug by iontophoresis, which is efficient and free from administration mistakes, by saving labor for arranging and exchanging exchange membranes.

Hereinafter, the technical structure of the present invention will be described in more detail. First, in order to obtain an understanding of the present invention, a basic configuration diagram of an iontophoresis device for performing a method of administering an ionic drug by the iontophoresis of the present invention will be described, and then using the main body configuration diagram. The conventional ionic drug administration method and its problems, and the features of the ionic drug administration method of the present invention will be described. In addition, although 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,
It goes without saying that the iontophoresis device applied to the method of administering the ionic drug of the present invention is not limited to those shown in the drawings.

FIGS. 1 and 2 show an iontophoresis in which an iontophoresis electrode (1) and a ground electrode (2) are non-integrally formed for implementing the method of administering an ionic drug according to the present invention. FIG. 3 shows a basic configuration diagram of the device (X). 1 is a perspective view, and FIG. 2 is a sectional view of a main part.

FIG. 3 shows an iontophoresis device (X) for carrying out the method for administering an ionic drug by the iontophorase of the present invention shown in FIG. 1 shows a basic configuration diagram (a cross-sectional view of a main part) of an iontophoresis device (X) at the time of implementation. (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 shows a basic configuration diagram of another iontophoresis device (X) for further improving the performance of the iontophoresis device (X) shown in FIG. As shown in FIG. 4, the ion exchange membrane of the ground electrode portion (2) in FIG. 4 is a combination of the cation exchange membrane (23) and the anion exchange membrane (25), as compared with that of FIG. It is different in that it is configured.

In FIGS. 1 to 4, 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 an iontophoresis electrode section (1) and a ground electrode section (2) integrally formed for carrying out the method of administering an ionic drug by the iontophoresis of the present invention. FIG. 2 is a diagram illustrating a basic configuration of the iontophoresis device (X), and is a diagram corresponding to FIGS. 1 and 2.

The most important feature of the method for administering an ionic drug by iontophoresis of the present invention is that the purpose of this type of iontophoresis is to apply the ionic drug to the skin (or mucous membrane) under a predetermined electromotive force. ), The amount of ions that move with a constant electromotive force (this depends on the ion concentration, the ion mobility, and the valency of the ions). The present invention focuses on the electrochemical reaction of each electrode portion, while
In particular, attention is paid to a defect factor (negative factor) based on an electrochemical reaction, and the iontophoresis technology is reconstructed therefrom.

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 based on eliminating the drawbacks caused by the electrochemical reaction occurring at the electrode portion in the iontophoresis.

According to the present invention, in order to solve the above-mentioned disadvantages of the conventional ionic drug administration method, the ionic drug is administered as shown in FIGS. In view of this, from the viewpoint of the iontophoresis device (X), the technical components (1) of the present invention described above as (i). The configuration of the iontophoresis electrode section (working side electrode section) (1). -2 to (1) to (1) to 3 (indicated by reference numerals 12 to 13 in FIGS. 2 to 3), and (ii). Technical component (2) -2 of the present invention described above as the side electrode portion) (2).
There is a feature in adopting a configuration to which (2) to (3) (in FIGS. 2 to 3, indicated by reference numerals 22 to 23) are added.

Further, the present invention provides a method of administering an ionic drug, which is different from the prior art, from the viewpoint of the iontophoresis device (X). And (2) a combination of a cation exchange membrane (23) and an anion exchange membrane (25) as an ion exchange membrane; (1) and the feature point (i
In the iontophoresis device (X) in which the ground electrode portion (2) having (i) or (iii) is not integrated or integrated, at least the iontophoresis electrode portion (1)
However, other components can be detached from the electrode material element (deta
chable).

In short, the method for administering an ionic drug by iontophoresis according to the present invention uses an ion exchange membrane in order to eliminate the above-mentioned drawbacks caused by the electrode reaction in the conventional method for administering an ionic drug. In this regard, attention is paid to the permselectivity of ions, and an iontophoresis device using two ion-exchange membranes in the iontophoresis electrode section and at least one ion-exchange membrane in the ground electrode section ( Under X), there is a feature point. Further, according to the present invention, a plurality of ion exchange membranes having different ion selective permeability are used as important components of the iontophoresis device (X) used as described above. It is assumed that the arrangement of the ion exchange membrane is changed depending on the characteristics of the ions (depending on whether the active ingredient of the ionic drug is positively or negatively charged). The feature is that labor is saved.

Further, in order to solve the above-mentioned drawbacks caused by the electrode reaction in the conventional ionic drug administration method, the present invention provides, in addition to the above-mentioned specific ion exchange membrane arrangement mode, (v). As a conductive medium for both electrode portions (iontophoresis electrode portion and ground electrode portion), a material containing an easily oxidizable or reduced substance having a redox potential lower than the redox potential of water was employed. There is a feature in administration under an iontophoresis device (X).

The characteristics of the above-described method for administering an ionic drug by the iontophoresis of the present invention are shown in FIG.
6 to FIG. 6 and a case where sodium ascorbate (As ⁻ Na ⁺ ) is used as an ionic drug. In this case, it goes without saying that the charged ion of the active drug component of the ionic drug is an anion (As ⁻ ).
Therefore, as shown in FIGS. 3 and 4, the iontophoresis electrode part (1) becomes a cathode (− pole) and the ground electrode part (2) becomes an anode (+ pole). Needless to say, when the ionic drug dissociates into positively charged ions, the polarity of the electrode portion and the type of ion exchange membrane (selective permeability of ions) are opposite to each other. Needless to say, it becomes something of.

In FIGS. 1 to 6, which show the basic structure of an iontophoresis device (X) for carrying out a method of administering an ionic drug by iontophoresis of the present invention, reference numeral 1 denotes an iontophoresis electrode section (working side). (Electrode part), 2 is a ground electrode part (non-working side electrode part), 3 is a power supply device, and 4 is 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),
(v). Cation exchange membrane (23), specifically 1 MAs ⁻
It may be constituted by a 0.9% NaCl aqueous solution containing Na ⁺ .

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 configuration, that is, an iontophoresis electrode section (see FIG. 1) will be described with reference to a basic configuration diagram of an apparatus (X) for performing an iontophoretic administration method of an ionic drug according to the present invention. The specific configuration of the working electrode section (1) will be described first, followed by the specific configuration of the ground electrode section (non-working electrode section, ground electrode section) (2).

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

In the present invention, the electrode material (11, 1
As 2), an active electrode known in the field of iontophoresis may be employed instead of the inactive electrode. 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-mentioned active electrode, the silver electrode and chlorine ion (Cl ⁻ ) easily react with each other, and Ag + Cl ⁻ → AgCl + e ⁻ causes insoluble AgC.
1 is generated. 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 device (X) of the present invention, as described above, since the iontophoresis system uses a plurality of ion exchange membranes having different ion selectivities, at least three or more, the active electrode 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, in the present invention, since a plurality of ion exchange membranes having different ion selectivities are used, it is preferable to use a more economical inert 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 apparatus (X) for carrying out the method for administering an ionic drug by iontophoresis of the present invention shown in FIG. 3, the negative (-) electrode material of the iontophoresis electrode section (1) ( The conductive medium (12) disposed so as to be in contact with the periphery of (11) is made of a material containing a compound that is easily reduced. Further, in the iontophoresis device (X) shown in FIG. 3, 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). Is composed of a compound containing a compound that is easily oxidized. The disposition site of the compound that is easily oxidized or reduced corresponds to an electrochemical reaction in each electrode plate, that is, a reduction reaction at a negative (-) pole and an oxidation reaction at a positive (+) pole. Needless to say.

The iontophoresis electrode section (1) of the iontophoresis apparatus (X) shown in FIG.
A cation exchange membrane (13) is provided between the 2) and the ionic drug (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 conductive medium (12) plays an important role as described later. This is the same for the conductive medium (22) containing a compound that is easily oxidized on the side of the ground electrode (2).

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 susceptible to oxidation or reduction than the above-mentioned electrolytic reaction of water (oxidation at the positive electrode and reduction at the negative electrode), for example, ferric sulfate is easily converted to ferrous ion at the negative electrode. Reduce to ions. In addition, ferrous sulfate easily oxidizes ferrous ions to ferric ions at the positive electrode. Thereby, as will be described in detail later, it is possible to remove the drawbacks caused by the electrolysis reaction of water, and has excellent effects such as high biosafety related to the specific ion exchange membrane disposition mode. Methods of administering ionic drugs by iontophoresis are 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) shown in FIG. 3, the conductive medium (12)
May be configured as desired.
The conductive medium (12) may be, for example, a solution type or a type in which a desired medium (such as gauze or a water-absorbing polymer material) is impregnated.

Here, as the conductive medium (12),
The advantages 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, a negative electrode is H ₂ gas, and a positive electrode is Cl ₂ and O _2.
2 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 As ^- Na ⁺ delivery described above,
Stable energization for a long time (30 minutes or more) becomes impossible. 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 very 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 (a substance having a redox potential lower than that of water) in an electrochemical reaction such as sodium ascorbate 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) shown in FIG. 3, a desired cation exchange membrane (13) can be used. The iontophoresis device (X) shown in FIG. 3 uses an anion exchange membrane (15) in addition to the cation exchange membrane (13) as described above. 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.

The iontophoresis device shown in FIG.
In (X), the ionic drug (As) ^-Na⁺) (14)
May be configured as desired.
The ionic drug (14) is, for example, a solution
Ip or desired medium (gauze, high water absorption
Material impregnated in the material)
No.

In the iontophoresis device (X) shown in FIG. 3, the ionic drug (As ^- Na ⁺ ) (1
Front of 4), i.e., an ion exchange membrane disposed on the skin side, charged ions of the drug component of the ionic drug (As ^-) anion exchange membrane having an ion-selective allogeneic (15) is used .

In the iontophoresis device (X) shown in FIG. 3, the iontophoresis electrode section (1)
With the technical configuration of the above, it is possible to obtain a long-term and stable iontophoretic effect and biosafety as compared with the conventional method. That is, the above-mentioned iontophoresis electrode section (1)
With the technical configuration of (1), it is possible to obtain a long-term and stable current-carrying characteristic. In other words, the ionic drug is applied to the skin (4).
, The drug can be efficiently penetrated (drug delivery) into the body for a long time and stably, and the generation of harmful substances due to the electrolysis reaction at the electrode portion can be prevented.

Next, the basic configuration of the ground electrode (+ electrode) (2) of the iontophoresis device (X) for performing the method of administering an ionic drug by the iontophoresis of the present invention is shown in FIG. It will be described with reference to FIG.

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 iontophoresis device (X) for carrying out the method for administering an ionic drug by iontophoresis according to the present invention has an overall configuration in addition to the configuration of the iontophoresis electrode section (1). In the context of the present invention, the ground electrode (2) is also different from the conventional technology from the viewpoint that it is possible to stably and stably administer an ionic drug by iontophoresis and to obtain a high level of biosafety. It adopts a strategic configuration.

The ground electrode part (2) of the iontophoresis device (X) shown in FIG. A conductive medium (22) disposed at least on a front surface of the electrode material (21); and a conductive medium (2).
It comprises an ion exchange membrane (23) disposed on the front surface of (2), that is, on the side of the skin (4) and selecting ions opposite to the charged ions of the ionic drug.

In the iontophoresis device (X) for carrying out the method for administering an ionic drug by iontophoresis of the present invention, the ground electrode section (2) is operated as shown in FIGS. It may be configured to be integrated with the iontophoresis electrode section (1) in order to improve the performance and convenience.

In order to further improve the operability and convenience of the iontophoresis device (X), the ground electrode (2) is integrated or not integrated with the iontophoresis electrode (1). Iontophoresis device (X)
In at least the iontophoresis electrode section (1)
However, it may be configured such that other components can be detachably attached to the electrode material (11). Further, the iontophoresis electrode section (1)
In addition, the ground electrode section (2) may be configured such that other components can be detachably attached to the electrode material (21).

In the iontophoresis device (X),
As described above, the provision of the ion exchange membrane (23) in the ground electrode portion (2) in order to enhance biosafety is a major feature not found in the prior art. In addition, in the iontophoresis device (X), in order to achieve the above-mentioned biosafety and long-term stable operation, similarly to the conductive medium (12) of the iontophoresis electrode unit (1), the ground electrode unit (2) is used. The conductive medium (22) may be made of a material containing a substance having an oxidation-reduction potential lower than that of water. A high value-added iontophoresis device (X) is obtained by combining the point of disposing the ion exchange membrane (23) on the ground electrode section (2) and the point of using the substance which is easily oxidized and reduced. This is another major feature not found in the prior art.

The ground electrode portion (2) of the iontophoresis device (X) shown in FIG. 2 may be constituted by disposing one ion exchange membrane (23) having a predetermined ion selectivity. Good thing. The advantage of disposing the ion exchange membrane (23) on the ground electrode section (2) will be described later with demonstration data. The advantage of adding a substance that is easily oxidized and reduced to the conductive medium (22) of the ground electrode part (2) is as described above for the conductive medium (12) of the iontophoresis electrode part (1). It is.

As shown in FIG. 3, the ionic drug is negative (−) such as sodium ascorbate (As ⁻ Na ⁺ ).
In the ground electrode section (2) of the iontophoresis device (X), the electrode material (21) is an anode (+), the conductive medium (22) is, for example, physiological saline, and the ion exchange membrane (23). ) Is constituted by a cation exchange membrane.

In the present invention, the conductive medium (22) of the ground electrode section (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) may use two types of ion exchange membranes having different ion selectivities as the ion exchange membrane.

In the method of 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, it goes without saying that the polarity of each electrode material (11, 12) and the ion-exchange characteristics of the ion-exchange membrane must be completely opposite to the case of the administration of sodium ascorbate (As ^- Na ⁺ ). That is. 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 (3) shown in FIGS. 1 to 6
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.

[0078]

EXAMPLES AND COMPARATIVE EXAMPLES The method of administering an ionic drug by the iontophoresis of the present invention is equivalent to the basic configuration of the iontophoresis device (X) shown in FIGS. 3 to 4 and 5 to 6. Using an experimental apparatus manufactured by modifying the experimental apparatus for collecting the comparative data, and sodium ascorbate (A) as an ionic drug.
Examples / comparative examples when an experiment on administration of (s ⁻ Na ⁺ ) was performed will be described. According to the examples / comparative examples described below, in the method of administering an ionic drug by the iontophoresis of the present invention, in particular, the cation exchange membrane (23) is provided on the ground electrode portion (2) of the iontophoresis device (X). The importance of providing an anion exchange membrane (25) can be understood.

<Experimental Apparatus> FIGS. 7 to 10 are schematic diagrams of the experimental apparatus used. 7 and 8 show an apparatus for a comparative experiment. FIGS. 9 and 10 show an experimental device equivalent to the iontophoresis device (X) for performing the method of administering an ionic drug by iontophoresis 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.

<About the transfer amount of the ionic drug (As ⁻ Na ⁺ )> The accommodation room for As ⁻ Na ^{+ in} the iontophoresis electrode section (in the experimental apparatus shown in FIGS. From the virtual skin tank (room) (Fig. 5
In the experimental apparatus shown in FIG. 8, the room is the room B or the room C. As to) - the amount of movement of ^(ascorbic acid ions) is obtained as follows.

. [0081] (1) .As ^- the amount of movement of the measured value: (i) the molar concentration of ascorbic acid Na (. Mol / l or less, represented by M) and the absorbance of a solution 265nm of measures, ascorbic acid Na Molar concentration (M) and absorbance (2
A standard curve (standard curve) showing the relationship of the absorption value at 65 nm is created. In addition, sodium ascorbate
The 1 molar concentration (1 M) of (molecular weight 198.11) is a state in which 198.11 g of sodium ascorbate is dissolved in 1 liter (liter) of a solvent. (ii). The number of moles of Na ascorbate contained in each chamber is calculated from the liquid volume (ml) of each chamber and the molar concentration of Na ascorbate obtained from the standard curve. For example, in the room B of FIG. 7, when the molar concentration of sodium ascorbate is 15 mM and the liquid volume in the room B is 8 ml, the sodium ascorbate (absolute value) contained in the room B is 15 mM × 8
ml = 15 μmol / ml · 8 ml = 120 μmol.

[0082] (2) .as ^- movement amount of theory:. (I) a predetermined ion species flows between the quantity of electricity Q (coulombs) was flowed in the chamber exists (moved) ionic species moles N ( mol), there is a relationship of N = Q / F, where F (coulomb) is a Faraday constant. (ii). The quantity of electricity Q actually passed is the product of the current value (I) and the time (t). That is, there is a relationship of Q = It. (iii). Therefore, the number of moles N of the ionic species flowing (moved).
(Mol) can be obtained by N = Q / F = I · t / F. For example, if I = 20 mA and t = 3600 seconds, N = (20/1000) · 3600 · (1/9)
6500) = 0.00746 mol. Furthermore, assuming that the total amount of the solution on the permeation side is 20 ml, the concentration of the ionic species on the permeation side is from 0 (mol) to 0.0373 (=
0.00746 x 1000 x 1/20) (mol).

Comparative Example 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.

Comparative Example 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 “Comparative Example 1” except that an aqueous solution of NaCl 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 “Comparative Example 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.

Embodiment 1 (A). Experimental conditions: room C and D of the experimental device shown in FIG.
The experiment was performed in the same manner as in "Comparative Example 2" except that the PP-made 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 an experiment of a method of administering an ionic drug using the iontophorase of the present invention. In this experimental device, one ground electrode (2)
It is characterized in that it is configured by arranging two cation exchange membranes (23). (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.

Embodiment 2 FIG. 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 conducted in the same manner as in "Example 1" 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.

Embodiment 3 FIG. (1) In the first embodiment, the electrode solution in the chamber D (positive ground electrode chamber) shown in FIG.
% NaCl aqueous solution. in this case,
By energizing for 30 minutes, the ground electrode chamber (D chamber) of the positive electrode shows a large drop in pH, and chlorine gas and hydrogen gas are generated, and the energizing conditions after that start to deteriorate. In Example 1, 1 MA was used as an electrode solution for the chamber A (a negative electrode iontophoresis electrode chamber) shown in FIG.
When it was composed only of a 0.9% NaCl aqueous solution without adding s ^- Na ⁺ (this is a substance easily oxidized and reduced having a redox potential lower than that of water),
By applying electricity for 30 minutes, the negative electrode generates hydrogen gas,
Subsequent energization conditions begin to deteriorate.

(2) Embodiment 2
Uses a 0.9M NaCl aqueous solution in which 1M As ⁻ Na ⁺ is dissolved as an electrode solution for the chamber A (a negative electrode iontophoresis electrode chamber) and the chamber E (a positive electrode ground electrode chamber) shown in FIG. . (3) In Example 3, ferrous sulfate and ferric sulfate were used as other substances that are easily oxidized and reduced (substances having a redox potential lower than the redox potential of water). The effect of using these equimolar solutions was examined using an experimental apparatus shown in FIG.

(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 tank) and room D, 0.9
% NaCl aqueous solution was used. (4). Energizing conditions Voltage: 30 V (initial setting value), current: 10 mA (constant current).

. [0098] (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.

<Reference Example> Next, some of iontophoresis devices (X) which can be used to carry out the method of administering an ionic drug by iontophoresis of the present invention are shown below as reference examples. . In the reference drawings, for clarity of illustration, the ion exchange membranes (13, 15, 2) are used.
3, 25) are indicated by wavy lines, and some of the components (members), the combination of the components (members), or the hatching is omitted. However, configurations omitted in the drawings can be easily understood from the description of each embodiment and other attached drawings.

FIG. 11 is a view for explaining a first reference example of an iontophoresis device (X) for carrying out a method of administering an ionic drug by iontophoresis of the present invention.
It is a longitudinal cross-sectional view. The iontophoresis device (X) of the first reference example is largely divided as shown in FIG.
(i). Cylindrical iontophoresis electrode (1), (ii).
A ground electrode part (2) configured separately from the cylindrical iontophoresis electrode part (1), and (i)
ii) A constant voltage / constant current power supply (3).

In the iontophoresis device (X) shown in FIG. 11, the ground electrode section (2) is configured separately from the iontophoresis electrode section (1). The meaning of “configured separately” means that the iontophoresis electrode section (11)
The ground electrode portion (2) is a non-integral type. For example, the ground electrode portion (2) is held by an iontophoresis treatment person and grounded.

Further, the iontophoresis device (X) of the first reference example shown in FIG.
It is configured on the assumption that Na ascorbate (As ⁻ Na ⁺ ) is administered by iontophoresis as 4). For this reason, in the iontophoresis device (X) shown in FIG. 11, the reference numerals of the respective components 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 ⁺ ), (v). The ion exchange membrane of the iontophoresis electrode part (1) shown by (15) is an anion exchange membrane, (v)
i). 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). , And (viii).
The ion exchange membrane of the ground electrode portion (2) shown by (23) indicates a cation exchange membrane.

As shown in FIG. 11, in the iontophoresis apparatus (X) of the first reference example, the iontophoresis electrode section (1) is roughly divided into (i). (A) and (ii) a non-conductive and cylindrical inner cylinder (b), which is referred to above under these elements (a, b). Code (11 to 15)
Are held or housed. The elements (a, b) may be made of, for example, non-conductive plastic.

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. As shown in FIG. 11, the outer cylindrical body (a) and the inner cylindrical body (b) are screwed together by screwing via a screw portion formed on the contact surface between them. belongs to. However, the outer cylinder (a) and the inner cylinder (b) may be integrated by other methods, for example, an engagement type, a locking type, an insertion type, and the like. It may be.

As shown in the figure, the cylindrical outer cylinder (a) is provided with (i) a cation exchange membrane for fixing the cation exchange membrane (13) in cooperation with the inner cylinder (b). Membrane (13) support (a1), (ii). Ionic drug (14) storage section (a2) for storing ionic drug (14), (ii)
i). support (a3) for anion exchange membrane (15) for fixing anion exchange membrane (15), (iv) pressing for anion exchange membrane (15) for fixing anion exchange membrane (15). A ring (a31), (v) a fixing pin (a32) for fixing the anion exchange membrane (15).

The iontophoresis device (X) includes the cation exchange membrane (13), the ionic drug (14), and the anion exchange membrane (15) in order to improve the operability and convenience. There is a significant feature in that at least one component is configured using an outer cylinder (a) previously arranged or housed in the outer cylinder (a).
In the iontophoresis device (X), morphine hydrochloride or the like charged positively (+) is used as the ionic drug instead of the sodium ascorbate in which the active ingredient of the ionic drug is negatively (-) charged. If
It goes without saying that the arrangement order of the ion exchange membranes and the polarity of the electrode plates must be changed in reverse.

In the iontophoresis device (X), the outer cylinder (a) of the constituent elements (13, 14, 15)
Various modifications can be made to the integration into the device. For example,
The anion exchange membrane (15) is provided on the pressing ring (a31).
Needless to say, instead of being fixed to the supporting portion (a3) by the fixing pin (a32), the fixing portion may be directly adhered or fused to the supporting portion (a). . Further, the cation exchange membrane (13) has a support (a
Instead of the method of fixing and integrating in 1), it may be mounted on the support portion (a1) and fixed in cooperation with the inner cylinder (b).

On the other hand, the cylindrical inner cylinder (b) cooperates with the support (a1) for the cation exchange membrane (13) of the outer cylinder (a) as shown in the figure. Pressing part (b1) for cation exchange membrane (13) to support fixation of cation exchange membrane (13), (ii). Housing for conductive medium (12) for housing conductive medium (12) (B2), (iii) a support portion (b) for the electrode plate (11) for supporting the electrode plate (11).
3), (iv) a guide hole (b4) for a lead wire (31) for guiding a lead wire (31) from a power supply unit (3), and (v) a lead wire (31) for supporting the lead wire (31). ) Support (b
5), (vi) a top disk portion (b6).

As shown in FIG. 11, the iontophoresis electrode section (1) composed of the outer cylinder (a) and the inner cylinder (b) having the above-described structure is composed of a (-) electrode plate (11), A conductive medium (12) containing a substance easily oxidized and reduced impregnated in gauze or a water-absorbing polymer material, a cation exchange membrane (13), an ionic drug (As ⁻ Na ⁺ ) (1)
4) and the anion exchange membrane (15) can be reliably held or accommodated therein. In the configuration of the outer cylinder (a) and the inner cylinder (b), when both are screwed together, the inner cylinder (b) is displaced relatively to the outer cylinder (a). Thereby, the anion exchange membrane (15) can be brought into close contact with the skin (4), and the iontophoresis effect can be improved.

Next, the ground electrode portion (2) of the iontophoresis device (X) of the first reference example shown in FIG.
Will be described. As shown in FIG. 11, the ground electrode portion (2) of the iontophoresis device (X) of the first reference example is roughly divided into (i). o) and (ii) a non-conductive and cylindrical inner cylinder (p), and the above-mentioned reference numerals (21 to 21) are given under these elements (o, p). 23)
Are held or housed.

The configuration of the outer cylinder (o) and the inner cylinder (p) of the ground electrode section (2) shown in FIG. 11 can be easily understood from the configuration of the iontophoresis electrode section (1). it can. That is, on the side of the ground electrode portion (2),
The cation exchange membrane (13) and the ionic drug (14) on the side of the iontophoresis electrode section (1) are not used, and in view of this point, the configuration of the ground electrode section (2) is as shown in FIG. It can be easily understood from the configuration of the outer cylinder (a) and the inner cylinder (b) of the iontophoresis electrode section (1) shown in FIG. For this reason, the description of the specific configuration of the outer cylinder (o) and the inner cylinder (p) of the ground electrode portion (2) is omitted. In addition, the outer cylinder (o) of the ground electrode portion (2) may be configured by integrating a cation exchange membrane (23) in advance in order to improve operability and convenience. Things.

In FIG. 11, the inner cylinder (p) of the ground electrode section (2) is connected to a lead wire (32) from the power supply section (3).
Is different from the configuration of the inner cylindrical body (b) of the iontophoresis electrode section (1) in that it is integrally embedded. Needless to say, the inner cylinder (p) of the ground electrode section (2) is configured in the same manner as the inner cylinder (b) of the iontophoresis electrode section (1). Operability, the lead wire (32) and the electrode plate (21) may be similarly held or housed.

In FIG. 11, the element (5) disposed on the front surface of the anion exchange membrane (15) of the iontophoresis electrode section (1) and the cation exchange membrane (23) of the ground electrode section (2) comprises: A medium impregnated with a conductive liquid such as physiological saline for improving conductivity between the ion exchange membranes (15, 23) and the skin (4), for example, gauze is shown. The iontophoresis device (X) of the first reference example
Needless to say, in the iontophoresis device (X) of another reference example shown below, the element (5) may be omitted. In this case, since the anion exchange membrane (15) and the skin (4) are in direct contact with each other, it goes without saying that the transport number of ions (the transport number of charged ions of the ionic drug) is improved.

In the iontophoresis device (X) of the first reference example shown in FIG. 11, although not shown for clarity of illustration, the iontophoresis electrode unit (1) and / or the ground electrode unit (2) are connected to the iontophoresis electrode unit (1) and / or the ground electrode unit (2). On the other hand, the conductive medium (12, 2
2) supply and discharge paths for the ionic drug (14), vent holes for gas generated from each electrode plate (11, 12), or an accommodating section for an adsorbent for adsorbing the gas, etc. Needless to say, it may be arranged.

FIG. 12 is a view for explaining a second reference example of the iontophoresis device (X) for carrying out the method for administering an ionic drug by iontophoresis of the present invention.
FIG. 12 corresponds to FIG. 11. The iontophoresis device (X) of the second embodiment can be said to be a modification of the first embodiment shown in FIG.

The iontophoresis device (X) of the second reference example shown in FIG. 12 is different from that of the first reference example shown in FIG. 11 only in the following configuration.
Other configurations are substantially the same. (i) The iontophoresis electrode part (1) is divided into two parts, the inner cylinder (b) of the iontophoresis electrode part (1) of the first reference example, and the inner cylinder (b) and the intermediate cylinder. (C). The components (a, b,
The specific configuration of c) is clear from FIG. (ii) The ground electrode portion (2) is replaced with a member (o) having a lid function by eliminating the outer cylindrical body (o) and the inner cylindrical body (p) of the ground electrode portion (2) of the first reference example. ) And a box-type component (q) composed of a member (p) having the function of a box body. The specific configuration of the component (q) in the second reference example is clear from FIG.

In the second reference example, the box-type component (q) was previously prepared as a cation exchange membrane (23).
The member (o) having the function of the lid and the member (p) of the box body are integrated with each other. The planar shape of the component (q) may be a desired one such as a rectangle or a circle.

As a modification of the second embodiment shown in FIG. 12, a configuration in which the cation exchange membrane (13) is held by the intermediate cylinder (c) instead of being held by the outer cylinder (a). The good thing is, of course. In this case, the support portion (a1) for the cation conversion membrane (13) of the outer cylinder (a) is removed, and for example, an intermediate cylinder (c) having a protruding portion inside the lower portion thereof is used, What is necessary is just to hold | maintain the cation exchange membrane (13) by the protrusion part of the said intermediate cylinder (c).

FIG. 13 is a view for explaining a third embodiment of the iontophoresis device (X) for carrying out the method for administering an ionic drug by iontophoresis according to the present invention, and corresponds to FIG. FIG. However, the ground electrode section (2) is omitted. The iontophoresis device (X) of the third embodiment can be said to be a modification of the second embodiment shown in FIG.

The iontophoresis device (X) of the third embodiment shown in FIG. 13 is different from that of the second embodiment shown in FIG. 12 only in the following configuration.
Other configurations are substantially the same. (i) The form of the conductive medium (12) and the ionic drug (14) is a solution type, while the other first and second reference examples use a medium impregnated with a desired medium. Can be accommodated by the components (a, b, c). (ii) The cation exchange membrane (13) was integrally held at the projection formed at the lower part of the intermediate cylinder (c).

FIG. 14 is a view for explaining a fourth reference example of the iontophoresis device (X) for carrying out the method for administering an ionic drug by iontophoresis of the present invention.
It is a longitudinal cross-sectional view. The iontophoresis device (X) of the fourth reference example is roughly divided as shown in FIG.
(i). Cylindrical iontophoresis electrode (1), (ii).
A ground electrode part (2) integrally formed on the periphery of the cylindrical iontophoresis electrode part (1);
ii) Constant voltage / constant current power supply (3).

The iontophoresis device of this type comprises an iontophoresis electrode (1) and a land electrode (2).
Are separate from each other, and during administration of the ionic drug, the user is forced to hold the ground electrode portion (2) by hand in order to ground (ground). However, in the iontophoresis device (X) of the fourth reference example, since the elements of the iontophoresis electrode unit (1) and the ground electrode unit (2) are integrated as described above, operability and convenience are improved. Are better. In addition, since both elements (1, 2) are integrated, the dose and administration of the ionic drug can be established by setting the interval between the two elements (1, 2) as desired or by integrating a plurality of sets of both elements. Can be adjusted.

In the iontophoresis device (X) for carrying out the method of administering an ionic drug by iontophoresis of the present invention, the main reason why both elements (1, 2) can be integrated is that the ground electrode (2) This is because the biosafety of ()) is much better than before. For this reason, the ground electrode part (2) integrated with the iontophoresis electrode part (1) may be in contact with a part of the skin that is more susceptible to fever, inflammation, irritation, etc. than the skin of the hand. However, there is no problem, and the ionic drug can be safely and efficiently administered by ions.

As described above, in the iontophoresis device (X) of the fourth reference example, the ground electrode portion (2)
As shown in FIG. 14, it is integrated with (integral with) the iontophoresis electrode section (1). The meaning of “integrated (integrally configured)” means that it is integrated with a part of the constituent members of the iontophoresis electrode unit (1) as shown in the figure. The integration is not limited to the embodiment shown in FIG. 14, and the integration should be interpreted in the broadest sense.

As shown in FIG. 14, in the iontophoresis device (X) of the fourth reference example, the elements of the iontophoresis electrode section (1) and the ground electrode section (2) are integrally formed. However, for convenience of explanation, the description will be made by dividing each element.

In the iontophoresis device (X) of the fourth reference example, the iontophoresis electrode section (1) comprises:
As shown in FIG. 14, there are broadly divided into (i) a non-conductive cylindrical outer cylinder (a) and (ii) non-conductive cylindrical inner cylinder (b). , And the elements indicated by the aforementioned reference numerals (11 to 15) are held or accommodated under these elements (a, b). The ground electrode part (2) is integrated with the outer peripheral edge of the insulating cylindrical body (a) so that both elements (1, 2) are substantially flush with the skin (4) surface. It is composed by being connected to.

The iontophoresis electrode section (1) shown in FIG. 14 has a circular plan view as shown in FIG. 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. As shown in FIG. 14, the outer cylindrical body (a) and the inner cylindrical body (b) are screwed together by screwing via a screw portion formed on the contact surface between the two. belongs to. However, the outer cylinder (a) and the inner cylinder (b) may be combined in another manner, for example, an engagement type, a locking type, an insertion type, or the like. Things.

In the cylindrical outer cylinder (a), the parts constituting the iontophoresis electrode (1) are, as shown, (i) cooperating with the inner cylinder (b). Cation exchange membrane (1) for fixing the cation exchange membrane (13)
3) Support portion (a1), (ii). Ion drug (14) storage portion (a) for storing the ionic drug (14)
2), (iii) a support (a3) for anion exchange membrane (15) for fixing anion exchange membrane (15), (iv) anion exchange membrane for fixing anion exchange membrane (15) ( 15) A pressure ring (a31), and (v) a fixing pin (a32) for fixing the anion exchange membrane (15).

The structure of the portion of the outer cylinder (a) is exactly the same as that of the first reference example shown in FIG. 11 in which the iontophoresis electrode section (1) and the ground electrode section (2) are not integrated. It is. Then, at the portion of the outer cylinder (a), the components (13, 14, 15) are integrally fixed to the outer cylinder (a) in advance similarly to the first reference example.

On the other hand, the cylindrical inner cylinder (b) cooperates with the support (a1) for the cation exchange membrane (13) of the outer cylinder (a) as shown in the figure. Pressing part (b1) for cation exchange membrane (13) to support fixation of cation exchange membrane (13), (ii). Housing for conductive medium (12) for housing conductive medium (12) (B2), (iii) a support portion (b) for the electrode plate (11) for supporting the electrode plate (11).
3), (iv) a guide hole (b4) for a lead wire (31) for guiding a lead wire (31) from a power supply unit (3), and (v) a lead wire (31) for supporting the lead wire (31). ) Support (b
5), (vi) a top disk portion (b6).

The structure of the portion of the inner cylinder (b) is exactly the same as that of the first embodiment shown in FIG. 11 in which the iontophoresis electrode (1) and the ground electrode (2) are not integrated. It is.

A cylindrical body (a) having the structure shown in FIG.
In the iontophoresis electrode portion (1) composed of the inner cylindrical body (b), a negative electrode plate (11), a conductive material containing a substance which is easily impregnated with gauze or a water-absorbing polymer material and is easily oxidized and reduced. The ionic medium (12), the cation exchange membrane (13), the ionic drug (As ⁻ Na ⁺ ) (14), and the anion exchange membrane (15) can be securely held or accommodated therein. Further, the outer cylinder (a)
In the configuration of the inner cylinder (b) and the inner cylinder (b), when both are screwed together, the inner cylinder (b) is relatively displaced with respect to the outer cylinder (a), so that the skin (4) is displaced. Thus, the anion conversion membrane (15) can be brought into close contact, and the iontophoresis effect can be improved.

Next, in the iontophoresis device (X) of the fourth reference example shown in FIG. 14, the ground electrode portion (2) integrally connected to the iontophoresis electrode portion (1) is formed. The configuration will be described. The two elements (1,
The integration of 2) may be performed, for example, by integral molding of a non-conductive plastic material.

As shown in FIG. 14, in the cylindrical outer cylinder (a), the parts constituting the ground electrode part (2) are roughly divided into (i). Ground electrode part (2). Plate (21) for accommodating the conductive plate (21) and the conductive medium (22) and the accommodating portion (a4) for the conductive medium (22), (ii). Cation exchange membrane (23) for fixing cation exchange membrane (23)
(Iii) a cation exchange membrane (23) pressing ring (a51, a52) for fixing the cation exchange membrane (23) on the side of the ground electrode section (2);
v). Cation exchange membrane (23) on the ground electrode (2) side
And a fixing pin (a53) for fixing the same.
1) to 23) are held or accommodated.

In FIG. 14, the ground electrode (2)
Is formed by integrally burying a lead wire (32) from a power supply section (3). However, in the ground electrode section (2), the arrangement of the lead wires (32) is as follows.
The lead wire may be supported by a support (b5) like the inner cylinder (b) of the iontophoresis electrode section (1).

In FIG. 14, the element (5) disposed on the front surface of the anion exchange membrane (15) of the iontophoresis electrode section (1) and the cation exchange membrane (23) of the ground electrode section (2) comprises: A medium, such as gauze, impregnated with a conductive liquid such as physiological saline for improving conductivity between the ion exchange membranes (15, 23) and the skin (4) is shown. It goes without saying that the element (5) may be omitted. In this case, the anion exchange membrane (1
Since 5) and the skin (4) are in contact, the ion transport number (transport number of charged ions of the ionic drug) is improved.

In the iontophoresis device (X) of the fourth reference example shown in FIG. 14, the iontophoresis electrode unit (1) and / or the ground electrode unit (2) are not shown for clarity. On the other hand, the conductive medium (12, 2)
2) and the supply path of the ionic drug (14), each electrode plate (1
Needless to say, a vent hole for the gas generated from (1, 12) or an accommodating portion for adsorbing the gas may be provided.

FIG. 15 is a view for explaining a fifth reference example of an iontophoresis device (X) for carrying out the method of administering an ionic drug by iontophoresis of the present invention.
FIG. 15 is a view corresponding to FIG. 14. The iontophoresis device (X) of the fifth reference example of the present invention can be said to be a modification of the iontophoresis device of the fourth reference example shown in FIG.

The iontophoresis device (X) of the fifth embodiment shown in FIG. 15 of the present invention is different from that of the fourth embodiment shown in FIG. 14 only in the following configuration. Yes, other configurations are substantially the same. (i) The iontophoresis electrode (1) is connected to the inner cylinder (b) of the iontophoresis electrode (1) of the fourth embodiment by two.
And an inner cylinder (b) and an intermediate cylinder (c). The components (a,
The specific configuration of (b, c) is clear from FIG.
The zone (m,
In (n), the (m) zone is a zone for administering an ionic drug, and the (n) zone is a zone for guiding a current flowing in the skin to a ground (earth) electrode portion. In the drawing, (mn) indicates an insulating portion (shield portion) of the negative electrode (11) and the positive electrode (21).

As a modification of the fifth embodiment shown in FIG. 15, the cation exchange membrane (13) is held by an intermediate tube (c) instead of the outer tube (a). Needless to say, it is good. In this case, the support (a1) for the cation exchange membrane (13) of the outer cylinder (a)
For example, if the intermediate cylinder (c) is provided with a projection inside the lower portion as the intermediate cylinder (c), and the projection of the intermediate cylinder (c) holds the cation exchange membrane (13), Good.

FIG. 16 is a view for explaining a sixth reference example of the iontophoresis device (X) for carrying out the method for administering an ionic drug by iontophoresis of the present invention.
FIG. 12 corresponds to FIG. 11. However, the iontophoresis electrode section (1) is omitted. The iontophoresis device (X) according to the sixth embodiment of the present invention can be said to be a modification of the first embodiment shown in FIG.

The iontophoresis device (X) of the sixth embodiment shown in FIG. 16 of the present invention is different from the iontophoresis device of the first embodiment shown in FIG. Yes, other configurations are substantially the same. (i) The configuration of the ground electrode portion (2) is changed from the configuration of the outer cylinder (o) and the inner cylinder (p) of the first reference example to FIG.
These elements (o, p) are made into a member (o) having a function of a lid and a member (p) having a function of a box body, as in the second reference example shown in FIG. (Q). (ii) In the component (q), the configuration of the member (o) corresponding to the outer cylinder (o) of the first reference example is changed by cation exchange so that the conductive medium (24) can be interposed. It was configured to hold the membrane (23) and the anion exchange membrane (25). That is, the cation conversion membrane (23) and the anion exchange membrane (25) were previously integrally fixed to the member (o), and the convenience and operability were enhanced. (iii) The conductive medium (22, 24) was composed of a physiological saline solution containing a substance that is easily oxidized and reduced. (iv). In the first reference example, the component (5) disposed on the front surface of the anion exchange membrane (15) of the iontophoresis electrode (1) and the cation exchange membrane (23) of the ground electrode (2) was removed.

FIG. 17 is a view for explaining a seventh reference example of an iontophoresis device (X) for carrying out the method for administering an ionic drug by iontophoresis of the present invention.
FIG. 15 is a view corresponding to FIG. 14. However, the iontophoresis electrode section (1) is omitted. FIG. 17 is an enlarged view of a main part of the ground electrode part (2).

The iontophoresis device (X) of the seventh embodiment shown in FIG. 17 of the present invention is different from that of the fourth embodiment shown in FIG. 14 only in the following constitution. Yes, other configurations are substantially the same. (i) In addition to the components (21, 22, 23) shown in FIG. 14, the configuration of the electrode plate (21) of the ground electrode portion (2) and the accommodating portion (a4) for the conductive medium (22) are added. Further, it is configured to be able to accommodate the conductive medium (24) and the anion exchange membrane (25). The conductive medium (24) and the anion exchange membrane (25) are arranged inside the accommodation section (a4),
It was configured to be held or housed by the illustrated members (a6, a7). The cation exchange membrane (23) and the anion exchange membrane (25) are preliminarily provided with the member (a).
6, a7) is used, and the accommodation part (a4) is used.
To be fitted to The two ion exchange membranes (23, 2)
5) conductive medium between (24) and electrode plate (21)
The surrounding conductive medium (22) may be supplied and discharged through a supply port and a discharge port (not shown). (ii). Components (5) disposed in front of the anion exchange membrane (15) (not shown) of the iontophoresis electrode (1) and the cation exchange membrane (23) of the ground electrode (2). Was removed.

The iontophoresis device (X) of the seventh reference example shown in FIG. 17 has two cation exchange membranes and two anion exchange membranes for each of the iontophoresis electrode section (1) and the ground electrode section (2). Four ion-exchange membranes are provided, each of which is the same as that of the sixth embodiment, but different from the other embodiments (total of three). The iontophoresis device (X) of the seventh reference example has excellent effects as demonstrated in an iontophoresis experiment using the experimental device shown in FIG. In the iontophoresis device (X) of the seventh reference example shown in FIG. 17, the cation exchange membrane (23) of the ground electrode part (2) is replaced with the anion exchange membrane (not shown) of the iontophoresis electrode part (1). It is needless to say that it is preferable to arrange them so as to be flush with (15).

[0146]

According to the present invention, there is provided a method of administering an ionic drug by iontophoresis which exhibits the following excellent effects. (i) The iontophoresis device applied to the method of administering an ionic drug by iontophoresis of the present invention has an iontophoresis electrode section (working side electrode section) and a ground electrode section (non-working example electrode section). Since a stable energized state (constant current and / or constant voltage) can be maintained for a long period of time, the positive (+)
Alternatively, a negatively (−) charged drug component can be efficiently transported to the skin (or mucous membrane) (drug delivery). (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) The iontophoresis device applied to the method of administering an ionic drug by iontophoresis of the present invention comprises an iontophoresis electrode section (working side electrode section) and a ground electrode section (non-working side electrode section). On the other hand, a plurality of ion exchange membranes having different ion selectivities are 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. However, since the ion exchange membrane provided in accordance with the charging characteristics of the ionic drug prepared in advance is detachably provided on each electrode part, the handleability (convenience) is improved and the efficiency is improved. An ionic drug can be administered specifically. 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. (iv) When the iontophoresis electrode section (working-side electrode section) and the ground electrode section (non-working-side electrode section) are integrated, it is necessary for the medical practitioner to take the ground (earth) as in the past. It is released and convenience is improved. In the integrated structure, when a plurality of sets of the iontophoresis electrode unit and the ground electrode unit are integrated, the degree of penetration of the ionic drug into the skin (depth from the skin surface) is adjusted as desired. be able to.

[Brief description of the drawings]

FIG. 1 is a basic configuration diagram (schematic perspective view) of a first iontophoresis device (X) used for a method of administering an ionic drug by an iontophoresis 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) used in a method for administering an ionic drug by the iontophoresis 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 a first reference example used for a method of administering an ionic drug by the iontophoresis of the present invention.

FIG. 12 is a diagram illustrating an iontophoresis device (X) according to a second reference example used for the method of administering an ionic drug using the iontophoresis of the present invention.

FIG. 13 is a diagram illustrating an iontophoresis device (X) according to a third reference example used for a method of administering an ionic drug using the iontophoresis of the present invention.

FIG. 14 is a diagram illustrating an iontophoresis device (X) according to a fourth reference example used in the method of administering an ionic drug using the iontophoresis of the present invention.

FIG. 15 is a diagram illustrating an iontophoresis device (X) according to a fifth reference example used for a method of administering an ionic drug using the iontophoresis of the present invention.

FIG. 16 is a diagram illustrating an iontophoresis device (X) according to a sixth reference example used in the method of administering an ionic drug using the iontophoresis of the present invention.

FIG. 17 is a diagram illustrating an iontophoresis device (X) according to a seventh reference example used for the method of administering an ionic drug using the iontophoresis 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 ... ………………………………………………………………………………………………………………………………………… Ion (anion) exchange membrane 2 ………………………………………………………………………………………. Conductive medium 23 ... Ion (cation) exchange membrane 3 ... Power supply unit 31, 32 ... Lead wire 4 ... Skin 5 ... Gauze impregnated with conductive liquid a ……………………………………………………………………………………………………………………………………………………………………………………………………………………. ……… Support for ion exchange membrane (15) a31 ………… ... Pressing ring for ion exchange membrane (15) a32 ... Fixing pin a4 ... Electrode plate (21) and conductive medium (2)
2) accommodation section a5 ...... support section for ion exchange membrane (23) a51, a52 ... press ring for ion exchange membrane (23) a53 ...... fixing pin a6, a7 ... ... Holding member b ... Inner cylinder body b1 on the side of the iontophoresis electrode section (1) b1 ... Pressing section for ion exchange membrane (13) b2 ... ... for conductive medium (12) Housing part b3 ... Support part for electrode plate (11) b4 ... Guide hole for lead wire (31) b5 ... Support for lead wire (31) b6 ... Top disk c c Intermediate cylinder on the iontophoresis electrode part (1) side o ...... Outer cylinder on the ground electrode part (2) side p ... Ground electrode part (2) ) Side inner cylindrical body q ........... Container (box type) of ground electrode portion (2) m1 to mX ..... Giving zone n1 to nX …………… Grand (earth) zone

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[Procedure amendment]

[Submission date] April 7, 1999 (1999.4.7)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0045

[Correction method] Change

[Correction contents]

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).

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0050

[Correction method] Change

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However, in the iontophoresis device (X) of the present invention, as described above, since the iontophoresis system uses a plurality of ion exchange membranes having different ion selectivities, at least three or more, the active electrode 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, in the present invention, since a plurality of ion exchange membranes having different ion selectivities are used, it is preferable to use a more economical inert 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.

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

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The ground electrode portion (2) of the iontophoresis device (X) shown in FIG. 3 includes an electrode material (21) having a polarity opposite to that of the electrode material (11) of the iontophoresis electrode portion (1). A conductive medium (22) disposed at least on the front surface of the electrode material (21), and the conductive medium (2);
It comprises an ion exchange membrane (23) disposed on the front surface of (2), that is, on the side of the skin (4) and selecting ions opposite to the charged ions of the ionic drug.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

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In the iontophoresis device (X), the outer cylinder (a) of the constituent elements (13, 14, 15)
Various modifications can be made to the integration into the device. For example,
The anion exchange membrane (15) is provided on the pressing ring (a31).
Needless to say, instead of being fixed to the support part (a3) by the fixing pin (a32), the support part (a3) may be directly adhered or fused and fixed. . Further, the cation exchange membrane (13) is fixed to the support portion (a1) instead of being fixedly integrated with the support portion (a1).
1) It may be placed on top and fixed in cooperation with the inner cylinder (b). ) And the anion exchange membrane (15) can be securely held or accommodated therein. In the configuration of the outer cylinder (a) and the inner cylinder (b),
When both are screwed together, the inner cylinder (b) is relatively displaced with respect to the outer cylinder (a) so that the skin (4)
The anion exchange membrane (15) can be brought into close contact with this, and the iontophoresis effect can be improved.

[Procedure amendment 5]

[Document name to be amended] Drawing

[Correction target item name] Fig. 9

[Correction method] Change

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FIG. 9

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Takehiko Matsumura 22-2 Kitaminemachi, Ota-ku, Tokyo (72) Inventor Yoriko Kobayashi 2-38-7 Motomiya, Otsu-shi, Shiga F-term (reference) 4C053 HH02 HH04

Claims (9)

[Claims] In a method of administering an ionic drug by iontophoresis, the ionic drug is provided with an iontophoresis electrode section (working-side electrode section) and a ground electrode section (non-working-side electrode section). A method for administering an ionic drug by iontophoresis, wherein the ionic drug is supplied to a portion of the iontophoresis electrode section of the laser apparatus where the ionic drug is disposed. (1) The iontophoresis electrode section, (1) -1.Electrode material connected to a power supply of the same polarity as the charged ions of the ionic drug, (1) -2.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. The ionic drug An ionic drug disposed on the front of the ion exchange membrane to select an ion opposite to the charged ion of, and (1) -5. Of the same type as the charged ion of the ionic drug disposed on the front of the ionic drug. An ion exchange membrane for selecting ions, and, (2) the ground electrode portion, (2) -1. An electrode material of the opposite polarity to the electrode material of the iontophoresis electrode portion, (2) -2.A conductive medium disposed at least on the front surface of the electrode material, and (2) -3. Location ionic drug charged ions opposite to the ion exchange membrane selecting ions,
(3) In the iontophoresis electrode portion and the ground electrode portion, at least the iontophoresis electrode portion is detachably mounted with another component to an electrode material element. Iontophoresis device configured as described above. 2. The method according to claim 1, wherein the ground electrode section is provided with the above-mentioned “(2) -2. Conductive medium disposed on the front surface of the electrode material” and “(2) -3. Ion disposed on the front surface of the conductive medium”. An ion exchange membrane for selecting an ion opposite to the ion exchange membrane between the ion exchange membrane for selecting an ion opposite to the charged ion of the active agent. How to administer ionic drugs. 3. The iontophoresis electrode section and the ground electrode section are configured such that other components are detachably attached to the respective electrode material elements. Of ionic drugs by iontophoresis. 4. An iontophoretic electrode section comprising: (2) -3. An ion exchange membrane for selecting ions opposite to charged ions of an ionic drug disposed on the front surface of the conductive medium; Claims: (1) -5. An ion exchange membrane for selecting ions of the same kind as the charged ions of the ionic drug disposed on the front surface of the ionic drug. Item 3. The method for administering an ionic drug by iontophoresis according to Item 1 or 2. 5. The method for administering an ionic drug by iontophoresis according to claim 1, wherein the ground electrode section is formed non-integrally with the iontophoresis electrode section. 6. The method for administering an ionic drug by iontophoresis according to claim 1, wherein the ground electrode portion is adjacent to and integrally formed with the iontophoresis electrode portion. 7. The ionicity of the iontophoresis according to claim 1 or 2, 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. How to administer the drug. 8. The method according to claim 7, wherein the conductive medium is composed of a solution containing ferrous sulfate and ferric sulfate as substances easily oxidized or reduced. Administration method. 9. The method for administering an ionic drug by iontophoresis 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 easily oxidized or reduced. .