Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/02—Details
  • A61N1/04—Electrodes
  • A61N1/0404—Electrodes for external use
  • A61N1/0408—Use-related aspects
  • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
  • A61N1/0432—Anode and cathode
  • A61N1/044—Shape of the electrode
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/02—Details
  • A61N1/04—Electrodes
  • A61N1/0404—Electrodes for external use
  • A61N1/0408—Use-related aspects
  • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
  • A61N1/0432—Anode and cathode
  • A61N1/0436—Material of the electrode
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/02—Details
  • A61N1/04—Electrodes
  • A61N1/0404—Electrodes for external use
  • A61N1/0408—Use-related aspects
  • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
  • A61N1/0448—Drug reservoir

Definitions

• the present invention generally relates to active devices for delivering a medicament to a patient transdermally, i.e., through the skin, and 5 more specifically relates to an active flexible electrode which can be used in an iontophoretic device and a method for making same.
• Transdermal administration provides a method by
• a medicament can be delivered in a controlled manner to target tissues either for localized effect or for systemic absorption.
• the transdermal administration of a medicament offers the advantage of being a noninvasive procedure which does not
• transdermal administration is ideally suited for sustained
• Passive transdermal drug delivery techniques There are two general types of transdermal drug delivery techniques i.e., “Passive” and “Active”.
• Passive transdermal drug delivery has its basis in natural physical phenomena such as osmosis, diffusion and differential solubility.
• iontophoresis Active transdermal delivery was first reported in 1908 when it was demonstrated that ions could be driven across the skin by means of an electric current.
• the active techniques are termed iontophoresis, electro-osmosis and electrophoresis and are collectively referred to here simply as iontophoresis.
• passive transdermal systems are most effective and used in the delivery of unionized lipophilic moieties which are active at low concentrations, e.g., nitroglycerin, nicotine, estrogen and others.
• Iontophoresis enables ionized solutes to be delivered transdermally and further allows control of delivery rate and duration of delivery.
• iontophoretic devices such as those described in U.S. Patent Nos. 4,820,263 ( Spevak et al. ) , 4,927,408 (Haak et al. ) , and 5,084,006 (Lew et al. ) , the disclosures of which are hereby incorporated by reference, are for actively delivering a medicament transdermally.
• these devices consist of two electrodes, i.e., a cathode and an anode. Both of these electrodes are disposed so as to be in electrical contact with some portion of the skin or other area of the patient, such as a mucous membrane.
• One electrode called the donor electrode is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by iontophoresis.
• the other electrode called the counter or return electrode, serves to close the electrical circuit through the body.
• the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery.
• a source of electrical energy e.g., a battery.
• the ionic substance to be delivered into the body is positively charged, i.e., a cation
• the anode will be the donor electrode and the cathode will serve to complete the circuit.
• the cathode will be the donor electrode and the anode will be the counter electrode. Further, it may be possible to deliver two drugs simultaneously by providing a cationic drug at the anode and an anionic drug at the cathode.
• Iontophoresis should be suitable for noninvasively delivering a medicament over a sustained period. It is often desirable to maintain a certain constant level of medicaments in the patient's system instead of periodically injecting a bolus dosage. In many current iontophoretic systems, such sustained delivery is not practical because of the danger of electrical and chemical burns.
• U. S. Patent 4,752,285 (Petelenz et al. ) , the disclosure of which is herein incorporated by reference, teaches these burns may stem from two sources, galvanic where the electrical current itself causes burns, and chemical where extremes in pH (which develop during the iontophoretic process) act in conjunction with electric current to cause chemical burns.
• Galvanic burns can be minimized or reduced by keeping the current density per unit area of skin below threshold values at which burning begins. Low current densities can be achieved by attention to design so as to maintain uniform electrode contact with the skin. Avoidance of folds, wrinkles and partial contact of the device electrode surface with the patient's skin, all help to eliminate high current density which induces galvanic burns.
• multiple electrodes and highly flexible devices may be useful in ensuring uniform contact with the patient's skin to avoid galvanic burns.
• Highly flexible devices are less likely to partially lift off the area of the patient's skin where they are placed, thus avoiding spots of high current density.
• the use of multiple small electrodes each with its own reservoir allow each electrode area to be maintained in uniform contact with the placement area on the patient's skin.
• H + and OH- ions which result from the electrolysis of water are extremely mobile, they migrate rapidly through the electrolyte solution away from the electrode and toward the skin of the patient. Thus, an area of extreme pH is ultimately created directly adjacent to the skin. This area of extreme pH is clearly undesirable and serious burns have been observed when these ions are actively transported through the skin.
• the problem of electrolysis of water with its concomitant generation of H and OH ions can be addressed by keeping the electrode potential below 1.23 volts relative to (SHE), or by the use of an electrode which is capable of reacting with the complementary ion of the medicament to form an insoluble precipitate at a voltage potential below the voltage potential for the electrolysis of water.
• a reactive electrode system into an iontophoretic device substantially eliminates the generation of H and OH ions, thus avoiding attack of the skin while maintaining the medicament at a desired pH.
• the use of an active electrode system with a counter ion which forms a precipitate with the electrode ion further precludes competition for transport between the counter ion and the medicament,
• a electrode formed from silver in conjunction with a chloride counter ion for the medicament fulfills the requirements for a reactive electrode system. While silver has been shown to perform satisfactorily in an iontophoretic system, cost constrains its use in commercial devices.
• the problem of burning a patient's skin during iontophoresis thus can be substantially reduced by ensuring intimate and uniform contact between an iontophoretic delivery device and the skin and incorporation of a reactive electrode into the device.
• an iontophoretic device particularly suitable for providing uniform contact with the skin, substantially eliminating burning of patient's skin while improving delivery efficiency by greatly reducing competitive ion transport can be constituted in accordance with the present invention.
• the invention includes an iontophoretic delivery device for delivering at least one medicament to an applied area of a patient.
• the device includes an electrode assembly for driving a medicament for absorption into the applied area to be absorbed by a patient's body.
• the electrode asse bly includes a flexible backing member.
• the backing member has an inside surface and an outside surface. The inside surface has a first area which has at least one flexible active electrode of a preselected pattern bonded to it, while a second area of the inside surface of the flexible backing member remains exposed.
• the iontophoretic delivery device further includes at least one reservoir for containing the medicament to be delivered situated in electrically conductive relation to the flexible electrode assembly.
• the device has a holder for holding the electrode assembly. The holder also maintains electrical communication between the electrode assembly and the reservoir.
• a flexible active electrode assembly for an active drug delivery device of the present invention includes a flexible backing member with an inside surface and an outside surface.
• the flexible backing member has an active metal member with a preselected pattern bonded to a first area of the backing member leaving a second area of the backing member exposed.
• the invention further includes a method for making a flexible active electrode for an active drug delivery device.
• the method includes providing a flexible backing member with an inside surface and an outside surface.
• the inside surface has two areas, a first area and a second area.
• An electroconductive material is applied in a preselected pattern to the first area of the inside surface while leaving the second area of the inside surface of the backing member exposed.
• the flexible active electrode assembly may be formed from at least one electrically conductive ink applied to the backing member or alternatively from a multi-layer active electrode including a layer of silver applied to an inert ink circuit rendered conductive by the inclusion of graphite or an intermediate metal conductive circuit layer bonded to the surface of the backing member.
• Alternative- ly/ the electroconductive ink may form the active electrode directly by including a first ink containing a metal selected from the group including silver, copper and molybdenum and a second electro- conductive ink containing an insoluble halide salt of the metal.
• an active electrode can be formed from an ink rendered conductive by inclusion of graphite which incorporates a metal selected from the group including silver, copper and molybdenum.
• the active electrode may further include an insoluble halide salt of the metal selected.
• Alternative embodiments may include a plurality of reservoirs, with a plurality of active elec ⁇ trodes.
• the active electrode assembly may include a system for activating the plurality of electrodes independently.
• An alternative method of assembly may include the backing member as a portion of a continuous web, with a plurality of individual electrodes being formed onto the web, a cutting step may be used ⁇ o release the individual electrodes from the web for subsequent assembly into devices.
• a plurality of iontophoretic devices may be formed on the web by adding reservoirs and holders to a plurality of the flexible active electrode assemblies formed on portions of the continuous web, a cutting step then being used to release the devices from the web.
• Fig. 1 is a cross-sectional view of a preferred embodiment of an iontophoretic device of the present invention having a flexible active electrode;
• Fig. 2 is a top plan view of the flexible electrode of the present invention.
• Figs. 3A-3E are a sequence of perspective views of stages in a preferred method for manufacture of a flexible electrode of the present invention.
• Figs. 4A and 4B are enlarged fragmentary, cross-sectional views of a flexible electrode ' of preferred embodiments of the present invention having a plurality of active metal members wherein the members are formed as (4A) a layered structure and (4B) as an electrically conductive ink;
• Fig. 4C is a top plan view of a flexible electrode of the present invention having a plurality of electrodes and electrode circuits;
• Fig. 5 is a top plan view of a plurality of the flexible electrodes of the present invention formed with a flexible backing member as a continuous web.
• the active drug delivery device of the present invention is illustrated in Figs. 1-5 and is generally designated as 20.
• the active drug delivery device of the present invention preferably an iontophoretic device 20
• the active drug delivery device of the present invention includes a flexible active electrode assembly 25 and at least one reservoir 42 for containing a medicament.
• the electrode assembly 25 includes a flexible backing member 30 with an inside surface 32 and an outside surface 34.
• the electrode assembly further includes an active metal member 36 bonded to a first area 38 of inside surface 32 in a preselected pattern 40 leaving a second area 41 of surface 32 exposed.
• Reservoir 42 is held in electrically conductive relation to the electrode assembly by a container or holder 43 which also serves to hold the flexible electrode assembly and maintain the electrode assembly and reservoir in electrical communication.
• the holder may include a connector 44 and conductors 46.
• Device 20 may further include a driver assembly 48 and a counter electrode 50 connected by con ⁇ ductors 46 to complete the electrical circuit.
• Device 20 may further include a protective release covering 52 held to the device by a layer of adhesive 53.
• the layer of adhesive 53 may also serve for mounting the device to an area of a patient to which the medicament is to be applied.
• the preferred device 20 may have flexible backing member 30 serve as the backing member for the reservoir, with inside surface 32 also serving as the inside surface of reservoir 42 and outside surface 34 serving as part of holder 43 for the device.
• Materials suitable for use as flexible backing member 30 include, but are not limited to, flexible films formed from polyethylene, polyethylene terephthalate, polyvinyl chloride and polyvinylidene fluoride.
• the particular material is not essential to the present invention as long as it provides flexibility, sufficient support for the active metal member and is compatible with the medicament system.
• the method of making the electrode assembly of the present invention is generally shown in Figs. 3A through 3E.
• the active electrode assembly 25 may be prepared with active metal member 36 bonded to inside surface 32 of flexible backing member 30.
• a flexible conductive metal layer, preferrably a flexible foil, 60 forms an electrode circuit 61 which then has a layer of metallic silver 62 bonded thereto to form the active metal member 36, with conductive foil 60 thereby intermediate silver layer 62 and backing member 36.
• An alternative for formation of active metal member 36 would be to form electrode circuit 61 from an ink rendered conductive by the incorporation of graphite and the like, then bonding metallic silver as a layer thereto.
• forming the preferred active metal electrode assembly includes bonding a layer of conductive metallic foil 60, preferrably a layer of copper, to inside surface 32 of flexible backing member 30.
• Preselected pattern 40, a photoresist or the like, as shown in Fig. 3C is then formed on a surface 63 of foil 60.
• the preselected pattern may be simple, as shown in Fig. 2, or complex, with multiple segments and the like.
• a portion of foil 60 is removed by, for example, etching the surface, with a portion 64 of the preferred foil not included in pattern 40 being removed, thereby forming electrode circuit 61 and exposing second area 41 of surface 32 (Fig. 3D).
• the etch process may be an acidic dissolution process, an electrochemical enhanced milling process, an ion milling, a laser milling process and the like for removal of portion 64 of the foil to leave electrode circuit 61 as shown in Fig. 3D.
• the particular process is not material to the present invention and is merely a matter of choice.
• metallic silver layer 62 is then bonded to at least a portion of the electrode circuit 61 forming an active metal member 36, as shown in Fig. 3E.
• Metallic silver layer 62 may be applied by an electroplating process, vacuum sputtering or any other method which results in a uniform layer of metallic silver being formed over the metallic foil electrode circuit.
• the preferred embodiment of the instant invention of forming a layer of metallic silver over the metallic foil electrode circuit instead of simply using silver for the entire electrode circuit serves to minimize the amount of the more expensive silver while maximizing the surface contact area of the silver with the reservoir, thereby enhancing the transfer of silver ions to the counter ion.
• by applying the silver after etching the foil to form the electrode circuit waste of the silver is also further eliminated.
• the amount of silver applied can vary depending upon the intended application. For example, a thicker layer of silver may be applied when the device is to be used for an extended period of time for delivery of larger quantities of medicament. Further, areas of an electrode circuit external to the reservoir may be left free of silver by masking during the silver application.
• the metallic silver portion may be treated to form silver chloride on its surface.
• a preferred method of treatment to form the silver chloride would be to treat the silver layer with aqueous hydrochloric acid while applying an electric current to the electrode.
• the preferred embodiment shown in Fig. 2 may have active metal member 36 formed from an electrically conductive ink containing a metal selected from the group including silver, copper and molybdenum, all of which form insoluble halide salts, with silver being preferred.
• the active metal member 36 may be formed from at least one electrically conductive ink applied in preselected pattern 40 on inside surface 32 (Figs. 3A and 3D).
• the electroconductive ink may further include graphite and an insoluble halide salt of the selected metal.
• a second electroconductive ink containing an insoluble halogen salt of the metal may be applied in a preselected pattern.
• a more preferred embodiment of the ink includes metallic silver with silver chloride.
• the techniques for application of ink 54 may include, but are not limited to, impression, lithography, offset, gravure, jet application, silkscreen and the like.
• electroconductive inks containing one of the metals selected from the group silver, copper and molybdenum with or without the insoluble halide salt of the selected metal may be applied so as to maximize the surface exposure of the included metal and halide, thereby ensuring maximum utilization of the metal and function of the electrode.
• the aforementioned ink application techniques may easily be utilized to apply preselected patterns of more than one electro ⁇ conductive ink for more than one circuit to a device, analogous to multicolor printing processes.
• the active electrode embodiment with a silver anode is preferred for cationic drugs having a chloride anion because silver chloride is very insoluble in aqueous systems and further, many cationic drugs are readily available and stable as the hydrochloride salts. .An iontophoretic delivery of such a drug with a silver anode, i.e., an active silver electrode, will result in the oxidation of silver to silver ion at the anode surface. The silver ion will react with the available chloride ion from the reservoir and precipitate near the electrode.
• Figs. 4A and 4B show enlarged cross sections of the preferred embodiments of active metal member 36 bonded to inside surface 32 of flexible backing member 30 in preselected pattern 40 leaving second portion 41 of inside surface 32 exposed.
• Fig. 4A shows the layered embodiment of active metal member 36, i.e. where the active metal, preferably silver, is layered over the electrode circuit formed from a bonded metal layer or from inert electroconductive ink as is shown in Fig. 3D.
• Fig. 4B shows the embodiment wherein the active metal member is electroconductive ink which directly incorporates the active metal and/or the insoluble chloride salt of the metal.
• any of the preferred embodiments of active metal member 36 may be used to provide a plurality of flexible electrodes 36 which may be formed on a single flexible backing member 30.
• the plurality of electrodes 36 may be attached to either a first conductor 66 or a second conductor 68. This arrangement of electrodes on two conductors allows the groups of electrodes to be activated independently " or simultaneously. This concept may be expanded to a plurality of conductors coupled with a plurality of electrodes to allow electrodes to be activated independently or together by the electrode assembly driver.
• this ability to form independent electrodes separately in a preselected pattern allows for the formation of a first active electrode circuit containing a metal selected from the group including silver, copper and molybdenum and a second active electrode circuit containing an insoluble halide salt of the metal.
• the first electrode may include both the active metal and an insoluble halide salt of the active metal.
• the instant invention allows more than one medicament to be contained in a plurality of reservoirs associated with the plurality of electrodes. The ability to replicate the electrodes allows a design for the device to provide optimum flexibility to conform to the application site on the patient thereby minimizing galvanic type burns caused by partial contact, creases and folds.
• flexible backing member 30 may be a continuous web 31 and a plurality of flexible electrode assemblies 25 may be applied to the web. Each device may be formed on a portion of the web, to be further assembled into iontophoretic devices. The finished devices could then be released from the web in a final cutting step.
• An alternative to the completion of an iontophoretic device on the web would be completion of a plurality of flexible electrode assemblies, each on a portion of the web. The individual electrodes would be released from the web by a cutting step followed by subsequent assembly steps to form completed devices.

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• Health & Medical Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
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• 1994
  • 1994-02-01 WO PCT/US1994/001152 patent/WO1994017853A1/en not_active Application Discontinuation
  • 1994-02-01 EP EP94907398A patent/EP0682541A4/de not_active Withdrawn
  • 1994-02-01 CA CA002155107A patent/CA2155107C/en not_active Expired - Fee Related
  • 1994-02-01 AU AU61001/94A patent/AU6100194A/en not_active Abandoned

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