Iontophoresis device

Details Iontophoresis device Iontophoresis device

2001-10-12

2003-07-22

Hayes, Michael J. (Department: 3763)

Surgery

Means for introducing or removing material from body for...

Infrared, visible light, ultraviolet, x-ray or electrical...

C604S890100

Reexamination Certificate

active

06597947

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a polarity-inverting type iontophoresis device capable of controlling transdermal or transmucosal drug administration for a long time. In particular, the present invention relates to an iontophoresis device which can effectively maintain safe and stable absorptivity for a long time utilizing electric driving force and which can be produced with a low cost.
BACKGROUND ART
Iontophoresis is a transdermal-absorption promotion system using electricity as external stimulation. It is based on a mechanism that across an electric field generated between an anode and a cathode mainly by energization, molecules with a positive charge move from the anode to the cathode while those with a negative charge move from the cathode to the anode, to generate force, which promotes penetration of a drug molecule through the skin barrier (See, Journal of Controlled Release, Vol. 18, 1992, pp. 213-220; Advanced Drug Delivery Review, Vol. 9, 1992, p.119; Pharmaceutical Research Vol. 3, 1986, pp. 318-326).
Iontophoresis generally involves a power supply, a drug reservoir electrode and an electrolyte reservoir electrode. An electrode which may be used in this system may be an active electrode such as a silver or silver chloride electrode or an inactive electrode such as a platinum or titanium electrode. In case of an inactive electrode, hydrogen ions and oxygen gas are generated on an anode side and hydroxyl ions or hydrogen gas are generated during energization on a cathode side. It is well known that hydrogen ions and hydroxyl ions generated by the inactive electrode may induce skin irritation or reduce of a drug delivery rate.
Anode side: 2H
2
O→4H
+
+O
2
+4e
−
Cathode side: 2H
2
O+2e
−
→20H
−
+H
2
On the other hand, in an active electrode, a redox reaction occurs at a lower voltage than that in electrolysis of water. Typical electrode materials include silver and silver chloride. Generally, an anode is made of a silver electrode and an electrolyte reservoir contains a counter material, e.g., chloride ions, required for a redox reaction with the electrode. Thus, metal ions (e.g., silver ions) eluted from the anode electrode react with chloride ions in the reservoir to form an insoluble precipitate (e.g., silver chloride). It can substantially inhibit transfer of the metal ions to the skin so that an active electrode is safer to the skin than an inactive electrode.
Anode
⁢
 
⁢
side
⁢
:
Ag
→
Ag
+
+
e
-
 
Ag
+
+
Cl
-
→
AgCl
Cathode
⁢
 
⁢
side
:
AgCl
+
e
-
→
Ag
+
Cl
-
Use of an active electrode has, however, encountered problems of competition between a cationic drug and counter ion species to chloride ions in an anode side and reduction in absorptivity due to competition between an anionic drug and chloride ions eluted from the electrode in a cathode side. An active electrode itself may be oxidized or reduced. It is, therefore, difficult to maintain performance as an active electrode for a long-term use.
Thus, devices and methods have been recently developed for solving the problem of competitive ions in the above electrode. In particular, there has been improvement in terms of competitive ions eluted from an electrode, which represents a problem in use of an active electrode. As a method for inhibiting such metal-ion transfer in an active electrode, National Publication of the International Patent Application Nos. 3-504813 and 3-504343 have disclosed a device where a material causing an electrode reaction at a lower voltage than that in hydrolysis of water is used as a current distributing member and a charge-selecting material layer is placed between an electrode and a drug reservoir or between the body surface and an electrode. The charge-selecting material contains counter ions reacting with the electrode. National Publication of the International Patent Application No. 5-506158 has disclosed a device comprising a donor electrode, an electrolyte reservoir, a selective permeable membrane and a drug reservoir, where the electrolyte reservoir contains counter ions reacting with the electrode. In these techniques, it has been indicated that counter ions to the counter ions reacting with the electrode have the same polarity as a drug, leading to a reduction in the drug delivery rate and that a chloride bound to a polymer (e.g., quaternary ammonium chloride) may be used to avoid the problem. Such modification, however, mainly aims at effective drug delivery and there have remained problems in terms of practicability and versatility due to its complex structure. There have been disclosed no means for maintaining electrode performance for a long-term use.
Electrode materials which may be used in an active electrode such as silver and silver chloride are generally expensive. Thus, in practical production, incorporating these metal materials (for example, a silver foil) in a device is undesirable in terms of productivity and a production cost. Furthermore, there have been significant problems for developing an iontophoresis device for a long-term use, i.e., problems in terms of maintaining electrode performance for a long time such as life expiration due to electrode deterioration in an active electrode such as a silver or silver chloride electrode, i.e., insulation in an electrode due to precipitation of non-conductive silver chloride on the electrode surface caused by long-term energization in an anode side and life expiration as an active electrode due to elution of chlorine from silver chloride during energization in a cathode side.
On the other hand, there have been developed electrodes improved for long-term use. Japanese Patent Laid-Open Publication No. 9-276416has disclosed an electrode comprising a main electrode consisting of an active electrode and a regeneration electrode as an inactive electrode. Japanese Patent Laid-Open Publication No. 4-312471 has disclosed a device which can be used for a long time using a removable electrolyte reservoir in a housing comprising an inactive electrode. This publication has, however, disclosed regeneration or reuse of an electrode itself in the device using an active electrode and has not consider effects on drug absorptivity induced by competing ions generated during energization and an electrolyte added so that absorption cannot be strictly controlled.
Furthermore, there have been developed devices using a polarity inverting apparatus. For inhibiting generation of harmful hydrogen or hydroxyl ions in an inactive electrode, adjustment of pH by switching polarity is disclosed in Japanese Patent Publication No.60-34396 in which a ratio of a positive current energy amount to a negative current energy amount is within a range of about 2:1 to 7:1 and in EP 0776676 using 0.0027 Hz to 10 Hz. Japanese Patent Laid-Open Publication No. 4-224770 has disclosed that a sign of voltage applied between electrodes is inverted to adjust pH. In such a device, an inactive electrode which is not deteriorated is used and polarity is inverted during energization to inhibit pH variation for improvement in skin irritation. The technique does not improve the problem of generation of gases such as oxygen and hydrogen so that when it is used for a long period, a gas may fill the device and a special structure such as a vent hole is necessary. There has not been thus solved the problem of difficulty in producing an electrode comprising such an element.
In addition, U.S. Pat. No. 4,406,658 has disclosed that a device by which polarity of an electrode can be inverted comprises means for inverting polarity of an electrode to conduct iontophoresis in both electrodes with one application. National Publication of the International Patent Application No. 9-503136 has described that polarity may be inverted to reduce irritation during energization. In the above prior art, no device has been described, which provides safe and stable absorption for a long period, rather than a polarity inverting device for long-term drug delivery.
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