Electrochemically reactive cathodes for an electrotransport...

Details Electrochemically reactive cathodes for an electrotransport... Electrochemically reactive cathodes for an electrotransport...

1999-01-28

2003-01-07

Casler, Brian L. (Department: 3763)

Surgery

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

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

C604S289000, C607S152000, C029S527500, C029S527700, C427S002310, C427S125000

Reexamination Certificate

active

06505069

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to improved cathodes for use in an electrotransport device for delivering a beneficial agent (e.g., a drug), or for sampling an agent (e.g., a body analyte such as glucose) through a body surface of a patient. More particularly, the present invention relates to electrochemically reactive cathodes for an electrotransport device.
BACKGROUND ART
The term “electrotransport” refers generally to the delivery or extraction of an agent (charged, uncharged, or mixtures thereof through a body surface (such as skin, mucous membrane, or nails) wherein the delivery or extraction is at least partially electrically induced or aided by the application of an electric potential. The electrotransport process has been found to be useful in the transdermal administration of many drugs including lidocaine, hydrocortisone, fluoride, penicillin, and dexamethasone. 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.
Electrotransport devices generally employ two electrodes, positioned in intimate contact with some portion of the animal's body (e.g., the skin). A first electrode, called the active or donor electrode, delivers the therapeutic agent (e.g., a drug) into the body. The second electrode, called the counter or return electrode, closes an electrical circuit with the first electrode through the animal'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 active electrode and the cathode is the counter electrode to complete 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.
A widely used electrotransport process, electromigration (also called iontophoresis), involves the electrically induced transport of charged ions (e.g., drug ions) through a body surface. Another type of electrotransport, called electroosmosis, involves the trans-body surface (e.g., transdermal) flow of a liquid 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 by applying high voltage pulses. In any given electrotransport system, one or more 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. 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 watersoluble 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. Nos. 4,747,819 and 5,573,503. 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.
The silver halide cathodes produce only halide (e.g., chloride) anions when they are electrochemically reduced (AgX→Ag+X
−
) which anions are naturally present in the body in significant quantities. Thus, delivery of the chloride ions from the cathode into the patient creates no biocompatability problems. While the silver halide cathodes are quite biocompatible, they have serious disadvantages.
These disadvantages stem in part from the methods used to make the prior art silver halide cathodes. Generally, the prior art silver halide cathodes are made by one of several methods. In two of these methods, a silver foil is either reacted electrolytically with hydrochloric acid or dipped in molten silver chloride in order to form a silver chloride coating on the foil. Such coatings tend to have a limited thickness, thereby limiting the electrochemical capacity of such cathodes. Furthermore, coatings formed in either of these manners are prone to flaking off when the silver foil is flexed. A further disadvantage in connection with the electrolytic reaction of silver foil with hydrochloric acid is that it is a very slow process and not easily amenable to commercial manufacturing.
The third method of making prior art silver halide cathodes involves mixing silver halide particles into a binder, such as a polymeric matrix. This technique is described in Myers et al. U.S. Pat. Nos. 5,147,297 and 5,405,317. Because the polymeric binder is an electrically insulating material, these composite film electrodes also preferably have electrically conductive fillers such as carbon or metal particles, flakes or fibers. Typically, such composite cathodes comprise at least 20 vol. %, and more typically at least 40 vol. % of the inert polymeric binder. The polymeric binder and the conductive filler can create several problems in electrotransport drug delivery devices. For example, polymeric binders have a tendency to absorb drug (and/or other non-agent excipients in the electrolyte reservoir formulation such as anti-microbial agents) from the immediately adjacent electrolyte (i.e., donor or counter) reservoir. In some applications, binders in the donor electrode can absorb up to 50% of the agent in the donor reservoir. Such absorption is problematic because the absorbed agent is not delivered through the body surface causing insufficient therapy or the need to excessively load the reservoir with agent to compensate for such absorption. This means that excess drug and/or excipients may have to be loaded into the reservoir in order to compensate for the drug absorption by the electrode binder. This increases the total drug/excipient loading in the system and makes such systems more expensive, particularly with high cost drugs. Secondly, when the conductive filler is carbon or graphite, such materials have a very high affinity to organic compounds and thus there is a strong tendency for the drug in the adjacent drug reservoir to be adsorbed onto the su

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