Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
2000-06-28
2003-07-01
Denion, Thomas (Department: 3748)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C604S304000, C604S306000, C604S307000, C424S449000
Reexamination Certificate
active
06587717
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an iontophoresis device suitable for percutaneous and mucosal applications of drugs and in particular to iontophoresis device of the type, which is activated before practically using as well as a method of assembling the same.
BACKGROUND ART
Recently, there have been developed a variety of dosage forms in the field of pharmaceutical preparations for external use (external pharmaceutical preparations) and the development has gradually become a matter of great concern. The reason for this is as follows: The administration of a drug, which may have a local or systemic pharmacological action, through the skin or the mucous membranes has many advantages. For instance, the sustained-release effect of the drug can be expected; such administration is not greatly influenced by the metabolism due to the first-pass effect in the liver unlike the oral administration and permits the effective use of the drug; and drugs accompanied by, for instance, liver disorders can relatively safely be administered.
However, the normal skin naturally has a protective effect against external stimulations and this makes the absorption and penetration of a drug through the skin relatively difficult. For this reason, in the existing circumstances, a drug is not absorbed in an amount sufficient for ensuring a sufficient effect even if the drug is administered in a dosage form for external use. Moreover, in the administration method, which makes use of absorption routes through biological membrane other than the skin, such as mouth, rectum, oral cavity and nose as well as the sublingual route, it is difficult to penetrate into or transmit through the related biological membrane depending on the kind of drugs and therefore, there have been known a large number of drugs having low bioavailability. Accordingly, there has been desired for the development of an absorption-promoting method, which can sufficiently enhance the permeability, penetrability and absorbency of a drug against the skin and other biological membranes, can ensure a sufficient pharmacological efficacy of the drug and is substantially free of, for instance, its local and systemic toxicity and is highly useful and safe.
As such absorption-promoting methods, there have recently been known, chemically promoting methods, which make use of absorption-promoting agents, and physically promoting methods in which iontophoresis or phonophoresis is employed. Among them, the iontophoresis has unexpectedly attracted special interest recently and has been expected as an administration method, which can solve the foregoing problems.
The iontophoresis is a method for the administration of a drug by applying a voltage to the skin or a mucous membrane to electrically induce the migration of an ionic drug and to thus administrate the drug through the skin or a mucous membrane. In general, an iontophoresis device is provided with a pair of electrodes for iontophoresis, i.e., an anode and a cathode and the device is so designed that these electrodes are arranged on or attached to the skin at a predetermined distance apart from one another and an electric current generated by a current generator is guided to these electrodes to thus carry out treatments.
Moreover, this iontophoresis device has a structure comprising a combination of these electrodes and a layer, which stores a drug therein, and a variety of additives for maintaining the drug efficacy are optionally enclosed in the layer in addition to a predetermined amount of the effective component in order to keep a desired blood concentration in the body over a long period of time.
The iontophoresis device of this type is, for instance, disclosed in Japanese Un-Examined Patent Publication Nos. Sho 62-268569, Hei2-131779, Hei3-268769 and Hei3-45271 and TOKUHYO Nos. Hei 3-504343 and Hei 3-504813.
However, if a drug (such as physiologically active peptides), which suffers from a problem of the solubility in water, ,is used in these iontophoresis device, the predetermined amount of the drug may be reduced due to the partial decomposition thereof with time. Moreover, if the drug is administered in a high concentration, the drug may be diluted during storing.
If a peptide drug is percutaneously administered by the iontophoresis, it is common that the drug is not maintained in an iso-electric environment, but is kept in an acidic or basic environment. For this reason, the stability of additives, which are incorporated into the device to assist the development of the pharmacological efficacy of the biologically active substance, is greatly influenced by such acidic or basic environment and accordingly, the drug efficacy may be reduced.
Moreover, it has been recognized that when physiologically active peptides are stored in the form of solutions, members constituting the pharmaceutical preparation may be adsorbed on the peripheral site and it is thus quite difficult to maintain a desired concentration of the drug over a long period of time.
As other problems, it has been reported that in a device, which is designed in such a manner that an electrically conductive layer containing a drug in the form of a solution is directly in contact with the electrodes immediately after the electrical charging, the drug is electrolytically decomposed on the electrode surface during electrically charging the device. Accordingly, it would be doubtful whether the decomposed drug through its internal absorption adversely affects the human body.
There have been proposed a variety of methods for the solution of such a problem. For instance, Japanese Un-Examined Patents Publication No. Sho 63-102768 and U.S. Pat. No. 5,310,404 disclose a method, which comprises the steps of arranging a capsule or porch enclosing water or an electrolyte solution above the electrode structure and breaking the capsule or porch immediately before the practical use to thus impregnate the drug-support layer therewith. This method is excellent in that the drug can be stored in a stable condition (dry state), but it is still insufficient since it takes a long time for uniformly permeating the moisture into the whole drug-support layer and the drug efficacy may be reduced due to the dilution of the drug.
In addition, Japanese Patent No. 2,542,792 discloses a method in which a drug-support layer and an electrode layer containing an electrolyte are separately disposed in distinct compartments, which are hinged to one another and then piling one upon another at the hinged portion to thus activate the device. This method permits the improvement in the long-term stability of a drug, but any means for activating the device upon application is not sufficiently devised and therefore, the method may include a lot of causes for artificial errors and cannot achieve sufficiently uniform distribution of the drug after the activation of the device.
Moreover, Japanese Un-Examined Patent Publication No. Hei 3-94771 discloses a device, which is so designed that a selective ion-permeable membrane (such as an ion-exchange membrane) is arranged such that the membrane is adjacent to the skin side of a water-support portion thereof, while a drug is dried and adhered to the side of the selective ion-permeable membrane, which is in contact with the living body, to thus prevent any dilution of the drug and to realize the administration of a trace a mount of the drug to a local site in a high concentration.
Japanese Un-Examined Patent Publication No. Hei 9-201420 discloses a device for iontophoresis, in which an electrode structure layer, a solvent-support layer and a drug-support layer containing a dried physiologically active substance are put in a layer structure in this order and a water-impermeable separator layer is positioned between the solvent-support layer and the drug-support layer. This device is so designed that the solvent-support layer is automatically brought into contact with the drug-support layer by pulling out the separator layer upon activation. This device is quite excellent in that the occurrence of any artificial error i
Higo Naruhito
Koga Nobuhiro
Kuribayashi Mitsuru
Maeda Hiroyuki
Denion Thomas
Hisamitsu Pharmaceutical Co., INC
Townsend & Banta
Trieu Theresa
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