Electrotransport device electrode assembly having lower initial resistance

The present invention relates generally to an electrotransport device for transdermally or transmucosally delivering a beneficial agent (e.g., a drug) to the body surface of a patient or for transdermally or transmucosally sampling a body analyte. Most particularly, the present invention relates to a configured and electrochemically reactive electrode assembly having improved start-up electrical performance and improved lag time to compliant agent delivery.

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.fwdarw.Ag.sup.+ +e.sup.-). 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 migration into the skin have their own
 disadvantages. For the first approach described in Phipps et al. U.S. Pat.
 No. 4,747,819 and Phipps et al. WO 96/39224, sometimes very large or
 "excess" amounts of halide drug salt must be loaded into the anodic
 reservoir in order to provide enough halide ions to prevent silver
 migration, particularly over longer drug delivery periods. This is
 disadvantageous because of the high cost of many drugs, thereby making
 this a costly solution to the silver migration problem. For the second
 approach described in Phipps et al WO 95/27530, the halide resins have
 been found to contain many impurities and unreacted monomeric components
 which cannot effectively be removed from the resins. At least some of
 these components have been found to cause undesireable skin irritation
 when the resins are used in electrotransport reservoirs, perhaps because
 the impurities are being transdermally delivered into the skin by the
 applied electrotransport current.
 One potential solution to the metal ion migration problem encountered with
 oxidizable metal anodes is the use of intercalation compounds as taught in
 Phipps, et al, U.S. Pat. Nos. 4,747,819 and 5,573,503. While the use of
 intercalation compounds does avoid the problem of migration of metal ions
 into the patient's skin, at least some of these materials (e.g.,
 polyanilines) have not been extensively used, in part because of their
 very high initial (i.e., at the time the electrotransport device begins
 applying electrotransport current) electrical resistance. The problem of
 high electrical resistance is discussed in more detail below in connection
 with prior art silver halide cathodes.
 Hence, there is a need for an improved anodic electrode which does not have
 the problems of (1) competing metal ion generation as is found in anodes
 formed of conventional oxidizable metals, and/or (2) high initial
 electrical resistance.
 On the cathode side, the silver halide cathodes produce only halide (eg,
 chloride) ions when they are electrochemically reduced
 (AgX.fwdarw.Ag+X.sup.-). Although the electrochemically generated halide
 (e.g., chloride) ions do tend to be delivered from the cathode into the
 patient, chloride is naturally present in the body in fairly high amounts
 so delivery of chloride ions from the cathode has no adverse effects.
 Thus, while the silver halide cathodes are quite biocompatible, they have
 one serious disadvantage in that they are substantially non-conductive, at
 least until enough of the silver halide has been reduced to form metallic
 silver. This is similar to the problem of high initial electrical
 resistance found in anodes formed of intercalation compounds such as
 polyanilines, which anodes don't conduct significant amounts of electric
 current until enough of the, eg, polyaniline has been oxidized. This may
 cause a delay in the start of compliant device operation because the
 silver halide cathode and/or the polyaniline anode has too high an
 electrical resistance for the relatively small voltages supplied by the
 small (eg, coin cell) batteries which are used to power small patient-worn
 electrotransport devices. Of course, electrochemical reduction of the
 silver halide to form metallic silver, and the electrochemical oxidation
 of the reduced (i.e., leuco) form of polyaniline to form a more conductive
 (i.e., an oxidized or emaraldine) form of polyaniline gradually takes
 place at the interface between the electrode and the liquid electrolyte in
 accordance with the following reactions:
 Anodic polyaniline (PA) oxidation: PA.sub.leuco.fwdarw.PA.sub.emaraldine
 +2H.sup.+ +2e.sup.-
 cathodic silver chloride reduction: AgCl+e.sup.-.fwdarw.Ag+Cl.sup.-.
 The reduction of the leuco form of polyaniline is discussed in detail in
 Cushman et al., "Spectroelectrochemical Study of Polyaniline: the
 Construction of a pH-potential phase diagram", Journal of
 Electroanalytical Chemistry, 291 (1986), 335-346. Although the formation
 of metallic silver at the cathode/liquid electrolyte interface and the
 formation of oxidized polyaniline at the anode/liquid electrolyte
 interface gradually improves the electrical conductivity of the electrode,
 it is a fairly slow process. As a result, traditional electrode
 configurations like that shown in FIG. 1 are undesirable because of their
 high electrical resistance at the beginning of electrotransport device
 operation. The electrode assembly 50 shown in FIG. 1 includes a housing 20
 with a depression or well 25 which contains an electrode 52, an
 electrolyte reservoir 53 and a conductive current collector 51. Current
 collector 51 comprises a portion of the electrical connection between the
 electrode 52 and the device power source (not shown in FIG. 1), the other
 portions of the electrical connection include a metal contact (ie, a tab)
 58 and a conductive member 72 which could be a metal wire but more
 typically is formed by depositing a conductive trace on a non-conductive
 circuit board 18. Initially, electrode 52 has a high electrical
 resistance, and therefore acts to insulate the conductive current
 collector 51 from the electrolyte reservoir 53, which is typically a gel.
 Due to such insulation, insufficient flow of electrons are available to or
 from the interface 56 between the electrolyte reservoir 53 and the
 electrode 52, severely inhibiting the oxidation or reduction of the redox
 material, thus, causing a higher electrical resistance across the
 electrode 52. That is, there is a large initial voltage drop across the
 electrode 52.
 The electrical resistance of the electrode 52 is calculated from Ohm's Law:
 R.sub.electrode =.DELTA.V/i, wherein .DELTA.V is the voltage drop across
 the electrode and i is the applied current. The electrical resistance at
 one "side" (ie, either the anodic side or the cathodic side) of an
 electrotransport device is generally considered to be the sum of the
 resistances of (1) the electrode assembly, and (2) the patient body
 surface to which the electrode assembly is applied (e.g., the skin).
 Although the initial skin resistance is generally quite high (e.g., more
 than about 50,000 ohm-cm).sup.2 when an electrotransport device is first
 turned on, the skin resistance drops very quickly during the first 2 to 5
 minutes of device operation to a level which is well within the compliant
 range of electrotransport device power sources, which typically apply
 voltages in the range of 2 to 10 volts. During this period, because it is
 important that all available energy is used for overcoming the skin's
 resistance, any excess voltage drop due to a resistive electrode will
 diminish the current available for therapy. If the electrode resistance is
 above a predetermined amount, compliance is lacking, which means that the
 device is unable to apply the prescribed current because the electrode
 resistance is too great for the limited voltage of the power source.
 Unfortunately, the electrical resistance of polyaniline anodes and silver
 halide cathodes does not drop quickly like human skin. Thus, there can be
 a long wait (e.g., more than 30 minutes) until the electrode resistance
 drops to a level at which the electrotransport device becomes compliant
 and can deliver the prescribed electrical current. This delay in reaching
 device compliance is also referred to as the start-up lag-time). During
 this start-up lag-time, the anode resistance drops as the, eg,
 polyaniline, reacts to form electrically conductive oxidized polyaniline,
 and the cathode resistance drops as the silver halide reacts to form
 electrically conductive metallic silver. More importantly, the lag time to
 compliant drug delivery makes the use of polyaniline anodes and silver
 halide cathodes in electrotransport drug delivery unacceptable for many
 applications. For example, many applications for transdermal
 electrotransport drug delivery require a very short lag time to
 compliance, such as delivery of an anti-migraine drug to treat migraines
 or delivery of a narcotic analgesic to treat pain.
 Of course, the delay in reaching compliant electrotransport device
 operation can be reduced by increasing the battery voltage, but this
 requires more (or more expensive) batteries to power the device which
 undesirably increases the cost of electrotransport drug delivery. The
 delay in reaching compliant electrotransport device operation can also be
 overcome by adding electrically conductive fillers, such as powdered metal
 or carbon, to the intercalation anode or to the silver halide cathode as
 taught in Myers et al. U.S. Pat. No. 5,147,297. However, this makes the
 manufacture of these electrodes more difficult since the conductive
 fillers must have very good and even distribution throughout the electrode
 matrix and also makes the electrodes more expensive.
 Hence, there is a need for an improved electrode for an electrotransport
 device that achieves compliant agent delivery quickly, without significant
 voltage drop due to high initial electrical resistance, and without the
 need for significant power supply voltages or other expensive conductive
 fillers to overcome any significant initial electrode resistance.
 DESCRIPTION OF THE INVENTION
 The present invention overcomes the disadvantages associated with the prior
 art electrode assembly 50 shown in FIG. 1, whereby the electrode 52
 initially acts as a high electrical resistance barrier between the current
 collector 51 and the interface 56 between the electrolyte reservoir and
 the redox species contained in electrode 52. The present invention
 provides an electrotransport device for delivering or sampling an agent
 through a body surface, such as skin. The device includes a pair of
 electrode assemblies, one anodic and one cathodic, both electrically
 connected to a source of electrical power (e.g., one or more batteries).
 At least one of the electrode assemblies includes an electrode, a current
 collector connecting the electrode to the power source, and an electrolyte
 reservoir in ion-transmitting relation to the electrode. In use, the
 electrolyte reservoir is positioned in ion-transmitting relation with the
 body surface (e.g., skin).
 The electrode is composed at least in part of a solid phase
 electrochemically reactive (i.e., electrochemically oxidizable or
 reducible) material. The electrode has a high initial electrical sheet
 resistance, typically greater than about 100 ohm/square which is lessened
 by exposure of the electrode to electric current. Upon such exposure, the
 electrochemically reactive material is oxidized or reduced to a form
 having a lower electrical resistance, such that the sheet resistance of
 the electrode is lowered below its initial sheet resistance.
 The current collector has a low initial resistance (ie, it is highly
 conductive) and comprises at least part of the electrical connection
 between the device power source and the electrode. Thus, the current
 collector conducts electric current between the power source and the
 electrode.
 At the time when the electrotransport device begins applying
 electrotransport current, the electrode, the current collector and the
 electrolyte reservoir form a common boundary. The common boundary
 condition gives the electrode assemblies of the present invention a
 shorter lag-time for achieving compliant electrotransport delivery and
 lower initial electrical resistance, thereby requiring lower power source
 voltages for device operation.
 The electrode assembly of the present invention can be either (1) an anodic
 electrode assembly wherein the electrode is composed of a resistive
 oxidizable material such as the leuco form of polyaniline, or (2) a
 cathodic electrode assembly wherein the electrode is composed of a
 resistive reducible material such as a silver halide.

MODES FOR CARRYING OUT THE INVENTION
 Definitions
 As used herein, the term "electrochemically reactive material" means a
 compound or composition capable of being electrochemically oxidized or
 reduced and wherein the reacted (i.e., oxidized or reduced) form of the
 material has a lower electrical resistance than the unreacted form (i.e.,
 oxidizable or reducible form, respectively) of the material. This term
 also includes intercalation host materials, which may themselves be
 directly oxidized or reduced, or may intercalate dopants that become
 oxidized or reduced.
 As used herein, the term "common boundary" means a macroscopic and
 measurable intersection of the current collector, the electrode, and the
 electrolyte reservoir.
 As used herein, the term "electrode assembly" includes a collection of at
 least the following three elements: a current collector, an electrode and
 an electrolyte reservoir.
 As used herein, the term "electrical sheet resistance" is the surface
 resistance between opposite edges of a unit square of a material.
 Electrical sheet resistance (also sometimes called surface resistivity in
 the literature) is generally designated in the literature by the symbol
 .rho..sub.S and is used to characterize current flow over a surface. The
 resistance across a square is independent of the size of the square and
 the unit of sheet resistance is the ohm, or more superfluously (and as
 used herein), ohm/square. Since a conducting surface is always a layer
 with a finite thickness, t, the sheet resistance is related to the volume
 resistivity, .rho..sub.P V, of the layer by the following equation:
 .rho..sub.S =.rho..sub.V.div.t. The sheet resistance of any given
 electrode or current conductor can be measured in accordance with the
 methods described in The American Society for Testing and Materials
 (ASTM), West Conshohocken, Pa., volume 10.02, Test Standard Designation D
 4496-87 (reapproved 1993), entitled "Standard Test Method for D-C
 Resistance or Conductance of Moderately Conductive Materials", the
 disclosures of which are incorporated herein by reference.
 As used herein, the term "body surface" includes the skin, mucosal
 membranes and/or nails of a living animal. In particular, it includes the
 skin of living humans.
 As used herein, the term "electrolyte reservoir" means a liquid which
 contains, or which receives during device operation, dissolved ions. The
 term includes saline solutions used in counter electrodes and drug
 solutions or suspensions in donor electrodes. The term also includes
 matrices such as a sponge, fabric, or a polymer such as a gel which
 contains such a solution or suspension. The term includes both aqueous
 solutions and non-aqueous solutions (e.g., solutions of dissolved
 electrolyte in a glycol or glycerol).
 As used herein, the term "compliant agent delivery" means that the agent is
 being delivered via electrotransport through the body surface at the
 prescribed electrotransport current. There is not compliant agent delivery
 when an electrotransport device is unable to supply the prescribed
 electrotransport current, even at the maximum applied voltage, because the
 device components and/or the skin have too high an electrical resistance.
 As used herein, the term "lag time" means the period of time during which
 an electrotransport device applies a non-compliant current. In general,
 the lag time is measured from the time when the electrotransport device
 begins applying electrotransport current until the time when the
 prescribed electrotransport current begins to be applied.
 FIG. 2 illustrates one example of an electrode assembly 60 in accordance
 with the present invention. Similar to the prior art electrode assembly
 50, electrode assembly 60 also includes a housing 20 having a well or
 depression 25 which contains a current collector 61, an electrode 62 and
 an electrolyte reservoir 63. The current collector 61 comprises a portion
 of the electrical connection between the electrode 62 and the device power
 source (not shown in FIG. 2), the other portions of the electrical
 connection including a metal contact (i.e., a tab) 68 and a conductive
 circuit 71, typically formed of a conductive trace deposited on a
 non-conductive circuit board 18. Like the electrode assembly 50 shown in
 FIG. 1, the electrode assembly 60 of the present invention includes an
 electrode 62 composed of a redox material which initially has a high
 electrical resistance. In general, the electrode 62 has an initial
 electrical sheet resistance of greater than about 100 ohm/square and
 preferably greater than about 10,000 ohm/square the electrode 62 being
 oxidizable or reducible to a form having a lower electrical sheet
 resistance than its initial electrical sheet resistance. The redox
 material of electrode 62 should be solid phase and should not readily
 dissolve in the liquid phase of the adjacent electrolyte reservoir 63.
 Preferably, the redox material has a solubility in the liquid within
 electrolyte reservoir 63 of less than about 1 mg/ml. Most preferably, the
 electrode 62 is completely, or substantially completely, composed of the
 redox material.
 Unlike the electrode assembly 50 of the prior art, the electrode assembly
 60 of the present invention utilizes an electrode 62 which has smaller
 lateral dimensions (i.e., length and/or width) than the current collector
 61, resulting in a common boundary 64, 64' between the current collector
 61, the electrode 62 and the electrolyte reservoir 63. The common boundary
 64, 64' provides a region in which the electrons carried by current
 collector 61, the redox material contained within electrode 62 and the
 electrolyte reservoir 63 are all in immediate contact with one another.
 The provision of these three elements in close proximity greatly reduces
 the initial electrical resistance of the electrode assembly 60 compared to
 the initial electrical resistance of electrode assembly 50 which provides
 no such common boundary condition.
 In the case where electrode assembly 60 is a cathodic electrode assembly,
 the electrode 62 is a cathode comprised of an electrochemically reducible
 material such as silver chloride. Silver chloride is a solid phase redox
 material which is substantially water insoluble. Thus, when the liquid
 within reservoir 63 is an aqueous liquid, the silver chloride does not
 appreciably dissolve in the liquid in reservoir 63. The electrolyte
 reservoir 63 is typically in the form of a polymeric gel containing a
 liquid electrolyte. In the case where the electrode assembly 60 is a donor
 electrode assembly, the liquid electrolyte within the gel is typically a
 drug solution. In the case where the electrode assembly 60 is a counter
 electrode assembly, the liquid electrolyte within the gel is typically
 saline.
 A perspective view of the current collector 61 and the electrode 62 is
 shown in FIG. 3. The electrolyte reservoir 63 is removed to better show
 the common boundary 64. In this embodiment, the common boundary 64
 comprises four lines, which together form the shape of a rectangle.
 Preferably, the current collector 61 has a sheet resistance that is less
 than one-half the sheet resistance of the electrode 62. More preferably,
 the current collector 61 has a sheet resistance less than about 50,000
 ohm/square, even more preferably less than about 1000 ohm/square, and most
 preferably less than about 10 ohm/square. The current collector 61 can be
 a metallic or carbon foil (e.g., silver, stainless steel, platinum or
 graphite) or can be a polymeric film loaded with a conductive filler such
 as carbon fibers, carbon particles or metal particles. Most preferably,
 the current collector 61 is in the form of an electrically conductive
 trace or an electrically conductive adhesive comprised of an adhesive
 polymeric binder containing metal and/or carbon conductive fillers. The
 adhesive adheres to both the contact 68 and the electrode 62 in order to
 maintain good electrical continuity between these elements.
 As the reduction reaction proceeds at the surface of cathodic silver
 chloride electrode 62, the reduction of silver chloride initially occurs
 at the common boundary 64,64' producing metallic silver causing the region
 proximate to the common boundary 64,64' to become more electrically
 conductive. As the device operates, the reduction of silver chloride
 proceeds, eventually covering the entire outer surface of cathodic
 electrode 62.
 At the common boundaries 64,64', the electrode 62 is quickly reduced
 because the current collector 61 provides a ready supply of electrons and
 because the liquid in the electrolyte reservoir 63 is available for the
 ions to migrate setting up an electrotransport current comprised of ions
 flowing between the electrolyte reservoir 63 and the patient's body
 surface. For example, when the electrode 62 includes silver chloride, the
 silver chloride is reduced, producing Ag metal and chloride ions. Anions
 within the electrolyte reservoir 63 migrate to the body surface
 establishing a current for delivering or sampling an agent. Agent is
 delivered or sampled through the skin at a compliant delivery rate without
 any significant voltage drop or lag time at the cathode because silver
 chloride is quickly and abundantly reduced all along the common boundaries
 64,64'.
 In contrast, as shown in FIG. 1, the prior art electrode assembly 50 has an
 electrode 52 which shares no common boundary with the current collector 51
 and the electrolyte reservoir 53. The interface 56 between the silver
 chloride electrode 52 and the electrolyte reservoir 53 has no ready supply
 of electrons because the silver chloride electrode 52 is substantially
 non-conductive. Thus, the electrode 52 substantially insulates the
 electrons provided by the current collector 51 from reaching the boundary
 56 between the electrolyte reservoir 53 and the electrode 52, thus,
 impeding reduction of the silver chloride at the interface 56 of electrode
 52. Thus, the net effect of the increase in electrical resistance is that
 the compliance voltage of the circuit may be insufficient to initially
 achieve compliant agent delivery.
 In the case where electrode assembly 60 is an anodic electrode assembly,
 the electrode 62 is an anode comprised of an electrochemically oxidizable
 material such as polyaniline. The electrolyte reservoir 63 is typically in
 the form of a polymeric gel containing a liquid electrolyte. In the case
 where the electrode assembly 60 is a donor electrode assembly, the liquid
 electrolyte within the gel is typically a drug solution. In the case where
 the electrode assembly 60 is a counter electrode assembly, the liquid
 electrolyte within the gel is typically saline.
 As the oxidation reaction proceeds at the surface of anodic polyaniline
 (leuco form) electrode 62, the oxidation of polyaniline initially occurs
 at the common boundary 64,64' producing oxidized polyaniline (emaraldine
 form, which is more electrically conductive than the reduced leuco form of
 polyaniline) causing the region proximate to the common boundary 64,64' to
 become more electrically conductive. As the device operates, the oxidation
 of polyaniline proceeds, eventually covering the entire outer surface of
 anodic electrode 62.
 At the common boundaries 64,64', the electrode 62 is quickly oxidized
 because the current collector 61 provides a ready of electrons and because
 the liquid in the electrolyte reservoir 63 is available for the ions to
 migrate setting up an electrotransport current comprised of ions flowing
 between the electrolyte reservoir 63 and the patient's body surface. For
 example, when the electrode 62 includes leuco-polyaniline, the
 leuco-polyaniline is oxidized, producing electrically conductive oxidized
 polyaniline. Cations within the electrolyte reservoir 63 migrate to the
 body surface establishing a current for delivering or sampling an agent.
 Agent is delivered or sampled through the skin at a compliant delivery
 rate without any significant voltage drop or lag time at the anode because
 polyaniline is quickly and abundantly oxidized all along the common
 boundaries 64,64'.
 In contrast, as shown in FIG. 1, the prior art electrode assembly 50 has an
 electrode 52 which shares no common boundary with the current collector 51
 and the electrolyte reservoir 53. The interface 56 between the e.g.,
 leuco-polyaniline electrode 52 and the electrolyte reservoir 53 has no
 ready drain of electrons because the polyaniline electrode 52 is initially
 (i.e., before significant oxidation has taken place) substantially
 non-conductive. Thus, the electrode 52 substantially insulates the current
 collector 51 from the boundary 56 between the electrolyte reservoir 53 and
 the electrode 52, thus, impeding oxidation of the leuco-polyaniline at the
 interface 56 of electrode 52. Thus, the net effect of the increase in
 electrical resistance is that the compliance voltage of the circuit may be
 insufficient to deliver the desired or necessary therapeutic current.
 The common boundary between the current collector 61, the electrode 62 and
 the electrolyte reservoir 63 can have any shape or configuration as long
 as at least one common boundary exists and as long as the common boundary
 has sufficient length to reduce the unacceptably high initial electrical
 resistance of electrode 62 to an overall acceptable initial resistance for
 the electrode assembly 60. For example, the electrode 62 may be offset
 from the current collector 61, forming a single common boundary (64 or
 64'). Alternatively, the common boundary may be circular, triangular,
 elliptical, or any other shape (individually or collectively) so long as
 there is at least one common boundary. Alternatively, the electrode 62 may
 have a hole or slot of any shape (eg, a donut-shaped electrode) allowing
 the electrolyte reservoir 63 to directly contact the current collector 61.
 In some instances, it may be desirable to coat the electrode 62 and/or the
 current collector 61 with a thin layer of a material such as an adhesive
 or a hydrophilic surface coating in order to improve the adhesion or
 hydrophilicity of the electrode 62 and/or the current collector 61, either
 to improve the adhesion between the electrode 62 and the current collector
 61 or to improve the adhesion of these elements to the electrolyte
 reservoir 63. A hydrophilic surface coating on the electrode 62 and/or the
 current collector 61 may also be used to improve the surface interaction
 between either or both of these elements and the (e.g., aqueous)
 electrolyte reservoir 63. Such coatings may act to physically separate the
 electrode 62 and/or the current collector 61 from the electrolyte
 reservoir 63. However, as long as any such coatings on electrode 62 and/or
 current collector 61 are thin and either electrically or ionically
 conductive, then the coatings should not be considered an impediment to a
 common boundary which would otherwise be present, but for the coating(s).
 The minimum necessary length of the common boundary will be dependent upon
 a number of factors including the maximum voltage which can be applied by
 the power source, the prescribed level of electrotransport current as well
 as the initial sheet resistance of the electrode 62. In general, small
 electrotransport transdermal delivery and sampling devices adapted to be
 worn unobtrusively under clothing will have power sources with maximum
 voltages in the range of less than about 20 volts, and more typically in
 the range of about 2 to 10 volts. Furthermore, such devices typically
 apply electrotransport currents of less than 1 mA, and more typically less
 than 0.5 mA. Furthermore, electrodes formed of a polymeric component
 containing a redox species in particle form (e.g., a polyisobutylene
 matrix containing silver chloride particles) will typically have an
 electrical sheet resistance of greater than about 1,000 ohm/square and
 more typically greater than about 10,000 ohm/square. Under such "typical
 conditions", the common boundary length should be at least about 0.1 cm
 and preferably at least about 1 cm. Expressed in terms of the ratio of
 common boundary length (I) to applied electrotransport current (i), the
 ratio should be at least 0.1 cm/mA and preferably at least about 1 cm/mA.
 Shown in FIG. 5 is another example of an electrode assembly 70 of the
 present invention. In this configuration, the facing sides of electrode 62
 and the current collector 61 have the same surface area and are laminated
 together to form a bi-layer laminate structure. As a result, the common
 boundary 64 is on the edge of the electrode 62/current collector 61
 laminate.
 Shown in FIG. 6 is another example of an electrode assembly 80 of the
 present invention. In this configuration, the electrode 62 is wider than
 the current collector 61. As a result, the common boundary 64 is beneath
 the "overhang" of the electrode 62.
 Shown in FIG. 7 is another example of an electrode assembly 90 of the
 present invention. In this configuration, a plurality of electrodes 62 are
 laminated to the current collector 61 with spaces therebetween. The
 electrolyte reservoir 63 contacts the current collector 61 to form a
 plurality of common boundaries 64. Other configurations are contemplated
 by the present invention so long as a common boundary of sufficient length
 is present. The configurations shown in FIGS. 2 through 7 are merely
 illustrative.
 In general, the electrode 62 comprises a material which is initially in a
 highly resistive state, but which when oxidized or reduced becomes less
 resistive. In the case of a cathodic electrode 62, the electrode is
 composed, at least in part, of an electrochemically reducible material.
 The reducible material can be selected from metal compounds, metal
 complexes, intercalation compounds, carbon intercalation hosts hosting an
 alkali metal, and electrochemically oxidizable or reducible polymers. A
 particularly preferred class of reducible materials are compounds defined
 by the formula MX, wherein M is a metal capable of being electrically
 reduced (other than alkaline earth metals) and X is selected from
 polymeric anions and low molecular weight anions such as halides,
 sulfates, and phosphates, but preferably a halide. Most preferably, X is
 chloride. Preferably, M is silver, zinc or copper, and more preferably
 silver. The most preferred electrochemically reducible material for use in
 cathodes of the present invention is substantially pure silver chloride.
 Another type of reducible material for use in cathodes of the present
 invention is an intercalation compound such as an alkali metal tungstate.
 The reduction reaction shown for an alkali metal tungstate is as follows:
EQU M.sup.+ +M.sub.x WO.sub.3 +e.sup.-.fwdarw.M.sub.1+x WO.sub.3
 wherein M is an alkali metal, preferably sodium.
 Other reducible and oxidizable species are listed in the CRC Handbook of
 Chemistry and Physics, 57.sup.th Edition, D-141 to D-146, which is
 incorporated herein by reference.
 The preferred electrochemically oxidizable material for use in anodes of
 the present invention is the leuco form of polyaniline.
 As used herein, the term "agent" includes both agents which are sampled
 from the body, e.g., for diagnostic purposes, as well as, therapeutic
 agents which are delivered from the device into the body in order to
 achieve a therapeutic effect. In the context of sampling agents for
 diagnostic purposes, the agent can be any body analyte including
 electrolytes or glucose which are sampled in order to perform a diagnostic
 test such as measurement of blood glucose. In the context of therapeutic
 agent delivery, the term "agent" is used interchangeably with "drug", and
 each are intended to be given its broadest reasonable interpretation in
 the art as any therapeutically active substance which when delivered to a
 living organism produces a desired, usually beneficial, effect. For
 example, "agent" includes therapeutic compounds and molecules from all
 therapeutic categories including, but not limited to, anti-infectives
 (such as antibiotics and antivirals), analgesics (such as fentanyl,
 sufentanil, buprenorphine, and analgesic combinations), anesthetics,
 antiarthritics, antiasthmatics (such as terbutaline), anticonvulsants,
 antidepressants, antidiabetics, antidiarrheals, antihistamines,
 anti-inflammatories, antimigranes, antimotion sickness preparations (such
 as scopolamine and ondansetron), antineoplastics, antiparkinsonisms,
 antipruritics, antipsychotics, antipyretics, antispasmodics (including
 gastrointestinal and urinary), anticholinergics, sympathomimetrics,
 xanthine and derivatives thereof, cardiovascular preparations (including
 calcium channel blockers such as nifedipine, beta-agonists (such as
 dobutamine and ritodrine), beta blockers, antiarrythmics,
 antihypertensives (such as atenolol), ACE inhibitors (such as lisinopril),
 diuretics, vasodilators (including general, coronary, peripheral and
 cerebral), central nervous system stimulants, cough and cold preparations,
 decongestants, diagnostics, hormones (such as parathyroid hormones),
 hypnotics, immunosuppressives, muscle relaxants, parasympatholytics,
 parasympathomimetrics, prostaglandins, proteins, peptides,
 psychostimulants, sedatives and tranquilizers.
 The electrotransport device of the present invention may also deliver drugs
 and/or agents including baclofen, beclomethasone, betamethasone,
 buspirone, cromolyn sodium, diltiazem, doxazosin, droperidol, encainide,
 fentanyl, hydrocortisone, indomethacin, ketoprofen, lidocaine,
 methotrexate, metoclopramide, miconazole, midazolam, nicardipine,
 piroxicam, prazosin, scopolamine, sufentanil, terbutaline, testosterone,
 tetracaine and verapamil.
 The electrotransport device of the present invention may also deliver
 peptides, polypeptides, proteins, oligonucleotides, polysaccharides and
 other macromolecules. Such molecules are known in the art to be difficult
 to deliver transdermally or transmucosally due to their size. For example,
 such molecules may have molecular weights in the range of 300-40,000
 daltons and include, but not limited to, LHRH and analogs thereof (such as
 buserelin, gosserelin, gonadorelin, naphrelin and leuprolide), GHRH, GHRF,
 insulin, insulinotropin, heparin, calcitonin, octreotide, endorphin, TRH,
 NT-36 or N-[[(s)-4-oxo-2-azetidinyl]carbonyl]L-histidyl-L-prolinamide],
 liprecin, pituitary hormones (such as HGH, HMG, HCG, desmopressin
 acetate), follicile luteoids, a-ANF, growth factor releasing factor
 (GFRF), b-MSH, somatostatin, bradykinin, somatotropin, platelet-derived
 growth factor, asparaginase, bleomycin sulfate, chymopapain,
 cholecystokinin, chorionic gonadotropin, corticotropin (ACTH),
 erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon,
 hirulog, hyaluronidase, interferon, interleukin-2, menotropins (such as
 urofollitropin (FSH) and LH), oxytocin, streptokinase, tissue plasminogen
 activator, urokinase, vasopressin, desmopressin, ACTH analogs, ANP, ANP
 clearance inhibitors, angiotensin II antagonists, antidiuretic hormone
 agonists, antidiuretic hormone antagonists, bradykinin antagonists, CD4,
 ceredase, CSF's, enkephalins, FAB fragments, IgE peptide suppressors,
 IGF-1, neurotrophic factors, colony stimulating factors, parathyroid
 hormone and agonists, parathyroid hormone antagonists, prostaglandin
 antagonists, pentigetide, protein C, protein S, renin inhibitors, thymosin
 alpha-1 antitrypsin (recombinant), and TGF-beta.
 FIG. 4 illustrates a representative electrotransport delivery device that
 may be used in conjunction with the present invention. Device 10 comprises
 an upper housing 16, a circuit board assembly 18, a lower housing 20,
 electrodes 42 and 42', electrolyte gel reservoirs 26 and 28, and
 skin-compatible adhesive 30. Upper housing 16 has lateral wings 15 which
 assist in holding device 10 on a patient's skin. Upper housing 16 is
 preferably composed of an injection moldable elastomer (e.g., ethylene
 vinyl acetate). Printed circuit board assembly 18 comprises one or more
 electrical components 19 (e.g., an integrated circuit) and battery 32.
 Circuit board assembly 18 is attached to housing 16 by posts (not shown in
 FIG. 4) passing through openings 13a and 13b, the ends of the posts being
 heated/melted in order to heat stake the circuit board assembly 18 to the
 housing 16. Lower housing 20 is attached to the upper housing 16 by means
 of adhesive 30, the skin distal side of adhesive 30 being adhered to both
 lower housing 20 and upper housing 16 including the bottom surfaces of
 wings 15.
 The outputs (not shown in FIG. 4) of the circuit board assembly 18 make
 electrical contact with electrodes 42' and 42 through current collectors
 22 and 24, respectively. Current collectors 22 and 24 are composed of an
 electrically conductive adhesive which adheres to the skin distal sides of
 electrodes 42' and 42, respectively. The skin distal sides of current
 collectors 22 and 24 adhere to the circuit outputs (not shown) on the
 underside of circuit board assembly 18 through openings 23', 23 formed in
 lower housing 20. Electrodes 42 and 42', in turn, are in direct mechanical
 and electrical contact with the skin-distal sides of electrolyte gel
 reservoirs 26 and 28. The skin-proximal sides of electrolyte gel
 reservoirs 26, 28 contact the patient's skin through the openings 29', 29
 in adhesive 30.
 Device 10 optionally has a feature which allows the patient to
 self-administer a dose of drug by electrotransport. Upon depression of
 push button switch 12, the electronic circuitry on circuit board assembly
 18 delivers a predetermined DC current to the electrodes/electrolyte
 reservoirs 42', 42 and 26, 28 for a delivery interval of predetermined
 length. The push button switch 12 is conveniently located on the topside
 of device 10 and is easily actuated through clothing. A double press of
 the push button switch 12 within a short time period, e.g., three seconds,
 is preferably used to activate the device for delivery of drug, thereby
 minimizing the likelihood of inadvertent actuation of the device 10.
 Preferably, the device transmits to the user a visual and/or audible
 confirmation of the onset of the drug delivery interval by means of LED 14
 becoming lit and/or an audible signal from, e.g., a "beeper". Drug is
 delivered through the patient's skin by electrotransport, e.g., on the
 arm, over the predetermined delivery interval.
 In accordance with the present invention, the electrodes 42 and 42' sit in
 depressions in the skin distal sides of electrolyte gel reservoirs 28 and
 26, respectively. Because the depth of these depressions are approximately
 equal to the thickness of electrodes 42 and 42', there exists an
 oval-shaped common boundary in each of the two electrode assemblies of the
 device 10. Thus, there is a common boundary between the current collector
 22, the electrode 42' and the electrolyte gel reservoir 26. There is also
 a common boundary between the current collector 24, the electrode 42 and
 the electrolyte gel reservoir 28. Although the device 10 illustrates the
 common boundary on both "sides" (i.e., the anodic side and the cathodic
 side) of the device 10, it is within the scope of the present invention to
 use the common boundary condition on only one side (i.e., the anodic side
 or the cathodic side) of the electrotransport device 10.
 The push button switch 12, the electronic circuitry on circuit board
 assembly 18 and the battery 32 are adhesively "sealed" between upper
 housing 16 and lower housing 20. Upper housing 16 is preferably composed
 of rubber or other elastomeric material. Lower housing 20 is preferably
 composed of a plastic or elastomeric sheet material (e.g., polyethylene or
 polyethylene terephthalate copolymer) which can be easily molded to form
 depressions 25, 25' and cut to form openings 23, 23'. The assembled device
 10 is preferably water resistant (i.e., splash proof) and is most
 preferably waterproof. The system has a low profile that easily conforms
 to the body, thereby allowing freedom of movement at, and around, the
 wearing sit. The electrolyte gel reservoirs 26 and 28 are located on the
 skin-contacting side of the device 10 and are sufficiently separated to
 prevent accidental electrical shorting during normal handling and use.
 The device 10 adheres to the patient's body surface (e.g., skin) by means
 of a peripheral (i.e., surrounding the periphery of electrolyte gel
 reservoirs 26 and 28) adhesive 30. The adhesive 30 has adhesive properties
 which assures that the device 10 remains in place on the body during
 normal user activity, and yet permits reasonable removal after the
 predetermined (e.g., 24-hour) wear period.
 The electrolyte gel reservoirs 26 and 28 each comprise liquid electrolyte
 contained in a gel matrix. In the case where device 10 is a transdermal
 drug delivery device, at least one of the gel reservoirs 26 and 28
 contains a drug solution or suspension. Drug concentrations in the range
 of approximately 1.times.10.sup.-4 M to 1.0 M or more can be used, with
 drug concentrations in the lower portion of the range being preferred.
 Suitable polymers for the gel matrix may comprise essentially any nonionic
 synthetic and/or naturally occurring polymeric materials. A polar nature
 is preferred when the active agent is polar and/or capable of ionization,
 so as to enhance agent solubility. Optionally, the gel matrix will be
 water swellable. Examples of suitable synthetic polymers include, but are
 not limited to, poly(acrylamide), poly(2-hydroxyethyl acrylate),
 poly(2-dydroxypropyl acrylate), poly(N-vinyl-2-pyrrolidone),
 poly(n-methylol acrylamide), poly(diacetone acrylamide),
 poly(2-hydroxylethyl methacrylate), poly(vinyl alcohol) and poly(allyl
 alcohol). Hydroxyl functional condensation polymers (i.e., polyesters,
 polycarbonates, polyurethanes) are also examples of suitable polar
 synthetic polymers. Polar naturally occurring polymers (or derivatives
 thereof) suitable for use as the gel matrix are exemplified by cellulose
 ethers, methyl cellulose ethers, cellulose and hydroxylated cellulose,
 methyl cellulose and hydroxylated methyl cellulose, gums such as guar,
 locust, karaya, xanthan, gelatin, and derivatives thereof. Ionic polymers
 can also be used for the matrix provided that the available counterions
 are either drug ions or other ions that are oppositely charged relative to
 the active agent.
 While the invention has been described in conjunction with the preferred
 specific embodiments thereof, it is to be understood that the foregoing
 description as well as the examples, which follow, are intended to
 illustrate and not limit the scope of the invention. Other aspects,
 advantages and modifications within the scope of the invention will be
 apparent to those skilled in the art.
 Comparative Example 1
 Shown in FIG. 8 is a comparison between (1) a prior art cathodic electrode
 assembly assembly according to FIG. 1 using a silver chloride cathode but
 no common boundary condition; and (2) a cathodic electrode assembly
 according to FIGS. 2 and 3 of the present invention, also using a silver
 chloride cathode and utilizing a common boundary between the current
 collector, the electrode and the liquid electrolyte.
 The prior art cathodic electrode assembly (Cathode A) included a silver
 chloride foil cathode laminated to a current collector consisting of an
 electrically conductive adhesive having a sheet resistance of 10
 ohm/square. The foil had an area of 2.85 cm.sup.2, and the liquid
 electrolyte was a saline-containing gel. In Cathode A, the gel was placed
 in contact with the silver chloride foil but not in contact with the
 conductive adhesive. Thus, there was no common boundary in accordance with
 the present invention. The gel/foil contact area was 2.0 cm.sup.2.
 The cathodic electrode assembly of the present invention (Cathode B)
 included a silver chloride foil laminated to an electrically conductive
 adhesive, also having a sheet resistance of 10 ohm/square. The foil was a
 circular disk with an area of 1 cm.sup.2, the adhesive had an area of 2.85
 cm.sup.2. Therefore, the gel/electrode contact area was 1.0 cm.sup.2 and
 the length of the common boundary was equal to the perimeter of the
 electrode; 3.54 cm. The prior art cathode was a 0.05 mm (0.002 inch) thick
 AgCl strip. Cathode B had a smaller silver chloride foil (i.e., 1.0
 cm.sup.2) than cathode A.
 The silver chloride foil was made from silver chloride strip supplied by
 Engelhard-CLAL of Carteret, N.J. The silver chloride strip had a thickness
 of 0.051 mm (0.002 inch) and was cut and laminated to the pieces of
 electrically conductive adhesive.
 In the cell assemblies for both cathodic electrode examples, the liquid
 electrolyte/gel formulation was about 10 ml of 15% polyvinyl alcohol
 (PVOH), 2% hydroxy propyl methyl cellulose (HPMC), 0.1 M NaCl, and the
 remainder deionized water. The initial pH of the saline was 6.26.
 Both electrode assemblies were discharged under identical current densities
 of 0.3 mA/cm.sup.2 (because Cathode A had a larger surface area (2
 cm.sup.2) than Cathode B (1 cm.sup.2), the discharge current for Cathode A
 (0.6 mA) was correspondingly higher than the discharge current for Cathode
 B (0.3 mA)). The discharge was conducted by electrically connecting the
 cathodic electrode assembly to the negative pole of a galvanostat. A
 silver foil anode was electrically connected to the positive pole of the
 galvanostat and placed against the free surface of the gel. During
 discharge, the voltages of cathodes A and B were measured versus Ag/AgCl
 quasi-reference electrodes.
 As illustrated in FIG. 8, the discharge behavior of the cathodes were
 significantly different during the early period of discharge (i.e. the
 lag-time period). As shown in FIG. 8, The prior art cathode (Cathode A)
 had an initial discharge voltage (i.e., start-up voltage) of 5.68 V,
 whereas the cathode of the present invention (Cathode B) had a start-up
 voltage of only 0.21 V. The lag time was defined in these experiments as
 the time required for the voltage applied by the galvanostat to fall below
 0.30 V. The lag time for Cathode A was 7.1 minutes, whereas the lag time
 for Cathode B was only 9 seconds.
 Additional experiments were run on three prior art cathodes and three
 cathodes of the present invention as described immediately above. The
 average start-up voltages for the prior art cathodes was 3.71 volts while
 the average start-up voltages for the three cathodes of the present
 invention was 0.41 volts. The average lag time for the prior art cathodes
 was 9.8 minutes while the average lag times for the three cathodes of the
 present invention was only 8.6 seconds.
 In an electrotransport system or almost any medical device, it is highly
 preferrable to have a low start-up voltage and lag time resulting in
 improved performance and reduced electrical power consumption. In sum, the
 performance of the present invention was unexpectedly superior to the
 prior art cathodes.
 Comparative Example 2
 Two electrotransport devices (device A and device B) are constructed, each
 of the devices having a power source and a pair of electrode assemblies,
 one anodic and the other cathodic. Each of the electrode assemblies
 includes a copper foil current collector, an electrode and a polyvinyl
 alcohol gel reservoir containing saline. The cathodic electrode assembly
 in each of the devices comprises a silver chloride cathode and has the
 configuration shown in FIG. 1, i.e., there is no common boundary condition
 in the cathodic electrode assembly of either device. The anodic electrode
 assembly of device A is comprised of a leuco-polyaniline strip and has the
 configuration shown in FIG. 1, i.e., there is no common boundary condition
 in the anodic electrode assembly of device A. On the other hand, the
 anodic electrode assembly of device B is comprised of a leuco-polyaniline
 strip and has the configuration shown in FIG. 2, i.e., there is a common
 boundary condition in the anodic electrode assembly of device B. The
 electrode assemblies of each of the devices are connected to a galvanostat
 which applies an electrotransport current of 0.5 mA. The start-up voltage
 of device B having the common boundary condition leuco-polyaniline anode
 is significantly lower than the start-up voltage of device A having the
 leuco-polyaniline anodic electrode assembly with no common boundary
 condition. Furthermore, the lag time for the galvanostat power source to
 reach an output voltage of 0.3 volts is significantly shorter with device
 B compared to device A.
 Having thus generally described our invention and described in detail
 certain preferred embodiments, it will be readily apparent that various
 modifications to the invention may be made by persons skilled in this art
 without departing from the scope of this invention and which is limited
 only by the following claims.