Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
1999-06-16
2001-09-11
Bockelman, Mark (Department: 3762)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
Reexamination Certificate
active
06289242
ABSTRACT:
TECHNICAL FIELD
This invention generally concerns apparatuses for the electrically assisted delivery of therapeutic agent through a body surface such as skin or a mucosal membrane. Such apparatuses are referred to broadly herein as electrotransport devices.
More specifically, this invention relates to electrotransport drug delivery devices or systems in which active species, agents or drugs are directly or indirectly delivered through a body surface (eg, skin) of a patient by application of electromotive force.
BACKGROUND OF THE INVENTION
The present invention concerns apparatuses for transdermal delivery or transport of therapeutic agents, typically through iontophoresis. Herein the terms “electrotransport”, “iontophoresis”, and “iontophoretic” are used to refer to methods and apparatus for transdermal delivery of therapeutic agents, whether charged or uncharged, by means of an applied electromotive force to an agent-containing reservoir. The particular therapeutic agent to be delivered may be completely charged (ie, 100% ionized), completely uncharged, or partly charged and partly uncharged. The therapeutic agent or species may be delivered by electromigration, electroosmosis or a combination of the two. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically-induced osmosis. In general, electroosmosis of a therapeutic species into a tissue results-from the migration of solvent, in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir, ie, solvent flow induced by electromigration of other ionic species. Thus, as used herein, the terms “iontophoresis” and “iontophoretic” refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
During the electrotransport process certain modifications or alterations of the skin may occur such as increased ionic content, hydration, dielectric breakdown, extraction of endogenous substances and electroporation. Any electrically assisted transport of species enhanced by modifications or alterations to a body surface (eg, formation of pores in the skin) are also included in the term electrotransport as used herein.
Iontophoretic devices for delivering ionized drugs through the skin have been known since the 1800's. Deutsch United Kingdom Patent No. 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices, namely, that the patient needed to be immobilized near a source of electric current. The Deutsch device was powered by a galvanic cell formed from the electrodes and the material containing the drug to be transdermally delivered. The galvanic cell produced the current necessary for iontophoretically delivering the drug. This device allowed the patient to move around during iontophoretic drug delivery and thus required substantially less interference with the patient's daily activities.
In present iontophoresis devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, agent, medicament, drug precursor or drug is delivered into the body via the skin by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, eg, a battery; and usually to circuitry capable of controlling current passing through the device. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Furthermore, existing iontophoresis devices generally require a reservoir or source of the beneficial agent or drug, preferably an ionized or ionizable species (or a precursor of such species) which is to be iontophoretically delivered or introduced into the body. Such drug reservoirs are connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired species or agents.
Perhaps the most common use of iontophoresis today is in diagnosing cystic fibrosis by delivering pilocarpine transdermally. lontophoretically delivered pilocarpine stimulates sweat production, the sweat is collected, and is analyzed for its chloride ion content. Chloride ion concentration in excess of certain limits suggests the possible presence of the disease.
Thus an electrotransport device or system, with its donor and counter electrodes, may be thought of as an electrochemical cell having two electrodes, each electrode having an associated half cell reaction, between which electrical current flows. Electrical current flowing though the electronically conductive (eg, metal) portions of the circuit is carried by electrons (electronic conduction), while current flowing through the liquid-containing portions of the device (ie, the drug reservoir in the donor electrode, the electrolyte reservoir in the counter electrode, and the patient's body) is carried by ions (ionic conduction). Current is transferred from the metal portions to the liquid phase by means of oxidation and reduction charge transfer reactions which typically occur at the interface between the metal portion (eg, a metal electrode) and the liquid phase (eg, the drug solution). A detailed description of the electrochemical oxidation and reduction charge transfer reactions of the type involved in electrically assisted drug transport can be found in electrochemistry texts such as J. S. Newman,
Electrochemical Systems
(Prentice Hall, 1973) and A. J. Bard and L. R. Faulkner,
Electrochemical Methods, Fundamentals and Applications
(John Wiley & Sons, 1980).
As electrical current flows, oxidation and reduction of a chemical species takes place. A variety of electrochemical reactions can be utilized, and these generally fall into two major classes. In one major class, the electrochemical reaction results in the generation of a mobile ionic species with a charge state (ie, + or −) like that of the drug in its ionic form. Such a mobile ionic species is referred to as a “competitive species” or a “competitive ion” because the species competes with the drug for delivery by electrotransport. Exemplifying this class of reactions is what is referred to in the art as a “sacrificial” reaction where electrode material is consumed in the reaction with generation of a competitive ion. A further example of this first major class of electrochemical reactions is a de-intercalation reaction where a competitive ion is expelled from the electrode. A third example of this first major class of electrodes is the common situation where a competitive ion is generated by oxidation or reduction of a substance in contact with the electrode. Reactions falling in the first major class may be either anodic or cathodic.
Examples of anodic reactions where a competitive cation is generated include:
M
0
→M
Z+
+Ze
−
(1)
where M
0
is a metal which is oxidized to the +Z state and M
Z+
is the competitive ion;
M
x
WO
3
→M
x-1
WO
3
+M
+
+e
−
(2)
where M
+
is the competitive ion, and
H
2
Q→Q
0
+2H
+
+2e
−
&em
Gyory J. Richard
Moodie Lyn C.
Phipps J. Bradley
Theeuwes Felix
ALZA Corporation
Bates Owen J.
Bockelman Mark
Stone Steven F.
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