Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
1999-01-28
2001-02-27
Kennedy, Sharon (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C604S019000
Reexamination Certificate
active
06195582
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to an electrotransport device for transdermally or transmucosally delivering a beneficial agent (e.g., a drug) to, or for transdermally or transmucosally sampling a body analyte (e.g., glucose) from, a patient. Most particularly, the present invention relates to a configured electrode assembly having improved electrical performance such as lower electrical resistance at device start-up and shorter time required to reach the prescribed transdermal agent flux.
BACKGROUND ART
As used herein, “electrotransport” refers generally to the delivery of at least one agent or drug (charged, uncharged, or mixtures thereof) through a membrane (such as skin, mucous membrane, or nails) wherein the delivery is at least partially electrically induced or aided by the application of an electric potential. As used herein, the terms “drug” and “agent” are used interchangeably and are intended to include any therapeutically active substance that when delivered into a living organism produces a desired, usually beneficial, effect. For example, a beneficial therapeutic agent may be introduced into the systemic circulation of a patient by electrotransport delivery through the skin.
Electrotransport processes have been found to be useful in the transdermal administration of drugs including lidocaine, hydrocortisone, fluoride, penicillin, dexamethasone, and many other drugs. A common use of electrotransport is in diagnosing cystic fibrosis by delivering pilocarpine iontophoretically. The pilocarpine stimulates production of sweat. The sweat is then collected and analyzed for its chloride content to detect the presence of the disease. More recently, “reverse” electrotransport methods have been used to transdermally extract body analytes such as glucose in order to measure blood glucose levels. For a description of reverse iontophoresis devices and methods for analyte sampling, see Guy et al. U.S. Pat. No. 5,362,307, the disclosures of which are incorporated herein by reference.
Electrotransport devices generally employ two electrodes, each positioned in intimate contact with some portion of the patient's body (e.g., the skin). For drug delivery, an active or donor electrode delivers the therapeutic agent (e.g., a drug) into the body. The counter, or return, electrode closes an electrical circuit with the donor electrode through the patient's body. A source of electrical energy, such as a battery, supplies electric current to the body through the electrodes. For example, if the therapeutic agent to be delivered into the body is positively charged (i.e., cationic), the anode is the donor electrode and the cathode is the counter electrode completing the circuit. If the therapeutic agent to be delivered is negatively charged (i.e., anionic), the cathode is the donor electrode and the anode is the counter electrode. The rate of drug delivery is generally proportional to the applied electrotransport current. For that reason, commonly used electrotransport systems employ electric circuitry that control the electric current applied by such devices. For body analyte extraction, an active or sampling electrode extracts the body analyte from the body. The counter, or return, electrode closes the electrical circuit with the active electrode through the patient's body. If the body analyte to be extracted from the body is cationic, the cathode is the active electrode and the anode is the counter electrode completing the circuit. If the body analyte to be extracted is anionic, the anode is the active electrode and the cathode is the counter electrode. In the case of glucose extraction, glucose being an uncharged molecule, either or both of the anode and cathode can be the active electrode. Since glucose will be extracted into both electrodes at relatively the same rate by the phenomenon of electroosmosis.
A widely used electrotransport process, iontophoresis (also called electromigration), involves the electrically induced transport of charged ions. Another type of electrotransport, called electroosmosis, involves the transdermal flow of a liquid solvent, containing an (eg, uncharged or non-ionic) agent to be delivered or sampled, under the influence of the applied electric field. Still another type of electrotransport process, called electroporation, involves forming transiently existing pores in a biological membrane (e.g., the skin) by applying high voltage pulses thereto. In any given electrotransport system, more than one of these processes may occur simultaneously to some extent.
Most transdermal electrotransport devices have an anodic and a cathodic electrode assembly, each electrode assembly being comprised of an electrically conductive electrode in ion-transmitting relation with an ionically conductive liquid reservoir which in use is placed in contact with the patient's skin. Gel reservoirs such as those described in Webster U.S. Pat. No. 4,383,529 are the preferred form of reservoir since hydrated gels are easier to handle and manufacture than liquid-filled containers. Water is by far the preferred liquid solvent used in such reservoirs, in part because many drug salts are water soluble and in part because water has excellent biocompatability, making prolonged contact between the hydrogel reservoir and the skin acceptable from an irritation standpoint.
The electrodes used in transdermal electrotransport devices are generally of two types; those that are made from materials that are not electrochemically reactive and those that are made from materials that are electrochemically reactive. Electrochemically non-reactive electrodes, such as stainless steel, platinum, and carbon-based electrodes, tend to promote electrochemical oxidation or reduction of the liquid solvent at the electrode/reservoir interface. When the solvent is water, the oxidation reaction (at the anodic electrode interface) produces hydronium ions, while the reduction reaction (at the cathodic interface) produces hydroxyl ions. Thus, one serious disadvantage with the use of electrochemically non-reactive electrodes is that pH changes occur during device operation due to the water oxidation and reduction reactions which occur at the electrode/reservoir interfaces. Oxidation and reduction of water can largely be avoided by using electrochemically reactive electrodes, as discussed in Phipps et al. U.S. Pat. No. 4,747,819. Preferred electrochemically oxidizable materials for use in the anodic electrode include metals such as silver, copper and zinc. Of these, silver is most preferred, as it has better biocompatability compared to most other metals. Preferred electrochemically reducible materials for use in the cathodic electrode include metal halides. Of these, silver halides such as silver chloride are most preferred. While these electrode materials provide an elegant solution to the problem of pH drift in the electrotransport reservoirs, they have their own set of problems. For example, a silver anode is oxidized to produce silver ions (Ag→Ag
+
+e
−
). The silver cations are delivered from the anode via iontophoresis into the patient's skin, where they cause grey or black discoloration as soon as the skin is exposed to sunlight. Attempts have been made to limit the electromigration of electrochemically generated silver ions from the anodic electrode. See for example Phipps et al. U.S. Pat. No. 4,747,819 and Phipps et al. WO 96/39224 which disclose using a halide drug salt in the anodic reservoir to provide halide ions which react with the electrochemically-generated silver ions to produce substantially insoluble silver halides, thereby preventing silver ions from migrating into the skin. See also Phipps et al WO 95/27530 which discloses using a halide resin in the anodic reservoir to provide halide ions which react with the electrochemically-generated silver ions to produce substantially insoluble silver halides, thereby preventing silver ions from migrating into the skin. Unfortunately, both of these approaches to preventing silver ion migratio
ALZA Corporation
Bates Owen J.
Kennedy Sharon
Miller D. Byron
Stone Steven F.
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