Abstract:
Embodiments of the invention provide electrode assemblies and associated methods for the iontophoretic transdermal delivery of therapeutic agents. Many embodiments provide a corrosion resistant electrode for the iontophoretic transdermal delivery of various therapeutic agents. Such embodiments allow for the iontophoretic transdermal delivery of therapeutic agents such as iron compounds for prolonged periods without any substantial corrosion of the electrode, impedance increases or discoloration or irritation of the skin. Embodiments of the invention are particularly useful for the long term treatment of various chronic medical conditions such as iron deficient anemia.

Description:
RELATIONSHIP TO OTHER APPLICATIONS 
     This application claims the benefit of priority to Provisional U.S. Patent Application No. 61/221,010, entitled “Corrosion Resistant Electrodes for Iontophoretic Transdermal Delivery Devices”, filed Jun. 26, 2009; the aforementioned priority application being hereby incorporated by reference for all purposes. 
    
    
     This application is also related to concurrently filed application entitled “Corrosion Resistant Electrodes for Iontophoretic Transdermal Delivery Devices and Methods of Use.”, which is being hereby incorporated by reference in its entirety for all purposes. 
     FIELD OF THE INVENTION 
     Embodiments described herein relate to electrode assemblies for iontophoretic transdermal delivery devices used for the delivery of various therapeutic agents. More specifically, embodiments described herein relate to conductive materials for electrode assemblies for iontophoretic transdermal delivery devices. 
     BACKGROUND 
     Iontophoresis is a non-invasive method of propelling high concentrations of a charged substance, known herein as the active agent, transdermally by repulsive electromotive force using a small electrical charge. The active agent can include a drug or other therapeutic agent. The charge is applied by an electrical power source to an active electrode assembly placed on the skin which contains a similarly charged active agent and a solvent in which it is dissolved. Current flows from the electrode assembly through the skin and then returns by means of a return or counter electrode assembly also placed on the skin. A positively charged electrode assembly, termed the anode will repel a positively charged active agent, or anion, into the skin, while a negatively charged electrode assembly, termed the cathode, will repel a negatively charged active agent, known as a cation into the skin. 
     Over time, metal electrodes used in iontophoretic transdermal patches may become corroded due to electrochemical corrosion of the metal during current flow through the electrode. Corrosion can increase the electrical impedance of the patch, decreasing the current delivered from that patch to the skin with a resulting decrease in the delivery rate of therapeutic agents from the patch. There is a need for electrochemically corrosion resistant electrode materials used in iontophoretic transdermal patches. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a lateral view showing an embodiment of a corrosion resistant electrode assembly for an iontophoretic transdermal delivery of a therapeutic agent. 
         FIG. 2  is a top down view of the embodiment of  FIG. 1 . 
         FIG. 3  is a prophetic plot showing the impedance for an embodiment of a corrosion resistant electrode during a period of current flow through the electrode and transdermal/iontophoretic delivery of a therapeutic agent. 
         FIG. 4  is a lateral view showing an alternative embodiment of a corrosion resistant electrode comprising carbon impregnated fibers. 
         FIGS. 5   a  and  5   b  are top views showing different embodiments for the shape of the electrode.  FIG. 5   a  shows an embodiment having a substantially disc shape.  FIG. 5   b  shows an embodiment having a substantially oval shape. 
         FIGS. 6   a  and  6   b  are lateral views showing different embodiments for the diameter of the electrode relative to the diameter of the porous tissue contacting layer.  FIG. 6   a  shows an embodiment where the diameter of the electrode is smaller than the diameter of the tissue contacting layer.  FIG. 6   b  shows an embodiment where the electrode and the porous layer have substantially the same diameter. 
         FIGS. 7   a - 7   d  are lateral views showing different embodiments for the contour of the edges of the electrode;  FIG. 7   a  shows an embodiment having a substantially squared edge;  FIG. 7   b  shows an embodiment having a substantially rounded edge;  FIG. 7   c  shows an embodiment having at least a partially tapered edge; and  FIG. 7   d  shows an embodiment of the electrode having a concave contour. 
         FIG. 8  is a lateral view showing an embodiment of a corrosion resistant electrode assembly including a reservoir for therapeutic agent where the electrode is positioned adjacent the reservoir. 
         FIG. 9  is a lateral view showing an embodiment of a corrosion resistant electrode assembly including a reservoir and a self sealing port for filling the reservoir with a therapeutic agent solution. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Embodiments described herein provide electrode assemblies for the iontophoretic transdermal delivery of therapeutic agents. Many embodiments provide a corrosion resistant electrode for the transdermal delivery of therapeutic agents. Such embodiments can be utilized for the delivery of a number of therapeutic agents including the delivery of iron containing compounds for the treatment of iron deficiency anemia and other iron deficiency diseases and conditions. 
     One embodiment provides a corrosion resistant electrode assembly for the iontophoretic transdermal delivery of a therapeutic agent, the electrode assembly comprising a conformable layer conformable to a contour of a skin surface and having a tissue contacting side and non-tissue contacting side; an electrical connector positioned on the non-tissue contacting side of the conformable layer, an electrode operatively coupled to the connector; and a tissue contacting porous layer positioned on the tissue contacting side of the conformable layer and operatively coupled to the electrode. The electrical connector is configured to be operatively coupled to an electrical power source such as an alkaline or lithium battery or other portable power source. The electrode is at least partially disposed in the porous layer. 
     In some embodiments, the electrode comprises a graphite or other electrochemically un-reactive material such that the electrode does not substantially corrode when current flows through the electrode from the power source during periods of iontophoretic transdermal delivery of the therapeutic agent. 
     Additionally, some embodiments provide that the electrode is structured to have sufficient corrosion resistance such that the impedance through the electrode does not substantially increase during periods of current flow through the electrode, for example, for periods of 12 to 96 hours or longer. Additionally, the electrode comprises a material which is sufficiently corrosion resistant and chemically inert such that it will not cause any appreciable discoloration or irritation of the skin from any corrosion that may occur. 
     In preferred embodiments, the electrode comprises a flexible compressed graphite material. Other graphites or organic compositions such as pyrolytic graphite are also considered. In alternative embodiments, the electrode can comprise a carbon impregnated polymer such as rubber or even polymer fibers such as cotton, polyesters, polysulphone or other polymeric fibers known in the art. 
     Typically, the electrode will have a thin disc shape with a preferred thickness of about 0.5 mm to about 2 mm. However, other shapes and thicknesses are also contemplated such as an oval shape. For disc and other shaped embodiments, the edges of the electrode can be square, rounded with a selected radius or even tapered partially or fully to minimize any electrical edge effects (e.g., current concentrations/increased current density at the electrode edges and resulting ohmic or other heating). The entire disc can also have a concave/dogbone contour to minimize edge effects by having the electrode have a larger thickness on the edges. In various embodiments, the electrode can be sized such that it has substantially the same surface area (e.g., diameter for disc shaped embodiments) as the underlying tissue contacting porous layer or it may have a smaller surface area, for example, 50% or 25% of the surface area of the porous layer. No matter what the size, the electrode can be centered above the tissue contacting porous layer, such that it is concentric with respect to the porous layer, though eccentric configurations are also contemplated. 
     In some embodiments, the electrode can also be sufficiently flexible so that it can bend and flex with the entire electrode assembly in order to conform to the contour of the skin surface. However, stiffer embodiments are also contemplated. Also, typically the electrode will be placed in direct contact with the tissue contacting porous layer and positioned directly above it relative to the non-tissue contacting side of the conformable layer. However, the electrode may also be operatively electrically coupled to the porous layer through an intermediary conductive material. 
     The tissue contacting porous layer is operatively coupled to the electrode such that the current from the electrode flows into the porous layer. In many embodiments, the porous layer will be in direct contact with the electrode, though use of an intermediary conductor is also contemplated to electrically couple the two structures. The porous layer can comprise compressed cotton or other fiber such as a polyester fiber or polysulphone and may be woven. The porous layer may have a sufficiently tight weave or other configuration such that it can capture any pieces of electrode material that break off from the electrode due to small amounts of corrosion during periods of current flow through the electrode. 
     In various embodiments, the electrode assembly can also include a reservoir for a solution containing the therapeutic agent. Typically, the electrode will be placed in direct contact with the reservoir, however, it may also be offset from the reservoir and operatively electrically coupled to it through an intermediary conductor. In embodiments having a reservoir, the electrode material comprises graphite or other material sufficiently resistant to electrochemical corrosion by an aqueous based therapeutic agent solution. 
     Still further, many embodiments include provide corrosion resistant electrodes and corrosion resistant electrode assemblies for use with iontophoretic transdermal delivery devices, such as various skin conformable patches for the iontophoretic transdermal delivery of various therapeutic agents (also described herein as the active agent). Such agents can include, for example, insulin, antibiotics, analgesics, chemotherapeutics and iron containing compounds for the treatment of anemia. Suitable iron compounds can comprise ionic iron in the form of ferrous (Fe 2+ ) or ferric (Fe 3+ ) iron. The ionic iron can comprise an iron salt, a ferrous salt, a ferric salt, ferric pyrophosphate, ferrous chloride or a combination thereof. Still other iron containing compounds known in the anemia treatment arts are also contemplated. 
     In specific embodiments, the active agent can comprise a sufficient amount of elemental iron for the treatment of iron deficiency anemia. The amount of elemental iron can be sufficient to provide between 1 to 100 mg of elemental iron to the patient a day for a period of days or even weeks. Further description on suitable iron compounds for the treatment of iron deficient anemia and like conditions may be found in U.S. patent application Ser. No. 12/459,862, filed Jul. 7, 2009 and entitled “Method For Transdermal Iontophoretic Delivery Of Chelated Agents”, which is fully incorporated by reference herein for all purposes. 
     Referring now to  FIGS. 1-2 , an embodiment of a corrosion resistant electrode assembly  10  for use with a iontophoretic transdermal delivery device  5  such as a patch device  5 , comprises a conformable layer  20 , an electrical connector  30 , an electrode  40  and a porous tissue contacting layer  50 . Conformable layer  20  is conformable to the contour of a skin surface and has a skin contacting side  21  and non-skin contacting side  22 . The conformable layer  20  can comprise various elastomeric polymers known in the art such as polyurethane or silicone and has sufficient flexibility to not only conform to a contour of the skin surface but also to bend and flex with movement of the skin. 
     Electrical connector  30 , hereafter connector  30 , is typically positioned on the non-tissue contacting side  22  of conformable layer  20  and comprises any number of standard electrical connectors such as various nipple connectors known in the medical instrument and electronics arts. The connector  30  is also directly or otherwise “electrically operatively” (hereinafter “operatively”) coupled to electrode  40 . It is also configured to be coupled to an electrical power source  60  which may comprise one or more portable batteries  65  such as alkaline, lithium, lithium ion or other battery chemistry known in the art. 
     Electrode  40  includes an electrochemically corrosion resistant material (hereinafter “corrosion resistance”) such that the electrode  40  does not undergo appreciable amounts of electrochemical corrosion (e.g., by oxidation or other related reactions) resulting from current flow through the electrode during iontophoretic transdermal delivery of the therapeutic agent or from any other current flow or electrical potential applied to the electrode. 
     The corrosion resistance of electrode  40  is also configured such that the conductive surface area  40 SAC of the electrode is substantially preserved during periods of iontophoretic transdermal drug delivery. The preservation of surface area  40 SAC in turn prevents any substantial increase in impedance of electrode  40 . In specific embodiments, electrode  40  is configured to resist corrosion and maintain a substantially constant impedance or otherwise resist any appreciable impedance increases for currents in the range of 0.1 ma to 10 ma and voltage from 1 v to 100 v for periods of current flow of 12, 24, 48, 72 or 96 hours or longer as is shown in  FIG. 3 . 
     Among other benefits, embodiments of a corrosion resistant electrode  40  provide several benefits for iontophoretic transdermal delivery of various therapeutic agents such as iron containing compounds, insulin, etc. These can include allowing the maintenance of a substantially constant voltage applied to an iontophoretic transdermal patch device during a period of iontophoretic transdermal delivery and/or keeping the voltage below a desired threshold. The applied voltage is used in iontophoretic transdermal delivery to provide the electromotive driving force for propelling charged therapeutic agents, such as ionic iron compounds, into the skin. If the impedance of the electrode increases as a result of corrosion, larger voltages may be required. Maintaining a substantially constant voltage during a period of iontophoretic delivery, or keeping it below a selected threshold, serves to increase battery life, (for embodiments of battery-powered iontophoretic patch devices) and reduces the likelihood of pain perception of the user by keeping the voltage below a pain threshold. 
     In particular embodiments, the voltage can be kept below a threshold of about 100 volts and still more preferably below about 40 volts. Additionally, having a corrosion resistant electrode can also allow the current density associated with electrode  40  and/or electrode assembly  10  to be kept below a threshold (for example, the threshold for causing pain to the patient). This is due to the fact that the conductive surface area  40 SAC of the electrode  40  remains substantially intact during the course of current delivery. In particular embodiments, the current density threshold associated with electrode  40  and/or electrode assembly  10  can be kept below about 1.0 ma/cm 2 , more preferably below about 0.8 ma/cm 2 , still more preferably below about 0.5 ma/cm 2  and still more preferably below about 0.2 ma/cm 2 . Still lower values for the current density are contemplated. 
     As an addition or alternative, electrode  40  comprises a material which is sufficiently corrosion resistant and chemically inert such that it will not cause any appreciable discoloration or irritation/inflammation of the skin or other foreign body response from any amount of corrosion that may occur (e.g., resulting in contact or penetration of the electrode material into the skin). In various embodiments, these results can be achieved by the selection of a carbon-based electrode material such as graphite, which is both corrosion resistant and relatively chemically inert to body tissue. 
     In many embodiments, electrode  40  comprises a conductive graphite material. Graphite is a layered carbon material in which the layers comprise hexagonal lattices of carbon atoms. Graphite can conduct electricity due to extensive electron dislocations within each layer. In preferred embodiments, the electrode comprises a flexible compressed graphite material such as a flexible graphite sheet which can be fabricated using a calendaring or other compression process known in the art. In such embodiments, the graphite material can have sufficient flexibility to allow the electrode  40  to flex along with the rest of electrode assembly  10  so as to conform to the contour of the skin at a selected application site. An example of a suitable graphite includes grade INTRS-PGS394 having a thickness of about 0.06″ available from the GraphiteStore.com (Buffalo Grove, Ill.). 
     Embodiments include use of other graphites such as pyrolytic graphite. Pyrolytic graphite is a unique form of graphite manufactured by decomposition of a hydrocarbon gas at very high temperature in a vacuum furnace. The result is an ultra-pure product which is near theoretical density and extremely anisotropic. Specific embodiments of pyrolytic graphite electrode  40  can be configured to allow for the electrical conduction through the electrode, but provide for thermal insulation in one or more directions. 
     In alternative embodiments, electrode  40  can comprise a graphite/carbon impregnated including polymer fibers such as cotton, polyesters, polysulphone other polymeric fibers known in the art. An example of a carbon/graphite impregnated fiber is shown in the embodiment of  FIG. 4 . In this embodiment, particles  43  of graphite powder are bound to fibers  44 . In other alternative embodiments, a corrosion resistant electrode  40  can comprise a carbon impregnated rubber or other carbon impregnated solid polymer, which can comprise various resilient polymers known in the art, allowing the electrode to bend and flex to conform to the contour of the skin surface. In use, such embodiments allow current to be delivered from an electrode assembly (including at least a portion of the electrode) in a bent position while preventing or minimizing any impedance rise in the electrode assembly due to corrosion of the electrode. 
     Still other alternative embodiments of a corrosion resistant electrode  40  can comprise carbon fibers (either turbostratic or graphitic carbon, or with a hybrid structure having both graphitic and turbostratic parts). In such embodiments, a disc or other shaped electrode  40 , can be cut from a carbon fiber rod. In still other alternative embodiments, a corrosion resistant electrode can comprise carbon black material, for example, compressed carbon black powder, or polymer, such as polymer fibers impregnated with carbon black. 
     Typically, the electrode  40  will have a thin disc shape  41  as is shown in the embodiments of  FIGS. 2 and 5   a . However, other shapes  40   s  are also contemplated, such as an oval shape  40   o  as is shown in the embodiment of  FIG. 5   b  which can be use in an oval shaped patch device  5 . The thickness  40   t  of the electrode  40  is selected to allow for both flexibility (e.g., to conform to the contour of the skin surface) and corrosion resistance of the electrode. In preferred embodiments, electrode  40  has a thickness  40   t  in the range of about 0.5 to about 2 mm. Other ranges of thickness are also contemplated, for example, about 2 mm to about 4 mm. Increased thickness&#39;s can be selected where more stiffness in electrode  40  is desired. 
     Typically, electrode  40  will be placed in direct contact with the tissue contacting porous layer  50  and positioned directly above it relative to the non-tissue contacting side  22  of the conformable layer  20 . In alternative embodiments, it may also be operatively electrically coupled to the porous layer through an intermediary conductive material (not shown). In still other alternative embodiments, portions of electrode  40  can be wrapped around porous layer  50  so that portions of the electrode are on the top and the sides of the porous layer  50 . 
     According to some embodiments, the electrode  40  can be positioned in various locations in or on conformable layer  20 . In preferred embodiments, electrode  40  is fully disposed within layer  20 , so that it is electrically insulated, but also may have all or a portion positioned on the tissue  21  or non-tissue contacting sides  22  of layer  20 . In these embodiments, the electrode  40  has an insulated coating (not shown) for those portions which are exposed. In some embodiments, all or a portion of electrode  40  can be placed in close proximity to the tissue contacting side  21 , (e.g., within 0.01″ or less). 
     Electrode  40  can have a variety of sizes depending one or more on the amount of conductive surface area  40 SAC desired, as well as the size of the underlying porous layer  50  and the various electrical parameters (e.g., current voltage, etc.) used for the iontophoretic transdermal delivery of therapeutic agent  85 . In various embodiments, electrode  40  can be sized such that it has substantially the same surface area  40 SA (and diameter  40 D for disc shaped embodiments of the electrode) as the surface area  50 SA (and diameter  50 D for disc shape embodiments of the porous layer) for the underlying tissue contacting porous layer  50 , as is shown in the embodiment of  FIG. 6   b . Alternatively, it may have a smaller surface area as is shown in the embodiment of  FIG. 6   a , for example, 50% to 25% of the surface area  50 SA of porous layer  50 . No matter what the size, the electrode is centered above the tissue contacting porous layer  50 , such that it is concentric with respect to the porous layer, though eccentric configurations are also contemplated. 
     Referring now to  FIGS. 7   a - 7   d , in various embodiments, the edges  40   e  of electrode  40  can also have a selectable shape  40   es  depending upon one or more of the size of the electrode and various electrical parameters (e.g., current, voltage, etc.) used for a particular iontophoretic transdermal patch  5 . In particular embodiments, the shape  40   es  of edge  40   e  can be square (shown in the embodiment of  FIG. 7   a ) or rounded with a selected radius (shown in the embodiment of  FIG. 7   b ) to minimize any edge effects or even tapered (shown in the embodiment of  FIG. 7   c ). For disc shaped embodiments of electrode  40 , the entire electrode can have a concave/dogbone contour  40   c  to minimize edge effects by having the electrode have a larger thickness  40   t  on the edges  40   e  (as is shown in the embodiment of  FIG. 7   d ). 
     Referring back to  FIGS. 1-6 , tissue contacting porous layer  50  is operatively coupled to the electrode  40  such that the current from the electrode flows into the porous layer. In many embodiments the porous layer  50  is in direct contact with electrode  40  as is shown in the embodiment of  FIG. 1 . However, in other embodiments, such as in the embodiment of  FIG. 8 , the use of an intermediary conductor, (in this case, a conductive therapeutic agent solution) is also contemplated to electrically couple the two structures. In various embodiments, porous layer  50  can comprise various fibers such as a polyester (e.g., PET) or polysulphone fiber and may be compressed and/or woven. Various polymeric foams may also be used. In preferred embodiments, the porous layer comprises compressed cotton. In one embodiment, the porous layer  50  has a sufficiently tight weave or other related property (e.g., porosity) such that it can capture any piece of electrode material that breaks off from electrode  40  due to small amounts of corrosion during periods of current flow through the electrode. In particular embodiments, the porous materials may also include various chemical functional groups or coatings selected to bind the graphite or other electrode material to provide an additional means for preventing the corrosive breakdown of electrode  40  and/or capturing pieces of corroded electrode  40  before they break off. 
     Referring now to  FIGS. 8-9 , in various embodiments, electrode assembly  10  can also include a reservoir  70  for a solution  80  containing a therapeutic agent  85  as is shown in the embodiments of  FIGS. 8 and 9 . Typically, in such embodiments, electrode  40  will be placed in direct contact with reservoir  70 ; however, it may also be offset from reservoir  70  a selected distance and operatively, electrically coupled to it through an intermediary conductor (not shown). In embodiments having a reservoir  70 , the electrode material comprises graphite or other material sufficiently resistant to electrochemical corrosion by an aqueous based therapeutic agent solution. As an addition or alternative to reservoir  70 , solution  80  and/or therapeutic agent  85  by itself may also be disposed in other locations within assembly  10 . It may for example, be disposed within porous layer  50  (e.g., by injecting solution  80  into the porous layer prior to use, or the therapeutic agent can be coated onto the fibers of porous layer  50  with solution  80  subsequently added so that agent then dissolves in the solution). Still other embodiments, contemplate operably associating therapeutic agent solution  80  to assembly  10  by an external source, for example, an external reservoir (not shown) or other that is fluidically coupled to porous layer  50  or other portion of assembly  10 . 
     In embodiments of electrode assembly  10  having a reservoir  70 , the electrode assembly  10  can also include a self sealing port  12  fluidically coupled to reservoir  70  for filling the reservoir with therapeutic agent  80 . The self sealing port  12  can comprise a silicone, or other elastomeric material, and allows the electrode assembly  10  to be filled with therapeutic solution  80  using a syringe and/or a mixing bottle with pointed tip and to do so using sterile technique. Typically, port  12  will include a channel  13  fluidically coupling the port  12  to the reservoir  70 . In these and related embodiments, electrode  40  is sized and positioned within layer  20  such that a needle or other port penetrating tip used to do the injection, will not make contact with electrode  40 . Also, an electrically insulating layer or barrier  14  can be positioned between port  12  and/or channel  13  and electrode  40  to minimize the likelihood of any electrical conduction between port  12  and/or channel  13  and the electrode. Barrier  14  can comprise various insulating polymers and other materials known in the art and can also have sufficient hardness to reduce the likelihood of penetration of electrode  40  by the needle tip or other port penetrating tip. 
     CONCLUSION 
     The foregoing description of various embodiments of the invention has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise forms disclosed. Many modifications, variations and refinements will be apparent to practitioners skilled in the art. For example, the iontophoretic electrode can be modified in material composition, size, and shape, depending upon one or more factors such as the type and amount of therapeutic agent; the tissue site, for the application of transdermal patch or other transdermal delivery device  5 , and the projected wear time and conditions (e.g., hours vs. days, temperature, humidity, etc). 
     Elements, characteristics, or acts from one embodiment can be readily recombined or substituted with one or more elements, characteristics or acts from other embodiments to form numerous additional embodiments within the scope of the invention. Moreover, elements that are shown or described as being combined with other elements, can, in various embodiments, exist as standalone elements. Hence, the scope of the present invention is not limited to the specifics of the described embodiments, but is instead limited solely by the appended claims.