STABLE ELECTRODE AND USES THEREJF

Cross-reference to related applications This application claims the benefit of U.S. Provisional Patent

Application Serial No. 60/631,193, filed November 29, 2004, of U.S. Provisional Patent Application Serial No. 60/639,400, filed December 28, 2004, and of U.S. Provisional Patent Application Serial No. 60/640,152, filed December 30, 2004. These related applications are assigned to the assignee of the present patent application, and their disclosures are incorporated herein by reference.

FIELD AND BACKGROUND OF THE INVENTION The present invention is of an electrode and uses thereof. In some embodiments, the present invention is of an electrode, which maintains electrode integrity on exposure or contact with water. Furthermore, the present invention is of an electrode for use with a current generating treatment device, such as an iontophoretic device. Still further, the present invention is of a current generating treatment device, method of production and uses thereof. Moreover, the present invention is of a dermal patch, which features at least one electrode, which maintains electrode integrity on exposure or contact with water.

Transdermal delivery devices, such as dermal patches are known in the art. These devices can incorporate a power source and electrical circuitry including electrodes for aiding transdermal delivery (active patch). There is also known in the art a range of dermal patches that incorporate a reservoir for holding a medicinal substance prior to administration. Some dermal patches may incorporate the reservoir as part of one or both of the electrodes, which deliver the current to the skin of the subject. Such electrodes are often referred to as bioelectrodes or donor electrodes. Bioelectrodes come in many sizes, shapes, and configurations. Examples of such bioelectrodes include those disclosed in U.S. Patent Nos. 5,037,380 and 5,248,295 which teach a patch having a refillable receptacle; U.S. Patent No. 5,846,217 which teaches a patch having a small access window for refilling; and

U.S. Patent Nos. 5,374,24, 5,730,716 and 6,223,075 which teach a patch that holds a dry medicament and must be hydrated. All such bioelectrodes are complex and consist of many parts and are therefore relatively bulky.

Reservoirs of donor electrodes may be manufactured by mixing or impregnating the active ingredient into a suitable matrix that may be for example a polymer hydrogel. The impregnated gel can be applied as a layer to the electrode, such as a Ag/ AgCl electrode printed onto a polymeric surface. Although this is a common method for preparing iontophoretic electrodes, it suffers from the disadvantage that the electrodes are relatively unstable in the presence of water and especially during long-term exposure to water or water containing material, such as hydrogel. Absorption of water by the electrode binder prevents the binder from binding the electroactive pole insoluble material to the electrode substrate and thereby results in an ineffective electrode.

Methods of overcoming this problem include employing iontophoretic devices with non-loaded electrodes, where the electrodes are loaded during treatment and application of the hydrogel prior to activation of the device. However, use of non-loaded electrodes can result in a less simple and slower method of use. The iontophoretic electrodes of the background art are therefore limited by their instability with water resulting in less effective electrodes and less facile use of the iontophoretic devices in which the electrodes are incorporated.

There is therefore a need for an electrode, such as is disclosed in the present invention, which is water resistant and maintains electrical properties in storage with water. There may also be a need for such an electrode with minimal added cost and which can be employed in a current generating treatment device, such as a dermal patch resulting in a simple to use patch.

BRIEF DESCRIPTION OF THE DRAWINGS

With reference now to the drawings in detail, it is stressed that the particulars shown, are by way of example and for the purposes of illustrative discussion of embodiments of the present invention only, and are presented for providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show

structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. FIG. Ia shows a schematic view of one embodiment of the electrode of the present invention.

FIG. Ib shows a schematic view of a further embodiment of the electrode of the present invention.

FIG. 2a shows a flow chart of a method of production of an electrode according to one embodiment of the present invention.

FIG. 2b shows a flow chart of a method of production of an electrode according to one embodiment of the present invention.

FIG. 3 a shows a schematic view of a current generating treatment device _; ^< > according to one embodiment of the present invention. . : ^{• ■ ■} FIG. 3b shows a schematic view of a dermal kit according to one embodiment of the present invention.

FIG. 4 shows a schematic view of an exemplary power source according to one embodiment of the present invention.

FIG.5a shows an exploded view of a device assembly, wherein the device is configured for use on the left side of the face according to one embodiment of the present invention.

FIG. 5b shows an exploded view of a device assembly, wherein the device is configured for use on the right side of the face according to one embodiment of the present invention. FIG. 6 shows a storage assembly of a device according to one embodiment of the present invention.

FIG. 7 shows a flow chart of a method of use of a device according to one embodiment of the present invention.

FIG. 8 shows a flow chart of a method of production of a device according to one embodiment of the present invention.

FIG. 9a shows a schematic view of a current generating treatment device for promoting delivery of an active substance according to one embodiment of the present invention.

FIG. 9b shows a schematic view of a dermal kit for promoting delivery of an active substance according to one embodiment of the present invention.

FIG. 10 shows an exploded view of a device assembly, according to one embodiment of the present invention. FIG. 11 shows a flow chart of a method of use of a device according to one embodiment of the present invention.

FIG. 12 shows a flow chart of a method of production of a device according to one embodiment of the present invention.

FIG. 13 shows graphical representation of depth of discharge (%DOD) of Electrode A with time of accelerated storage.

FIG. 14 shows graphical representation of CCV (closed circuit voltage) of Electrode A with time of accelerated storage.

FIG. 15 shows graphical representation of depth of discharge (%D0D) of Electrode B with time of accelerated storage. FIG. 16 shows graphical representation of CCV of Electrode B with time of accelerated storage.

FIG. 17 shows graphical representation of depth of discharge (%D0D) of Electrode A with time of room temperature (RT) storage.

FIG. 18 shows graphical representation of CCV of Electrode A with time of room temperature (RT) storage.

FIG. 19 shows graphical representation of depth of discharge (%DOD) of Electrode B with time of room temperature (RT) storage.

FIG. 20 shows graphical representation of CCV of Electrode B with time of room temperature (RT) storage. FIG. 21 shows graphical representation of corneometer data from example 3.

FIG. 22 shows graphical representation of expert grading from example 3.

FIG. 23 shows graphical representation of visual photo score - percentage of subjects with marked-moderate improvement around the eye area after single 20- minute treatment from example 3. FIG. 24 shows graphical representation of expert grading from example 4.

FIG. 25 shows graphical representation of visual photo score - percentage of subjects with marked-moderate improvement around the eye area after single 20- minute treatment from example 4.

FIGS. 26 and 27 are graphical representations of caffeine penetration from example 5.

FIG. 28 shows graphical representation of arbutin skin penetration from example 6.

DETAILED DESCRIPTION

The present invention is of a stable electrode and uses thereof. Moreover, the present invention is of an electrode, featuring a substrate, at least one electroactive insoluble pole material, and a binder material. Further, the present invention is of an electrode, featuring a substrate, at least one electroactive insoluble pole material, an aqueous conductive substance, and a binder material. The binder material may be a material which binds the electroactive insoluble pole material to the substrate and which does not absorb water. As used herein the term 'non-water absorbing binder' includes, but is not limited to a binder, which does not substantially absorb water. >. The term also includes a binder, which may absorb water, but which is not affected by water in any significant way, such as does not undergo any physical changes, or binding characteristic changes and no chemical or electrical property changes on absorbing water. The term further includes a hydrophobic binder. The aqueous conductive substance may be a hydrogel. Furthermore, the present invention may provide a use of such an electrode device in a current generating treatment device, such as for example in an iontophoretic patch.

Embodiments of the present invention include a current generating treatment device. In some embodiments current generating treatment device is for delivering current. In some embodiments current generating treatment device is configured to promote delivery of an active substance. In some embodiments current generating treatment device is configured for facilitating a combination of at least two of promoting delivery of an active substance, electrical stimulation and moisturizing of the skin. In some embodiments, current generating treatment device can be a dermal patch, hi some embodiments the dermal patch is a powered dermal patch. In some embodiments, dermal patch is an integrated patch which includes at least one main electrode, at least one counter electrode, at least one power supply and an integrated conductive composition, disposed on a base layer substrate, hi an embodiment wherein device is for promoting delivery of an active substance, device may include

at least one main active electrode, at least one counter electrode, at least one power supply, a holding means for containing an integrated conductive composition layer and an active agent, at least one conductive composition and at least one active agent, and wherein the patch components are disposed on a base layer substrate. In some embodiments at least one of the electrodes is stable and resistant to water. In some embodiments at least one of the electrodes includes an electrode substrate, at least one electroactive insoluble pole material and a binder material, wherein the binder material does not absorb water. In some embodiments, conductive composition is an aqueous conductive composition. In some embodiments the device is thin and flexible.

Embodiments of the present invention also include a dermal kit including a current generating treatment device and a conductive composition. In some embodiments the current generating treatment device features at least one water resistant first electrode and at least one second electrode of opposite polarity to the . - first electrode and at least one power supply to provide power for the current ., generating treatment device. In some embodiments at least one water resistant electrode features an electroactive insoluble pole material and a binder material, wherein the binder material does not absorb water. In some embodiments the conductive composition is a hydrogel. Optionally, the conductive composition can be attached to the current generating treatment device before use, can be disposed on at least one of the electrodes before use or can be applied to a body area region prior to use.

Embodiments of the present invention also include a dermal kit including a current generating treatment device for promoting delivery of an active substance, at least one active substance and at least one conductive composition. Optionally, the at least one active substance or the at least one conductive composition can be separate components or can be integrally formed together. In an embodiment, wherein the at least one active substance and at least one conductive composition are separate components, one of either component can be integrally formed with the current generating treatment device. In some embodiments the current generating treatment device features at least one water resistant first electrode and at least one second electrode of opposite polarity to the first electrode and a power supply to provide power for the device. In some embodiments at least one water resistant

electrode features an electroactive insoluble pole material and a binder material, wherein the binder material does not absorb water. In some embodiments the conductive composition is a hydrogel. Optionally, the conductive composition and active agent can be attached to the current generating treatment device before use, can be disposed on at least one of the electrodes before use or can be applied to a body area region prior to use.

Embodiments of the present invention also include a current generating treatment device for moisturizing a skin portion. In some embodiments the device includes an aqueous composition comprising an osmosis inducing component for delivery of water into the skin, a current providing means for facilitating delivery of water from the aqueous composition and/or from water in the skin and an occlusion means for preventing water from being released externally from the skin. In some embodiments the device includes an aqueous composition comprising an osmosis inducing component for delivery of water into the skin and a current providing means for facilitating delivery of water from the aqμeous composition and/or from water in skin. In some embodiments, the device includes an aqueous composition, a current providing means for facilitating delivery of water from the aqueous composition and/or from water in skin and an occlusion means for preventing water from being released externally from the skin. Embodiments of the present invention also include uses and methods of use of a current generating treatment device of the present invention, hi some embodiments, current generating treatment device, such as but not limited to a dermal patch may be used to reduce and eliminate wrinkles, fine facial lines, laugh lines, aging skin, dry skin, sundamaged skin, age spots, hyperpigmented spots, cellulite, puffy eyes, scars, warts, varicose veins, stretch marks, under eye dark circles, lifting skin, increasing blood flow, pain management, onychomycosis, wound treatment, bone healing, treating hyperhidrosis, acne treatment, hair growth disorders, Hp plumping, facilitating muscle contraction, for massage, promoting metabolic processes and combinations thereof. Embodiments of the present invention also include uses and methods of use of a current generating device treatment device for promoting delivery of an active substance of the present invention, hi some embodiments, device for promoting active substance delivery, such as but not limited to a dermal patch is used for

treatment of acne, age spots, dermatitis, wrinkles, fine facial lines, laugh lines, aging skin, dry skin, sun damaged skin, puffy eyes, lip plumping, lifting skin, skin and nail viral, fungal and bacterial infections, onychomycosis, disorders of the hair follicles and sebaceous glands, scaling disease, scars, wounds, cellulite, skin and tooth whitening, pigmentation disorders, wrinkles, warts, benign tumors, malignant tumors, pain management, increasing blood flow, treating hyperhidrosis, bone healing, facilitating muscle contraction, promoting metabolic processes, body decoration, as a general drug delivery system to deliver any suitable drug or active ingredient to any suitable body region and combinations thereof. Embodiments of the present invention also include methods of production of a current generating treatment device of the present invention.

As used herein the term 'current generating treatment device' refers to any device or arrangement of components which is configured to facilitate an electrical current, which can be used for a cosmetic or medical application. The term includes, but is not limited to a powered dermal patch, a galvanic stimulation device or any. delivery device, which is powered and can facilitate a change in a skin or body condition, by any suitable mechanism. The term includes, but is not limited to a topical delivery iontophoretic device, topical delivery ultrasonic device, topical delivery RF device, topical delivery micro-needle device, topical physical therapy device, such as, but not limited to TENS, EMS, electric wound healing device, skin stimulator, neural stimulator, muscle stimulator, oral care stimulator and a combination thereof.

As used herein the term 'contact with water' includes, but is not limited to, contact with any form of water and any purity of water. The term includes contact with any water containing substance or formulation. The term includes contact or exposure to any environment containing water or moisture. The term includes contact with alcoholic solutions.

As used herein the term 'treatment' includes, but is not limited to prevention, elimination, reducing severity, alleviating direct symptoms and related symptoms and curing of a condition. The term also includes facilitating change of a condition. The term further includes an improvement in appearance of a condition.

Manufacture of an active electrode as described in the background art includes several steps, wherein a first step may include providing a substrate. The

substrate can be a conductive substrate, such as a conductive polymer film. An electroactive insoluble pole substance is then applied to the substrate. However, an inherent deficiency of electroactive insoluble pole substances is that they do not bind sufficiently to the substrate, hi order to improve the binding of the electroactive insoluble pole substance to the substrate, a binder may be applied with the electroactive insoluble pole substance, which readily facilitates binding of the electroactive insoluble pole substance to the substrate. A problem associated with most binders is their water absorbing properties. Therefore, if a water absorbing binder is used in an electrode, which is to be used in a water containing environment, such as wherein a hydrogel is applied or integrally contained therein, the water from the hydrogel will be absorbed by the binder and prevent or hinder binding of the electroactive insoluble pole substance to the substrate, resulting in degradation of the electrode and poor electrical properties. As such this is also a problem associated with a current generating treatment device, with an integrated aqueous conductive layer. . .

The present invention provides a solution to this problem by providing a novel electrode and/or a current generating treatment device which includes a novel electrode, wherein the electrode may include a non-water soluble binder, which does not substantially react with the water in the hydrogel, maintaining the binding of the electroactive insoluble pole material and therefore resulting in an electrode with improved electrical properties.

The principles and operation of an electrode and current generating treatment device according to the present invention may be better understood with reference to the figures. The figures show non-limiting embodiments of the present invention. Figure Ia shows a schematic view of one embodiment of the electrode of the present invention 10. As can be seen in figure Ia, electrode of the present invention 10 features a substrate 12, a pole insoluble electro-active substance 14, and a binder material 16.

Electrode 10 may feature a layer of substrate 12. In some embodiments, substrate 12 is a first inner layer. The substrate may be made from a material, which is sufficiently strong and stable to hold the layers of electrode 10. Optionally, substrate can be made from at least one of or a combination of any suitable substrate material, such as, but not limited to, a conductive material, a non-conductive

material, a woven material, a non-woven material, vinyl, polyester, paper, or a combination thereof. The substrate 12 may be a conductive substrate 12. hi some embodiments, conductive substrate may be electrically conductive, but is not ionically conductive, hi some embodiments, conductive substrate 12 may be a conductive polymer film 12. hi some embodiments, conductive polymer film 12 may be a conductive vinyl film 12, which may be a vinyl including a conductive material. One example of a conductive vinyl film is a vinyl conductive web, such as manufactured by InteliCoat, such as, but not limited to 2264 and 2252, which are thin, flexible and conductive films. Conductive substrate 12 may accommodate a layer of electroactive insoluble, pole substance 14. Electroactive insoluble pole substance 14 can optionally be any suitable negative or positive pole electroactive insoluble substance 14. Examples of suitable electroactive insoluble pole substances 14 include, but are not limited to silver/silver chloride, zinc, manganese dioxide, graphite, aluminum, platinum, stainless steel, tin oxide, silver oxide, gold and titanium, hydrophobic polymer . "matrix containing a conductive filler such as metal powder/flakes, powdered graphite, carbon fibers or other known electrically conductive filler material, conductive plastic of any kind and combinations thereof, hi one embodiment, electroactive insoluble pole substance 14 may be silver/silver chloride. Silver/silver chloride is commonly made up of a mixture of fine particles of silver and silver chloride. Electroactive insoluble pole substance 14 maybe selected depending on the desired electrode properties and use of electrode 10.

Electroactive insoluble pole substance 14 may contain a binder material 16. Binder material 16 may be applied with electroactive insoluble pole substance 14, in order to maintain contact between the particles and adhesion to substrate 12. In some embodiments, binder material 16 may be a non-water absorbing material, hi one embodiment, binder material 16 may be a non- water absorbing resin, hi another embodiment, binder material 16 may be a vinyl resin, hi one embodiment vinyl resin may be a thermoplastic vinyl resin, hi some embodiments, vinyl resin may be a hydroxyl modified vinyl copolymer, such as VAGD. Binder material 16 may be dissolved in a suitable non-aqueous solvent and mixed with electroactive insoluble pole substance 14. hi some embodiments, the mixture of binder material 16 and electroactive insoluble pole material 14 may be prepared as an ink formulation. The

binder material 16 and electroactive insoluble pole substance 14 formulation may be applied onto substrate 12 using any suitable technique. In some embodiments, the solvent may be removed by evaporation.

The combined electroactive insoluble pole substance 14 and binder material 16 formulation may be water resistant. The term 'water resistant' as used herein includes a mixture of binder and an electroactive insoluble pole material (ink formulation) wherein the binding properties of the ink formulation and the resulting physical and electrical properties of an electrode in which the ink formulation is used, are not affected or damaged, when the ink formulation is in contact with water or any type of aqueous environment. Further the term includes, such a mixture or formulation which optionally does not absorb water or does absorb water or moisture, but wherein the binding properties of the ink and physical and electrical properties of the resulting electrode are unaffected by the water or moisture. Still ^• further, the term includes an electrode, which is stable in water (water stable . electrode), wherein the physical and electrical properties of the electrode are , _; ; substantially not affected by water.

One method of making electrode 10 is shown in FIG. 2a and may include the following steps. An electrode substrate maybe provided 150. The substrate maybe a vinyl web. Binder material may be dissolved in a suitable non-aqueous solvent and mixed with electroactive insoluble pole substance 152. In some embodiments, the binder and electroactive insoluble pole substances are mixed into an ink. Optionally, ink can include other components such as graphite or carbon to increase conductivity. The ink formulation of binder material and electroactive insoluble pole substance may be applied onto electrode substrate 154. Any suitable method of application can be used including a printing method. In some embodiments, the solvent may be removed by any suitable method such as but not limited to evaporation 156.

FIG. Ib shows a schematic view of another embodiment of the electrode of the present invention 100. As can be seen in FIG. Ib, electrode of the present invention 100 may feature a substrate 12, a pole insoluble electro-active substance 14, binder material 16, and conductive substance 18.

Substrate 12, electroactive insoluble pole substance 14, and binder material 16 of electrode 100 are as described hereinabove in FIG. Ia for electrode 10. A

conductive substance 18 maybe applied onto electrode 100. Conductive substance 18 may be disposed onto the layer of electroactive insoluble pole 14 and binder 16 material formulation. Conductive substance 18 may readily facilitate providing a conductive interfacing layer between the body/skin and electrodes 100. Conductive substance 18 may be a conductive adhesive or a conductive fluid or any suitable substance which includes conductive particles. Optionally, conductive adhesive is a hydrogel or an acrylic adhesive. In one embodiment, conductive fluid may be a hydrogel, such as an aqueous hydrogel. Conductive substance 18, such as hydrogel can optionally be connected to, integrally formed with, partially formed with, or disposed in many different ways, with electrode 10. Conductive substance 18 may be applied onto and may be in direct contact with layer of binder 16 and electroactive insoluble pole substance 14. Optionally, hydrogel 18, can include other substances, such as but not limited to an active agent or moisturizing agent, such as a drug, a pharmaceutical, a cosmeceutical or a cosmetic, a pigment/ink, water, surfactants, emulsifiers, diglycerides, triglycerides, stabilizing agents, thickening agents, alpha-hydroxy carboxylic acids, antioxidants, preservatives, moisturizers, petroleum, mineral oil, glycerol, ethanol, propanol, isopropanol, butanol, vitamins, such as vitamin C and E, caffeine, polymeric gelling agents, flavoring, colorant and odorant agents and other formulation components, used in the art of pharmaceutical and cosmetic formulary, for delivery into a subject.

One method of making electrode 100 is shown in FIG. 2b and may include the following steps. In a first step, an electrode substrate may be provided 160. The substrate may be a vinyl web. In a second step, binder material may be dissolved in a suitable non-aqueous solvent and mixed with electroactive insoluble pole substance 162. In some embodiments, the binder and electroactive insoluble pole substances are mixed into an ink. Optionally, ink can include other components such as graphite or carbon to increase conductivity. The ink formulation of binder material and electroactive insoluble pole substance may be applied onto electrode substrate 164. Any suitable method of application can be used including a printing method, hi some embodiments, the solvent may be removed by any suitable method such as but not limited to evaporation 166.

In some embodiments, conductive substance, such as for example hydrogel may then be applied onto electroactive insoluble pole layer 168. Conductive

substance can be applied using any suitable method such as coating and printing. In some embodiments, conductive substance may be applied by lamination or using a pick and place procedure. Conductive substance can be applied directly to electrode 100 or can be contained in a separate compartment (not shown in FIG. Ib), which may be attached to electrode 100 and wherein conductive substance is only in fluid connection on use of the electrode, such as by removing a separating means.

Referring back to FIG. Ia and FIG. Ib, in some embodiments, electrode 10 and electrode 100 may be a thin and flexible electrode. Optionally, electrodes 10, 100 may be of any size and shape. In some embodiments, electrode 10, 100 may be made by a printing technique. Electrodes 10, 100 may optionally be provided as a thin sheet, or alternatively printed onto a substrate. The electrode area can be continuous, or formed as a drawing, in any shape, to provide a decorative form, hi some embodiments, electrode may be a perforated electrode or in a mesh form. Electrode 100 may optionally include a corrosion inhibitor. A corrosion inhibitor may be useful, wherein electroactive insoluble pole substance 14 is corroded in contact with water, such as, but not limited to zinc, hi some embodiments, electrode of the present invention 10 100, has medical and cosmetic application, hi some embodiments, electrode 10, 100 may be used in a current generating treatment device, such as a dermal patch, for iontophoretic delivery of a substance or for electrical stimulation of the skin, hi one embodiment of the present invention wherein electrode 10, 100 is used in a dermal patch, the patch may include at least one first electrode, identified as 'cathode' and at least one second electrode, identified as 'anode' and a power source and a conductive substance.

Optionally, both electrodes of patch may be electrodes of the present invention 10, 100 as shown and described in FIGS. la,b, or alternatively one electrode may be an electrode according to the present invention and the other electrode may be any suitable electrode. In an embodiment wherein one of the electrodes of the dermal patch is a zinc water resistant electrode according to the present invention, the zinc electrode facilitates a patch, which produces high current and high voltage. Further, the water resistant properties of the zinc electrode of the present invention facilitate use with a hydrogel or other aqueous conductive substance.

Optionally electrode 10, 100 may be used in any suitable current generating treatment device known to those skilled in the art, such as, but not limited to an iontophoretic device, a tens devise or galvanic stimulation device.

Optionally, wherein conductive substance 18 is a conductive adhesive, such as but not limited to hydrogel or an acrylic adhesive, electrode 100 may be used in a detection device or sensor device.

FIG. 3 a shows a schematic view of a fully integrated patch device according to one embodiment of the present invention. The patch device 200 is fully integrated in the sense that the conductive substance/layer 212 is incorporated into the device, hi this embodiment, patch 200 may comprise first electrode 214, identified as "cathode," second electrode 216, identified as "anode", electrochemical cell 218 as the power supply of patch 200 and at least one conductive substance 212 (1), 212 (2). Optionally, patch 200 may include a plurality of cathodes 214, a • plurality of anodes 216 and a plurality of power supplies 218. In some embodiments, patch 200 may comprise conductive layer/s 212(1), 212(2) to provide an interfaping layer between patch 200 and a body area of a subject. Further, conductive layer 212 disposed on main electrode can provide ions, which are delivered into the skin, to facilitate hydration of skin and elimination of wrinkles.

As shown in FIG 3 a, electrodes 214, 216, conductive layers 212(1), 212(2), and electrochemical cell 218 may be supported on a base layer substrate 220.

Electrode 214 may be disposed in any suitable way on substrate base layer 220 in spaced relation to electrochemical cell 218 and electrode 216 to define a gap between the two electrodes 214, 216. Optionally, the same conductive layer 212 can be disposed on both anode 216 and cathode 214 or conductive layers 212(1) and 212(2) can be different conductive substance layers, hi some embodiments, a hydrogel 212 is disposed on the main electrode and any suitable conductive substance, which can facilitate providing a conductive adhesive interface is disposed on the counter electrode, hi some embodiments, hydrogel 212 is an aqueous hydrogel. hi some embodiments, patch 200, including patch components, is thin and flexible, to suit the contour of a body area of a subject, hi some embodiments, patch 200 is electrically powered. Patch may optionally be any size, color and shape suitable for application to a desired body area. The thickness of patch 200 can be in

some embodiments up to about 10 mm to ensure flexibility, but may be thicker, depending on the application. The thickness of the patch may also be dependent upon the type of material used and the flexibility of that material, the quality of the material and the duration of treatment. Patch 200 is in some embodiments disposable, but may be reusable. Optionally, patch can be modular, including a reusable part, such as the frame and disposable parts, such as conductive substance, electrodes and battery. Patch 200 is stable to a wide range of temperatures and humidity, hi some embodiments patch can be biocompatible or dermatologically approved. Patch 200 can be configured to be used on any suitable area of the body, including, but not limited to skin, mucous membrane, face, neck, arms, hands, legs, thighs, buttocks, feet, toes, fingers, nails, nail appendage, teeth, palms, soles, back, head, hair, shoulders and torso and combinations thereof. In some embodiments, patch 200 can be for use under and near the eyes, on the crows-feet area, on the cheeks, laugh lines, forehead, lips, chin and neck and a combination thereof. Any power supply 218, of any suitable size or shape, which provides an, electrical potential of between about 0.2' Volt and about 100 Volt can be used according to the present invention. In some embodiments, power supply 218 is an electrical battery, providing an electrical potential of between about 0.5 Volt and 12 Volts, hi some embodiments power supply 218, can supply a voltage of 1.5 V or 3 V. hi some embodiments, power supply 218 is thin and flexible. Li some embodiments, power supply 218 is disposable. In some embodiments, power supply thickness should not exceed 4 mm and in some embodiments, power supply thickness should be less than 2 mm. hi some embodiments, power supply 218 is at least one electrochemical cell. The term 'electrochemical cell' as used herein includes any suitable open, closed or semi-open cell in any suitable physical or chemical state in which chemical energy is converted to electric energy by a spontaneous electron transfer reaction. The term includes cells with non- spontaneous reactions, cells with spontaneous reactions, galvanic cells, electrolytic cells, and a combination thereof. Optionally, power source can be rechargeable. FIG. 4 illustrates a schematic representation of an exemplary power source

300 in accordance with an embodiment of the invention. In some embodiments, power source 300 is thin and flexible, hi the embodiment of FIG. 4, the power source is depicted as an electrochemical cell. The thickness 301 of the

electrochemical cell 300 may be up to about 4 mm, in some embodiments up to about 2 mm and in some embodiments up to about 1 mm.

In one embodiment, electrochemical cell 300 includes a positive pole layer 302, a negative pole layer 304, and an electrolyte layer 306 interposed therebetween. In some embodiments, electrochemical cell 300 includes one or more additional conductive layers 308 and 310 to improve the conductivity of pole layers 302 and 304. Suitable conductive layers 308 and 310 are in some embodiments made from any suitable conductive material, such as carbon, graphite, silver, platinum or gold or combinations thereof. In some embodiments conductive layers (current collectors) 308 and 310 are graphite or carbon based layers, which can be printed or applied in any suitable way to cell 300. Examples of graphite and carbon based layers include graphite or carbon webs, sheets, inks and cloth. In some embodiments, electrochemical cell includes negative terminals 312 and positive terminals 314, which are in contact with the corresponding pole layer 304 and 302 or with the corresponding conductive layer 308 and 310 or both. Terminals are made of any suitable material such as, but not limited to, graphite or metal and are in some embodiments applied to cell 300 by a suitable printing technology. Terminals may be located in any desired location of cell 300 and may acquire any suitable shape and size, depending on the specific application. Optionally, terminals may protrude from the surface of cell 300.

By way of example, a suitable electrochemical cell 300 is described in U.S. Patent Nos. 5,652,043, 5,897,522, and 5,811,204, each of which are incorporated herein by reference in their entireties. Briefly, the electrochemical cell described in the above-identified U.S. Patents is an open liquid state, electrochemical cell, which can be used as a primary or rechargeable power source for various miniaturized and portable electrically powered devices of compact design. In one embodiment, a preferable electrochemical cell 300 may comprise a first layer of insoluble negative pole 304, a second layer of insoluble positive pole 302, and a third layer of aqueous electrolyte 306 disposed between the first 304 and second 306 layers and may include (a) a deliquescent material (not shown) for keeping the open cell wet at all times; (b) an electroactive soluble material (not shown) for obtaining required ionic conductivity; and, (c) a polymer such as a water-soluble polymer (not shown) for

obtaining a required viscosity for adhering the first and second layers to the third layer.

Yet, in another preferred embodiment, an electrochemical cell may comprise a plurality of self-contained, serially connected galvanic power sources, as described for example in United States Patent 6,421 ,561 , which is incorporated herein by reference in its entirety.

Several preferred embodiments of the disclosed electrochemical cell include (i) engaging the electrolyte layer in a porous substance, such as, but not limited to, a filter paper, a plastic membrane, a cellulose membrane and a cloth; (ii) having the first layer of insoluble negative pole include zinc powder and the second layer of insoluble positive pole include manganese-dioxide powder; (iii) having the first layer of insoluble negative pole and/or the second layer of insoluble positive pole further include carbon powder; (iv) selecting the electroactive soluble from zinc-chloride, zinc-bromide, zinc-fluoride and potassium-hydroxide; (v) having the first layer of insoluble negative pole include silver-oxide powder and the second . . layer of insoluble positive pole include zinc powder and the electroactive soluble material is potassium-hydroxide; (vi) having the first layer of insoluble negative pole include cadmium powder and the second layer of insoluble positive pole include nickel-oxide powder and selecting the electroactive soluble material to be potassium-hydroxide; (vii) having the first layer of insoluble negative pole include iron powder and the second layer of insoluble positive pole include nickel-oxide powder and selecting the electroactive soluble material to be potassium-hydroxide; (viii) having the first layer of insoluble negative pole and the second layer, of insoluble positive pole include lead-oxide powder, then cell is charged by voltage applied to the poles and the electroactive soluble material is selected in this case to be sulfuric-acid; (ix) the deliquescent material and the electroactive soluble material can, be the same material such as zinc-chloride, zinc-bromide, zinc-fluoride and potassium-hydroxide; (x) the deliquescent material is selected from the group consisting of calcium-bromide, potassium-biphosphate and potassium-acetate; (xi) the water-soluble polymer can be polyvinyl alcohol, polyacrylamide, polyacrylic acid, polyvinylpyrolidone, polyethylenoxide, agar, agarose, starch, hydroxycthylcellulose and combinations and copolymers thereof; (xii) the water-soluble polymer and the deliquescent material can be the same material such

as dextrane, dextranesulfate and combinations and copolymer thereof. Optionally, electroactive insoluble material includes one of or a mixture of silver, silver/silver chloride, graphite, manganese dioxide, platinum, carbon, graphite, zinc, nickel, iron, magnesium, gold and copper. In some embodiments, electrochemical cell 300 includes poles of carbon and zinc film. An electrochemical cell may in some embodiments incorporate any one or more of the embodiments described above. Preferred configurations for electrochemical cells according to the present invention involve those combinations, which are devoid of poisonous compounds. hi some embodiments, the power source is applied using a suitable printing technique.

Referring back to FIG. 3a, power supply 218 in patch 200 may be a single electrochemical cell. However, power supply 218 need not be limited to one cell, but may include a plurality of connected electrochemical cells, a plurality of batteries, and/or electronics configured to increase; control, regulate and change phase of the supplied electric current, voltage and time duration and wherein the . power supply is thin and flexible. Electrochemical cell 218 in patch 200 in some embodiments provides electrical potential (voltage) to the desired body area of the subject, hi some embodiments, the electrical potential may be adjusted to satisfy at least one of the following three criteria. First, the patch voltage may be adjusted to enable an iontophoretic delivery or other mechanism of delivery of the water and/or other ions onto and into the body area. Second, the patch voltage may be adjusted to minimize the penetration of the water and/or other ions through the body, and to maximize the amount into the desired body area. Third, the patch voltage may be adjusted to minimize body area irritation, which may result from excessive electric current, passing into and through the body.

The power supply 218 may optionally be located in any suitable position on the patch 200. hi one embodiment, the power supply may be disposed between counter electrode and substrate. Optionally, power source 218 can be located externally from patch.

A power supply 218 to patch 200 may provide a duty cycle and pulse partition rate of between about 1% and about 99%. The frequency of the power supply may in some embodiments be from about IHz to about 1000Hz. The power

supply may provide voltage in a preferable range of from about 0.5 V to about 100V to the patch.

Current provided by the current generating treatment device, such as a patch may be any suitable form of current, including DC ₅ AC, pulse or other phase form. In some embodiments current generating treatment device provides DC current. In some embodiments, the current provided is from about 0.5μA/cm ² to about 500μA/cm ² . In some embodiments, wherein a 1.5 V power supply is used, the current provided is from about 0.5μA/cm to about 50μA/cm . In some embodiments, wherein a 3 V power supply is used, the current provided is from about 1.0μA/cm ² to about 200μA/cm ² . In some embodiments, power supply 218 is attached to substrate base layer 220 with any suitable means, such as, but not limited to adhesive. In some embodiments adhesive may be an acrylic adhesive.

Cathode and anode electrodes 214 and 216 are in some embodiments composed of a conductive material. Any suitable conductive" material can be used, such as, but not limited to silver, silver/silver chloride, zinc, manganese dioxide, graphite, carbon, copper, aluminum, platinum, stainless steel, tin oxide, silver oxide, gold and titanium, hydrophobic polymer matrix containing a conductive filler such as metal powder/flakes, powdered graphite, carbon fibers or other known electrically conductive filler material and combinations thereof, hi some embodiments, at least one electrode is a main electrode and at least one electrode is a counter electrode. Optionally, the main electrode can be the cathode or anode or both the cathode and the anode. Defining which electrode is the main electrode is dependent on the charge of the ions contained in the conductive formulation 212(2), which is to be disposed on the main electrode facilitating delivery of the ions into/onto a body area. In some embodiments, anode 216 is the main electrode, hi some embodiments anode 216 is made from graphite, hi some embodiments, cathode 214 is the counter electrode. In some embodiments, cathode 214 is made from silver/silver chloride.

In some embodiments at least one of the electrodes 214, 216 is a water resistant/stable electrode as shown and described in FIGS. la,b. In some embodiments, main electrode is a water resistant/stable electrode, hi some embodiments both the anode 216 and cathode 214 are water resistant/stable electrodes. In some embodiments, the water stable/resistant electrode as herein described is an electrode, which is more flexible than electrodes of the art. As such,

a current generating treatment device, such as a patch comprising a water stable/resistant electrode will have improved flexibility properties.

Electrodes 214 and 216 may optionally be provided in any suitable form, such as, but not limited to as thin sheets, linked to the power source, or printed onto a substrate in spaced relation to each other to define a gap therebetween. Optionally, the electrode area can be continuous, in a net form, or formed in any shape or configuration. Optionally, cathode 214 and anode 216 may not have the same shape and/or same area. Optionally, cathode and anode may be in any suitable conformation in relation to each other including but not limited to a coplanar and cofacial arrangement. Optionally, patch can include a plurality of anodes and a plurality of cathodes. Such a multi-electrode patch facilitates providing simultaneously a plurality of treatments in different body areas or the same body area. Optionally, patch can include one internally disposed electrode, such as disposed on substrate/frame 220 and a second counter electrode which is external to the patch 200 or is located on an external side of the substrate/frame. J ₁₁

In some embodiments, cathode 214 and anode 216 are connected to battery 218 by any suitable connection means, 222, 224, such as electrical conduction means/media. Examples of connection means 222, 224, include, but are not limited to wiring, conductive ink, conductive adhesive tape, printed connection means, soldered connection means, connection means attached by UV, adhesive connection means and a combination thereof, hi some embodiments, electrode 214 and main electrode 216 are attached to substrate base layer/frame 220 by adhesive.

Substrate base layer/frame 220 is optionally any suitable material, which can accommodate the patch components. Suitable materials include, but are not limited to woven material, non- woven material, polymers, conducting material, nonconducting material, paper, cardboard, plastic, synthetic materials, natural materials, fabric, metals, wood, glass, Perspex, or a combination thereof. In some embodiments, substrate material may be a non-conductive material, hi some embodiments, substrate is made from polyester. In some embodiments, the substrate base layer 220 can be made from a biocompatible porous elastic nonwoven tape with mild adhesive, such as polyurethane with an acrylic adhesive. Optionally, substrate base layer 220 can be made up of a plurality of substrate base layers 220, which can be stacked or connected in a co-planar way by any suitable attachment

means. In some embodiments, substrate layer 220 may be made up of one continuous piece of substrate layer 220. Optionally, substrate base layer 220 can be any suitable size, shape or color. In some embodiments, the left side and right side of substrate base layer 220 may not be the same. In some embodiments, the shape of the substrate base layer can be configured according to the shape of the electrodes 214, 216. In some embodiments, the shape of the substrate base layer 220 may be configured according to the body area region where the patch 200 is to be used. In one non-limiting example, wherein the patch 200 is to be used on the forehead, the patch 200 shape and therefore the substrate base layer 220 may be configured to be ergonomic with the shape of the forehead.

In some embodiments the shape and size of the substrate base layer 220 and patch 200 is different, depending on what side of the body area, such as face, it is to be applied to. In one non-limiting example, wherein the patch 200 is to be used under and/or around the eye area, the configuration of the electrodes and resulting ^• > ^• patch 200 for the right side of the face can be different from a patch configured for the left side of the face (FIGS. 5a and 5b).

Optionally, substrate base layer 220 may readily facilitate attachment of the device 200 to a desired body area. Attachment mechanisms may include but are not limited to conductive adhesive, adhesive strip, ties strips, release liners, suction cups and/or any combinations thereof. In the embodiment of FIG. 3 a, patch 200 is configured to attach to the body area by conductive layers 212(1), 212(2). In some embodiments, the patch may be attached to the body area by, for example, the frame of the substrate and/or other attachment mechanisms.

In some embodiments, patch further comprises a release liner (not shown in FIG. 3a), which is removed to facilitate attachment, by attachment means. In some embodiments release liner is disposed on the conductive substance layers, such as hydrogel. In some embodiments, release liner is made from polyester film, wherein one side of release liner can be silicon coated.

Conductive substance layers 212(1) and 212(2) may optionally be any suitable conductive composition, such as an aqueous gel, hydrogel or a conductive adhesive.

Conductive composition/fluid 212 will generally be "pharmaceutically acceptable" or "physiologically acceptable" formulations for cosmetic or therapeutic

or moisturizing use. In some embodiments, the conductive fluid 212 is electrically conductive and adhesive hydrogel, suitable for use as a skin contact adhesive and, particularly, suitable for use as an electrical interface for electrodes of medical devices. The hydrogels can be cationic acrylates and may be, for example, made from acrylic esters of quaternary chlorides and/or sulfates or acrylic amides of quaternary chlorides. They can be formed by free radical polymerization in the presence of water, such as by ultra-violet curing with initiator and multi-functional cross-linking agent. The hydrogel may include a buffer system to help prevent discoloration of the hydrogels and/or hydrolysis of the hydrogels and/or to improve shelf-life.

Other additives may be incorporated into the present hydrogels either before or after curing (e.g., conductivity enhancers, pharmaceuticals, humectants plasticizers, etc.) depending on intended end-use. An additive that can be added to " the hydrogel is a conductive adhesive matter that serves to allow the conductive ■ , : fluid to both attach dermal device to the skin of the subject and to serve as the j _; , conductive interface between 'the electrode and the skin. The adhesive additive is in some embodiments a polymeric adhesive and may be pressure or temperature activatable or it may be activated by the exposure to the ambient atmosphere.

In one embodiment, the hydrogel is sufficiently cohesive, yet remains readily separable. Further details pertaining to hydrogels suitable for use in the context of the present invention are described in, for example, U.S. Patent No. 5,800,685, which is incorporated herein by reference. An aqueous conductive composition/fluid in accordance with the teachings of the present invention can typically comprise water, alcoholic/aqueous solutions, at least one salt or any other charged agent and a buffering medium.

In some embodiments, conductive layer 212(2) disposed on main electrode can be a hydrogel. hi some embodiments hydrogel is an aqueous hydrogel. Optionally, the conductive substance, such as a hydrogel can be anhydrous or in a dehydrated state, hi such an embodiment, water can be added prior to use. Hydrogel can have different formulation compositions, such as but not limited to including NaCl or KCl. In some embodiments hydrogel can include water, glycerol, KCl and AMPS. In some embodiments, glycerol (occlusion substance) can facilitate prevention of water from being released from the skin. In some embodiments,

purified water facilitates a water reservoir for electro osmosis. In some embodiments AMPS may be a polymerizing ionic monomer, which may be configured to facilitate a buffer component in the hydrogel.

In some embodiments conductive substance 212 can include at least one additional formulation, which can optionally include active ingredients, such as drugs, ions, salts, additives or other materials known in the art of cosmetics and pharmaceutics. Optionally, conductive substance can include at least one occlusion substance, in addition to or instead of glycerol , which can facilitate prevention of water from being released from the skin. In some embodiments, conductive composition 212 is applied onto electrodes 214, 216. hi some embodiments, conductive substance 212 is applied onto water stable/resistant electrode (FIG. Ia) and maybe disposed onto the layer of electroactive insoluble pole 14 and binder 16 material formulation. Conductive substance 212, such as hydrogel may in some embodiments be integrally formed with, partially formed with, or disposed in many different ways, onto or with , electrode 10. i

Conductive composition layer is of any suitable thickness, hi some embodiments, thickness of conductive composition layer is from about 0.5mm to about lmm. hi some embodiments, conductive composition layer is about 0.7mm thick.

In some embodiments, conductive substance 212 readily facilitates providing at least one of or a combination of the following functions: a conductive interfacing layer between the body/skin and electrodes 214, 216; a conductive adhesive facilitating attachment of the patch to the skin; providing a water reservoir for local passive diffusion and active electro osmosis of water to the stratum corneum; providing osmosis inducing ions (osmosis inducing component) for additional osmosis of water from the epidermis to the stratum corneum. Non-limiting examples of osmosis inducing ions include potassium ions, sodium ions and calcium ions. In some embodiments, conductive substance 212 is a conductive adhesive or a conductive fluid. Optionally, conductive adhesive is a hydrogel or an acrylic adhesive.

FIG.5a shows an exploded view of a dermal patch device assembly comprising an electrode as described in FIGS. la,b configured for application on the

left side of the face according to one embodiment of the present invention. As can be seen in FIG. 5a, patch device 400 includes substrate base layer/frame 402. In some embodiments the frame 402 may be made of a biocompatible material, such as, but not limited to porous elastic non woven tape with mild adhesive. Anode 404 is main electrode in the embodiment shown and may be disposed on substrate base layer/frame 402. The electrode 404 is optionally a water resistant electrode as hereinabove described (FIG. Ia, b) and can comprise a conductive polymer material printed with graphite. The anode 404 can be attached to the substrate base layer/frame 402 by suitable means, such as with adhesive. In some embodiments a connection means, such as a connective tape 405 can connect battery terminals with electrodes. In some embodiments, conductive tape can be pressure sensitive tape. In some embodiments a first end of conductive tape

405 can be attached to anode 404 and second end of conductive tape 405 can be attached to positive tab of battery 406. , , ^■ Cathode 408 is counter electrode in the embodiment shown in FIG. 5a and can be disposed on opposite side of substrate base layer 402 in the same plane as the anode 404. In some embodiments, the cathode 408 is a water resistant electrode as hereinabove described (FIG. Ia, b) and can be composed of a conductive polymer printed with silver/silver chloride ink. The cathode 408 may be attached to the frame 402 by adhesive. In some embodiments a first end of a second conductive tape 409 can be attached to cathode 408 and a second end of second conductive tape 408 can be attached to negative tab of battery 406.

Battery 406 may be disposed on the substrate base layer/frame 402. An insulating material 414, which is configured as a battery cover 414 may be disposed on battery 406. In some embodiments the battery cover 414 can be made from a porous elastic non-woven tape and one side can be coated with pressure sensitive adhesive. Battery cover 414 can be configured to adhere to one side of the battery

406 and the substrate base layer/frame 402.

A conductive adhesive layer 410, such as hydro gel can be disposed on anode 404. Conductive adhesive layer 410 can be cut in the same shape as the anode 404. A conductive adhesive layer 412 can be disposed on cathode 408. Conductive adhesive layer 412 can be cut in the same shape as the cathode 408.

A release liner 416 can be disposed over the conductive adhesive layers 410, 412.

FIG. 5b shows an exploded view of a device configured for use on the right side of the face according to one embodiment of the present invention 450. As can be seen from FIG. 5b, the patch components and arrangement are substantially the same as for FIG 5a. A difference between a device configured for use on the right side and a device for the left side of the face may be the shape of anode 454 and the shape of the conductive adhesive 460, which is disposed on the anode 454 compared with the shape of anode 404 and the shape of conductive adhesive 410 disposed on anode 404 (FIG. 5a). In some embodiments devices for the left and right hand side of the face or other body part are the same.

Referring back to FIGS. 3a, 3b, as noted, the embodiment depicted in FIG. 3 a is a fully integrated patch device. The present invention may also be practiced with a patch device 230 that does not have a conductive substance incorporated into it, but which instead is part of a kit 250, such as shown in FIG. 3b. FIG. 3b shows a patch device 230, which is similar to the embodiment of the fully integrated patch device depicted in FIG. 3 a and described hereinabove. However, in this alternative embodiment, the conductive layer 212 of the patch is optionally not integrally formed with the patch 230. Optionally, when the patch device 230 is part of a kit 250, conductive layer 212 is a separate component from the patch device 230.

Optionally, conductive layer 212 may be disposed and stored in a separate holding component (not shown), which may not be integrally attached to the patch 230. Optionally, separate holding component can be attached to patch 230 just before use, such as for example when separate holding component is a chamber. Alternatively, separate holding component can be applied onto body area, such as for example when separate holding component is a sponge or other type of material absorbing means. Alternatively, conductive substance 212 may be applied directly onto body area or onto electrode, without use of a separate holding component.

Certain features of the patch of the present invention 200 are the same regardless of whether the patch 200 is a fully integrated patch device or a patch 230 that is part of a kit 250, such as, but not limited to the substrate base layer/frame, cathode, anode, power supply, battery and electrode connections, liner and battery cover, which have been described hereinabove.

The current generating treatment device of the present invention as herein described is configured for a plurality of uses including but not limited to eliminating wrinkles. Without wishing to be limited by a single mechanism, one hypothesis of how the device achieves an anti-wrinkle effect may be as follows. The device may non-invasively moisturize the stratum corneum. By improving hydration in the stratum corneum, the device can reduce the appearance of fine lines and wrinkles, hi some embodiments the device can include hydrogel, which includes water, which facilitates moisturizing the skin, hi some embodiments, the hydrogel also includes KCL and glycerol, which improve the ability of the stratum corneum to retain the additional water and help preserve the moisturizing effect. The water can move to the stratum corneum in at least three distinct ways, which include passive diffusion, electro-osmosis and osmosis.

The water in the hydrogel can passively diffuse to the surface of the stratum corneum. This diffusion occurs because the skin typically is less moistthan the hydrogel. The current of the device can pass through the hydrogel and can carry the, water molecules to the surface of the stratum corneum by electro-osmosis. The current from the device, which passes through the hydrogel can cause potassium ions from the hydrogel to accumulate under the anode and on the stratum corneum. These potassium ions and glycerol from the hydrogel can remain on the skin after the device has been removed, hi order to balance the localized increase in potassium ions, water from the epidermis can diffuse by osmosis into the area resulting in a further increase in localized water concentration on the stratum corneum.

The combination of passive diffusion and electro-osmosis from the hydrogel and osmosis from the epidermis can facilitate a localized increase in surface water concentration on the stratum corneum.

FIG. 6 shows a schematic view of a storage assembly of a device according to one embodiment of the present invention 500. Optionally, one or a plurality of patches may be stored together. Plurality of patches 502, 504 can include patches of different sizes and shapes, patches configured for the same body area, patches configured for different sides of a body area, patches configured for different body areas and patches configured for different treatments or a combination thereof, hi some embodiments, patches can be stored in a wrapper 506. The wrapper 506 can enclose the patch and provide protection, such as a means for preventing

evaporation from the hydrogel. The wrapper 506 may also protect against microbiological contamination. In some embodiments, the wrapper 506 can be made of at least one laminated layer. In some embodiments, the wrapper 506 can be made from three laminated layers, which are impermeable to water, moisture and reactive gases such as oxygen, hi some embodiments, wrapper can include a vacuum or may be filled with an inert gas. hi some embodiments wherein a plurality of patches are stored in a wrapper 506, the patches 502, 504 can be stored back to back.

FIG. 7 is a flow chart of an exemplary method of use of a patch according to embodiments of the present invention. The flowchart applies to a method of use of a fully integrated patch device. A current generating treatment device, such as a patch as herein described may be provided 610. In some embodiments, the electrically powered device includes at least one first electrode, and at least one second electrode and at least one power source, supported on a base member in spaced relation to each other to define a gap therebetween and an integrated conductive substance layer, wherein at least one of the electrodes is a water stable/resistant i electrode. The patch may be configured to facilitate providing an electrical current, hi an embodiment, wherein the patch includes a protective liner, protective liner may be removed from the patch. The subject may contact a body area to be treated with the device 620. hi some embodiments, device is a thin and flexible device, which conforms to the contours of the body and which includes attachment means, for ready attachment to the body area to be treated. hi some embodiments, the contact of the device with the body area facilitates current flow and promotes body area treatment 630. In another embodiment such electrical stimulation may be aided by delivery of a biologically active substance to exert its effect.

The device is removed from the body area at the end of treatment time 640. Time of treatment can vary. The device is in some embodiments removed from contact with the body area after a time period, which can optionally be predetermined or is determined according to the desired dosage, the time it takes for the electrode to be depleted, or until sufficient effect or no more improvement can be seen, hi some embodiments, device can include an electronic time control. Li some embodiments a pretreatment can be applied prior to use of the device. Non-limiting examples of pretreatments include applying a cleanser,

applying a moisturizing composition, applying an anti-wrinkle composition, applying a formulation comprising a pharmaceutically active ingredient, applying a formulation comprising a cosmetically active ingredient, a method to enhance penetration, such as hair removal, peeling, scrubbing, electroporation, applying an agent to increase penetration, such as applying a permeation enhancer, such as urea, or a combination thereof. hi some embodiments, use of the device is a pretreatment itself, before applying a different type of treatment, such as application of a formulation.

In some embodiments a post treatment can be applied to the body area after application of the device. Non-limiting examples of post treatments include applying an occlusion formulation, applying a cleanser, applying a moisturizing composition, applying an anti-wrinkle composition, applying a formulation comprising a pharmaceutically active ingredient, applying a formulation comprising a cosmetically active ingredient or a combination thereof. , ' . The treatment can optionally be a one-time treatment or can be repeated in suitable time intervals any suitable number of times. Repeated treatment results in a cumulative effect. Use of the present invention can facilitate temporary alleviation and elimination of the above conditions. Duration of effect can be affected by time and frequency of application, type and amount of current used and severity of condition. In one embodiment, a typical treatment may last up to about an hour with resulting anti- wrinkle effect for up to about 10 hours, hi one embodiment, the dermal patch is configured for home use. hi other embodiments, the dermal patch can be applied in a supervised environment.

FIG. 8 shows a flow chart of a method of making a current generating treatment device, such as a patch according to one non-limiting embodiment of the present invention. A substrate base layer/frame is provided 702. hi some embodiments, at least one cathode and at least one anode are provided 704. hi some embodiments both electrodes are water stable/resistant electrodes and can be made as shown in FIGS. 2a,b, which shows a flow chart of a method of making a water stable/resistant electrode according to one embodiment of the present invention and which is described hereinabove.

Optionally, both electrodes of patch are water stable/resistant electrodes as herein described, or alternatively one electrode is an electrode according to the present invention and the other electrode is any suitable electrode.

Cathode and anode are disposed on substrate base layer/frame and attached in any suitable way, such as by using adhesive 706. In one embodiment, electrodes can be printed directly onto substrate base layer/frame.

Power supply is provided 708. Power supply, such as thin and flexible electrochemical cell is made using any suitable method such as a printing technique and lamination technique and can optionally be printed directly onto the substrate base layer/frame or can be printed on a separate substrate layer, which can be attached to patch substrate layer 710. Electrodes may be connected to the power supply using any suitable connection means such as conductive tape 712 Alternatively, connection means can be printed onto patch substrate.

A battery cover can be provided 714. Battery cover can be applied by any suitable means to be disposed on power supply/battery 716. In some embodiments adhesive is used to attach battery cover to the substrate base layer/frame and battery.

A conductive substance is provided 718. Conductive substance, such as for example hydrogel can be applied onto anode and cathode 720. Conductive substance can be applied using any suitable method such as coating and printing, hi some embodiments, conductive substance is applied by lamination or using a pick and place procedure.

Optionally, a release liner is provided 722. Optionally, a release liner is applied onto conductive substance layers 724.

The order of the steps of making a patch device as described herein are not limited to the order described. Any suitable order may be used.

The device of the present invention may optionally be made using any suitable methods, which include a roll-to-roll production assembly, a fully automated pick and place assembly, a semi-automated assembly, a manual production line or hand made production. In some embodiments, the homogeneity and thickness of the layers of the patch are more uniform in a fully automated roll- to-roll production, facilitating an improved product, with improved electrical properties. Some of the components of the patch device of the present invention may

be made by a printing method. Alternatively, the patch may be a fully printable patch.

FIG. 9 a shows a schematic view of a current generating delivery treatment device configured as a fully integrated patch device for promoting delivery of an active agent according to one embodiment of the present invention. The patch device 800 is fully integrated in the sense that the conductive substance/layer 812 and active substance 814 is incorporated into the device. In this embodiment, patch 800 may comprise first electrode 816, identified as "cathode," second electrode 818, identified as "anode", electrochemical cell 820 as the power supply of patch 800, at least one holding means 822 for accommodating a conductive substance 812 and at least one active substance 814 and at least one conductive substance 812 (1), 812 (2). Optionally, patch 800 may include a plurality of cathodes 816, a plurality of anodes 818 and a plurality of power supplies 820. In some embodiments, patch 800 may comprise conductive substance/s 812(1), 812(2) to provide an interfacing layer- ■ ^• . between patch 800 and a body area of a subject. ,».

As shown in FIG 9a, electrodes 816, ,818, holding means 822, conductive substance 812(1), 812(2), active substance 814 and electrochemical cell 818 maybe supported on a base layer substrate 824. Electrode 816 may be disposed in any suitable way on substrate 822 in spaced relation to electrochemical cell 820 and electrode 818 to define a gap between the two electrodes 816, 818. Optionally, the same conductive layer 812 can be disposed on both anode 818 and cathode 816 or conductive layers 812(1) and 812(2) can be different conductive substance layers. In some embodiments, a hydrogel 812 is disposed in/on the holding means 822 on the main active electrode and any suitable conductive substance, which can facilitate providing an adhesive conductive interface is disposed on the counter electrode. In some embodiments, hydrogel 812 is an aqueous hydrogel. hi some embodiments, patch 800, including patch components, is thin and flexible, to suit the contour of a body area of a subject. In some embodiments, patch 800 is electrically powered. Patch may optionally be any size, color and shape suitable for application to a desired body area. The thickness of patch 800 can be in some embodiments up to about 10 mm to ensure flexibility, but may be thicker, depending on the application. The thickness of the patch may also be dependent upon the type of material used and the flexibility of that material. Patch 800 is in

some embodiments disposable, but may be reusable. Patch 800 is stable to a wide range of temperatures and humidity. In some embodiments patch can be

VC biocompatible/dermatologically tested. Patch 800 can be configured to be used on any suitable area of the body, including, but not limited to face, neck, arms, hands, legs, thighs, buttocks, feet, toes, fingers, nails, teeth, palms, soles, back, shoulders, hair, mucous membrane and torso. In some embodiments, patch 800 can be for use under and near the eyes, on the crows-feet area, on the cheeks, laugh lines, forehead, lips, chin and neck and a combination thereof.

The power supply 820 is as described hereinabove in FIGS. 3a and 4. Cathode and anode electrodes 816 and 818 are in some embodiments composed of a conductive material as described hereinabove for FIG. 3 a. In some embodiments at least one of the electrodes 816, 818 is a water stable/resistant electrode as described in FIGS. Ia, b. In some embodiments, main active electrode is a water stable/resistant electrode, hi some embodiments both the anode 818 and cathode 816 are water stable/resistant electrodes. Defining which electrode is the main/active electrode is dependent on the charge of the ions contained in the conductive/active agent formulation 812(2), 814 which is to be disposed on the main active electrode and delivered into/onto a body area. In one embodiment, anode 818 is the main electrode and cathode 816 is the counter electrode. In an alternative embodiment, cathode 816 is the main active electrode and anode 818 is the counter electrode, hi an embodiment, wherein device 800 includes at least one holding means disposed on the anode and at least one holding means disposed on the cathode and each holding means includes an active formulation, with opposite charged ions, both anode 818 and cathode 816 can be configured as active electrodes, hi some embodiments, anode 818 is made from graphite and cathode 816 is made from silver/silver chloride. hi some embodiments, cathode 816 and anode 818 are connected to battery 820 by any suitable connection means, 826, 828, such as described hereinabove in FIG. 3a. Substrate base layer/frame 824 is optionally any suitable material, which can accommodate the patch components as described hereinabove for FIG. 3 a. Attachment means (not shown in FIG. 9a) for device 800 are as described hereinabove for FIG. 3 a.

Conductive substance layers 812(1) and 812(2) may optionally be any suitable conductive composition/fluid, such as an aqueous gel, hydrbgel or a conductive adhesive as described hereinabove for FIG. 3 a. In some embodiments, conductive layer 812(2) disposed in holding means 822 on main electrode can be a hydro gel. In some embodiments conductive substance 812 can include at least one additional formulation, which can optionally include active ingredients 814, such as drugs, cosmetics, ions, salts, additives or other materials known in the art of cosmetics and pharmaceutics.

In some embodiments, device 800 includes a holding means 822 for accommodating a conductive formulation, which can include a conductive gel and an active substance. Optionally, holding means can include a retainer/substrate made of a porous non-conductive material, such as, but not limited to a sponge, pad, paper, non-woven polypropylene etc, that serves to retain the conductive fluid therein. One non-limiting example of a holding means 822 is a hydrogel, which can accommodate an active formulation. : .

In one embodiment, holding means.822 may only include conductive formulation and active substance can be applied as a separate layer optionally on the holding means or directly on the body area region to be treated. In an alternative embodiment, holding means 822 may only include active substance and conductive formulation can be applied as a separate layer optionally on the holding means or directly on the body area region to be treated.

FIG.10 shows an exploded view of an assembly of a dermal patch for delivery of an active substance according to one embodiment of the present invention. As can be seen in FIG. 10, patch device 900 includes substrate base layer/frame 902. In some embodiments the frame 902 is made of a biocompatible porous elastic non woven tape with mild adhesive. Cathode 904 is main active electrode in the embodiment shown and is disposed on substrate base layer/frame 902. The electrode 904 is optionally a water resistant electrode as hereinabove described (FIGS. Ia, b) and can comprise a conductive polymer material printed with silver/silver chloride. The cathode 904 can be attached to the substrate base layer/frame 902 by suitable means, such as with adhesive.

In some embodiments a connective tape can connect battery terminals with electrodes. In some embodiments, connective tape may be conductive tape, such as

pressure sensitive tape. In some embodiments a first end of conductive tape 905 can be attached to cathode 904 and second end of conductive tape 905 can be attached to positive tab of battery 906.

Anode 908 may be counter electrode in the embodiment shown in FIG. 10 and can be disposed on opposite side of substrate base layer 902 in the same plane as the cathode 904. In some embodiments, the anode 908 is a water resistant electrode as hereinabove described and can be composed of a conductive polymer printed with graphite ink. The anode 908 can be attached to the frame 902 by adhesive. In some embodiments a first end of a second conductive tape 909 can be attached to anode 908 and a second end of second conductive tape 908 can be attached to negative tab of battery 906.

Battery 906 is disposed on the substrate base layer/frame 902. An insulating material 914, which is configured as a battery cover 914 can be disposed on battery 906. m some embodiments the battery cover 914 can be made from a porous elastic non- woven tape and one side can be coated with pressure sensitive adhesive. Battery cover 914 may be configured to adhere to one side of the battery 906 and the substrate base layer/frame 902.

A holding means 910 is disposed on active main electrode 904. Holding means 910 can accommodate a conductive formulation, which may include an active agent. Holding means 910 can be in any suitable shape and can be cut in the same shape as active electrode 904. A conductive adhesive 912 is disposed on counter electrode 908. Conductive adhesive layer 912 can be cut in the same shape as the counter electrode 908.

In some embodiments, a release liner 916 is disposed over the holding means and conductive adhesive layers 910, 912.

As noted, the embodiment depicted in FIG. 9a is a fully integrated patch device configured to facilitate promoting delivery of an active substance. The present invention may also be practiced with a patch device 830 that does not have a holding means with conductive substance and active agent incorporated into it, but which instead is part of a kit 850, such as shown in FIG. 9b. FIG. 9b shows a patch device 830, which is similar to the embodiment of the fully integrated patch device depicted in FIG. 9a and described hereinabove. However, in this alternative embodiment, the holding means and conductive active formulation disposed therein

of the patch is optionally not integrally formed with the patch 830. Optionally, when the patch device 830 is part of a kit 850, holding means 822 is a separate component from the patch device 830. Optionally, separate holding component can be attached to patch 830 just before use, such as for example when separate holding component is a chamber. Alternatively, separate holding component can be applied onto body area, such as for example when separate holding component is a sponge or other type of material absorbing device. Alternatively, conductive substance and active agent may be applied directly onto body area or onto electrode, without use of a separate holding component. Certain features of the patch of the present invention 800 are the same regardless of whether the patch 800 is a fully integrated patch device or a patch 830 that is part of a kit, such as, but not limited to the substrate base layer/frame, cathode, anode, power supply, battery and electrode connections, liner and battery cover, which have been described hereinabove. FIG. 11 is a flow chart of an exemplary method of use of a patch according to embodiments of the present invention. The flowchart applies to a method of use of a fully integrated patch device for promoting delivery of an active substance. A current generating treatment device for delivery of an active agent, such as a patch as herein described may be provided 1010. In some embodiments, the device includes at least one first electrode, and at least one second electrode and at least one power source, supported on a base member in spaced relation to each other to define a gap therebetween and a holding means for accommodating a conductive active formulation and a conductive adhesive layer, wherein at least one of the electrodes is a water stable/resistant electrode. The patch may be configured to facilitate providing an electrical current and delivering an active agent.

In an embodiment, wherein the patch includes a protective liner, protective liner may be removed from the patch. The subject may contact a body area to be treated with the device 1020. In some embodiments, device is a thin and flexible device, which conforms to the contours of the body and which includes attachment means, for ready attachment to the body area to be treated.

In some embodiments, the contact of the device with the body area facilitates current flow and promotes delivery of active agent and body area treatment 1030.

Body area region can optionally be treated by electrical stimulation and by active agent.

In some embodiments dermal device comprises an active cathode electrode and an anode counter electrode, such as, but not limited to wherein cathode is a silver/silver chloride electrode and anode is a graphite electrode, and an active substance and hydrogel disposed in a holding means, which is disposed on the cathode and a hydrogel disposed on the anode, hi such an embodiment, dermal device can be configured for combination treatments which include but are not limited to combination of electrical stimulation treatment; promotion of delivery to a body area region of an active substance from the active cathode and subsequent treatment with the active substance; and moisturizing of the stratum corneum. Moisturizing of the skin may be achieved by a combination of passive diffusion and electro-osmosis from the hydrogel and osmosis from the epidermis, which can facilitate a localized increase in surface water concentration on the stratum corneum. ^■ Combination treatments of delivery of active substance, electrical

' stimulation and moisturizing effect, can also be possible in an embodiment wherein , the anode is active, with an active drug disposed in a holding means thereon and the cathode is a counter electrode with hydrogel disposed thereon.

The device may be removed from the body area at the end of treatment time 1040. Time of treatment can vary. The device is in some embodiments removed from contact with the body area after a time period, which can optionally be predetermined or is determined according to the desired dosage, the time it takes for the electrode to be depleted, the time it takes for the power source to be depleted, or until sufficient effect or no more improvement can be seen. hi some embodiments a pretreatment can be applied prior to use of the device. Non-limiting examples of pretreatments include applying a cleanser, applying a moisturizing composition, applying a formulation comprising a pharmaceutically active ingredient, applying a formulation comprising a cosmetically active ingredient, applying a method to enhance penetration, such as hair removal, peeling, scrubbing, electroporation, applying an agent to increase penetration, such as applying a permeation enhancer, such as urea, or a combination thereof. In some embodiments, the device can include an electronic time control.

In some embodiments a post treatment can be applied to the body area after application of the device. Non-limiting examples of post treatments include applying an occlusion formulation, applying a cleanser, applying a moisturizing composition, applying a formulation comprising a pharmaceutically active ingredient, applying a formulation comprising a cosmetically active ingredient or a combination thereof. The treatment can optionally be a one-time treatment or can be repeated in suitable time intervals any suitable number of times. Use of the present invention can facilitate temporary alleviation and elimination of the treated conditions. Duration of effect can be affected by time and frequency of application, dose of active agent, type and amount of current used and severity of condition. In one embodiment, the dermal patch is configured for home use. In other embodiments, the dermal patch can be applied in a supervised environment.

The dermal device of the present invention may be used to deliver almost any active substance/drug. The term ' active substance' as. used herein includes, but : < is not limited to any 'active formulation', 'active composition', 'active agent', , . pharmaceutical, drug, cosmeceutical, cosmetic substance, therapeutic substance, natural and synthetic, which has an effect on any condition, such as, but not limited to a physical, physiological, biochemical, biological, chemical condition or a combination thereof. The term includes a therapeutic effect, cosmetic effect, an inhibitory effect, stimulatory effect, physical effect, biological effect, physiological effect, preventative effect, placebo effect or combination thereof. This includes therapeutic substances in all of the major therapeutic areas including, but not limited to, antiinfectives such as antibiotics and antiviral agents, analgesics including fentanyl, sufentanil, buprenorphine and analgesic combinations, anesthetics, anorexics, antiarthritics, antiasthmatic agents such as terbutaline, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, antiinflammatory agents, antimigraine preparations, antimotion sickness preparations such as scopolamine and ondansetron, antinauseants, antineoplastics, antiparkinsonism drugs, cardiostimulants such as dobutamine, antipruritics, antipsychotics, antipyretics, antispasmodics; including gastrointestinal and urinary, anticholinergics, sympathomimetics, xanthine derivatives, cardiovascular preparations including calcium channel blockers such as nifedipine, beta-blockers, beta-agonists such as salbutamol and ritodrine, antiarrythmics, antihypertensives such as atenolol, ACE

inhibitors, diuretics, vasodilators, including general, coronary, peripheral and cerebral, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones such as parathyroid hormone, growth hormone and insulin, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetics, anti-oxidants; nicotine, prostaglandins, psychostimulants, sedatives and tranquilizers, herbal preparations and homeopathic remedies.

The dermal device of the present invention is particularly useful for the delivery of cosmetic and cosmeceutical substances, since those are more effective when delivered into the skin but not through the skin. Such substances, include, for example, skin acting anti-oxidants, such as caretenoids, ascorbic acid (vitamin C) and vitamin E, as well as other vitamin preparations and other anti-oxidants; anti wrinkling agents such as retinoids, including retinol (vitamin A alcohol), peeling agents such as alpha-hydroxic acids, beta-hydroxy acid, better known as salicylic acid, combination-hydroxy acids and poly-hydroxy acids, and hydrolyzed and soluble collagen and others; moisturizers such as hyaluronic acid and others; anticellulite agents and acetyl-hexapeptide-3 (Argireline), pentatpeptide-3, palmitoyl-tetrapeptide-3, GHK, Myoxinol LS, N6 and Boswellic acids, caffeine and skin whitening agents such as arbutin. It is understood that the invention may be used for delivery of a wide range of dosages of the above listed and other substances over a desired duration of time.

Active substances for the treatment of skin disorders of dermatological nature may be selected from the group comprising antibiotic, antibacterial, antifungal, antiviral, anesthetic, analgesic, antiallergic, corticosteroid, retinoid, anti- histamine, sulfur, immunosuppressant and antiproliferative medications, and mixtures thereof at any proportion. The concentration of the active substances may be adopted to exert a therapeutic effect on a disease when applied to an afflicted area.

Examples of skin disorders of cosmetic nature and cosmetic procedures for which the device of the present invention may be used are set forth in the following list: aging skin, dry skin, sun damaged skin, wrinkles, fine lines, laugh lines, age spots, various hyperpigmented spots, melasma, puffy eyes, acne, redness of the skin, telangiectasia, skin and tooth discoloration, cellulite, and obesity, skin and tooth

whitening, application of body decoration, such as temporary and permanent makeup and tattoos, skin lifting and lip plumping.

Examples of skin disorders of dermatological nature, as well as active substances which may be used to treat them, are set forth in Table 1. Table 1 - A non-exhaustive listing of dermatological disorders, suitable for usage of the iontophoretic system of the present invention and exemplary drugs for such disorders.

Treatment according to the present inventions may be beneficial in all body areas. Being thin, flexible and versatile in shape and form, the devices of the present invention can be designed to fit any area of the body and to have any desirable size, according to the area having the disorder. FIG. 12 shows a flow chart of a method of making a current generating treatment device for promoting delivery of an active substance, such as a patch according to one non-limiting embodiment of the present invention. A substrate base layer/frame is provided 1102.

In some embodiments, at least one cathode and at least one anode are provided 1104. In some embodiments both electrodes are water stable/resistant electrodes and can be made as shown in FIG. 2a, which shows a flow chart of a method of making a water stable/resistant electrode according to one embodiment of the present invention.

Optionally, both electrodes of patch can be water stable/resistant electrodes as herein described, or alternatively one electrode is an electrode according to the present invention and the other electrode can be any suitable electrode.

Cathode and anode can be disposed on substrate base layer/frame in any suitable way, such as by using adhesive 1106.

Power supply can be provided 1108. Power supply, may be a thin and flexible electrochemical cell and can be made using any suitable method such as a printing technique and lamination technique and can optionally be printed directly onto the substrate base layer/frame or can be printed on a separate substrate layer, which can be attached to patch substrate layer 1110. Electrodes can be connected to the power supply using any suitable connection means such as conductive tape 1112.

Optionally, one electrode, such as cathode or anode can be disposed on substrate base layer/frame. Power supply can then be disposed on substrate base layer/frame and the power supply can be connected to the electrode disposed on the frame. Then second electrode can be disposed on frame and second electrode can then be connected to power supply.

A battery cover can be provided 1114. Battery cover can be applied by any suitable means to be disposed on power supply/battery 1116. In some embodiments

adhesive can be used to attach battery cover to the substrate base layer/frame and battery.

A holding means can be provided 1118. Holding means can be configured to accommodate a conductive formulation, which optionally can contain at least one of a conductive gel and an active substance.

A conductive substance can be provided 1120. Conductive substance, such as for example hydrogel can be administered onto/into holding means 1122. Optionally, hydrogel can be configured as a holding means. An active substance can be provided 1124. Active substance can be administered onto/into holding means 1126. Optionally, conductive substance and active substance can be administered together into holding means. In an embodiment, wherein holding means is a hydrogel, no additional conductive substance need be added to the hydrogel holding means. Holding means can be disposed/attached onto active electrode 1128. Conductive substance can be attached or disposed onto counter electrode 1130. Optionally, a release liner can be provided 1132. Optionally, release liner can- be applied onto conductive substance layer and holding means layer 1134.

The order of the steps of making a patch device as described herein are not limited to the order described. Any suitable order may be used.

The device of the present invention may optionally be made using any suitable methods, which include a roll-to-roll production assembly, a fully automated pick and place assembly, a semi-automated assembly, a manual production line or hand made production, hi some embodiments, the homogeneity and thickness of the layers of the patch are more uniform in a fully automated roll- to-roll production, facilitating an improved product, with improved electrical properties. Components of the device for promoting delivery of an active substance of the present invention may be made by a printing method. Alternatively, the patch may be a fully printable patch.

While the principles of the invention have been discussed in relation to exemplary embodiments discussed herein, it is understood that the principles of the invention are not limited thereto.

Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the

various embodiments and aspects of they present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples. EXAMPLES Reference is now made to the following examples, which together with the above descriptions illustrate the invention in a non-limiting fashion.

Example 1: Improved Storage Properties of an electrode of the present invention Materials and Method The electrical properties of electrodes A and B when in contact with hydrogel were compared. Ag/ AgCl electrode, containing silver/silver chloride inks with a polyester based binder is referred to as Electrode A and Ag/ AgCl electrode containing silver/silver chloride inks with a vinyl resin based binder, is referred to as Electrode B. As such Electrode A is an electrode not according to the present invention, whereas Electrode B is a water stable electrode according to an embodiment of the present invention.

Electrodes A and B were cut into a keyhole shape with a surface area of about 2cm ² . Hydrogel was then placed in contact with the top of each electrode and the electrodes were then stored in aluminum laminate bags. The hydrogel was protected in the original liner, in order to prevent drying out of the hydrogel.

Electrodes A and B were stored under the following conditions: 4O ⁰ C, 55% relative humidity. These experimental conditions simulate accelerated storage conditions. Samples of electrodes A and B were also stored at room temperature. Electrodes A and B were tested in a three electrode system electrochemical cell. The three electrode system electrochemical cell was made up of a working electrode, which was stored electrode A or B; a counter electrode (Electrode C), which was a fresh, non-stored Silver electrode, that was cut into a keyhole shape with a surface area of about 2cm ² and a hydrogel was then placed in contact with the top of the electrode; and a reference electrode, which was a non-stored Ag/ AgCl electrode containing silver/silver chloride inks with a vinyl resin based binder (non- stored Electrode B), cut into about 2mm wide 30mm long rectangular shape that was placed between the counter and the working electrode..

Between 3 to 6 electrodes were tested every 1-4 weeks for about 36 weeks, using Autolab PGSTAT30+FRA2 system for measuring electrochemical parameters, such as Capacity, open circuit voltage (OCV) and closed circuit v PoCltage (CCV).

Results

The results are shown in FIGS. 13-20.

FIG. 13 shows the depth of discharge (%DOD) over time of stored Electrode A. As can be seen from FIG. 13, there is about 30% fading of capacity of Electrode A in accelerated storage within 4 weeks. This is reflected in electrochemical parameters. FIG. 14 shows CCV over time of stored Electrode A. From FIG. 14, it can be seen that there is about a 2 fold decrease in CCV of Electrode A over 36 weeks of accelerated storage.

FIG. 15 shows depth of discharge (%D0D) over time of stored Electrode B. As can be seen from FIG. 15, there is an increased capacity of Electrode B in accelerated storage over 36 weeks. Figure 16 shows CCV over time of stored

Electrode B. As can be seen from Figure 16, there is retention of CCV of Electrode B in accelerated storage of 36 weeks.

In a separate test, electrodes A and B were stored at room temperature and results are presented in FIGS. 17-20. The same behavior can be seen, with electrode A capacity fade of about 30% and a 2 fold decrease in CCV value for electrode A (FIGS. 17,18) and an increased capacity and a retention of the CCV for electrode B (FIGS. 19,20).

Conclusions The discharge capacity of Electrode A fades after a short period of accelerated storage and longer periods of room temperature storage. After 2 weeks at accelerated storage, capacity of Electrode A is below the minimal operative value of 80% depth of discharge. In contrast, Electrode B, an electrode according to an embodiment of the present invention, has enhancement of the electrical properties over an extended time period of accelerated storage.

The binder in the electrodes keeps contact between the particles and maintains adhesion to the substrate. In Electrode A, an electrode not according to the present invention, the polyester based binder absorbs water from the hydrogel,

which results in decreased binding of the conductive particles to the substrate and therefore fading of the electrical properties of electrode A. In contrast, the vinyl resin binder of Electrode B of the present invention, does not absorb water from the hydro gel, thereby maintaining the integrity of the bound ink particles to the substrate and resulting in better constant electrical properties.

Example 2: Method of making electrode

A conductive vinyl web (MeliCoat 2264) electrode substrate was provided. A vinyl resin binder material was provided and a silver/silver chloride electroactive insoluble pole substance was provided. The silver/silver chloride and vinyl resin binder were mixed into an ink. The conductive vinyl web substrate was coated with the silver/silver chloride ink, wherein the ink was based on the vinyl resin binder, using a printing technique with draw down equipment. The silver/silver chloride ink was then dried using any suitable drying technique, such as in an oven at 50-120°C. The dry thickness of the silver layer was typically about 2 to 25 microns.

Example 3: The anti- wrinkle effect of a single 20 minute treatment with a 1.5V dermal patch, which includes a water resistant electrode according to an embodiment of the present invention Materials and Methods

Powered Dermal Patches according to one embodiment of the present invention as described in FIGS. 5a and 5b, which include a water resistant main electrode, a water resistant counter electrode, a 1.5 V thin and flexible electrochemical cell and hydrogel disposed on the electrodes were used. The patch was shaped to fit the under-eye contour and crow's feet area, covering a total surface area of 10 cm ² . The interface between the dermal patch and the skin is a hydrogel.

40 female subjects aged between 30 to 70, with wrinkled skin above grade 2 around the eye contours were included in the study after fulfilling inclusion and exclusion criteria. 20 minutes before the dermal patch was applied, subjects were instructed to rinse their face with water and were allowed to acclimatize for at least 10 minutes to the environment. At the end of this period, the subject's skin integrity was assessed by an initial reading of Trans Epithelial Water Loss and noted in the Case Report

Form (CRF), as was a digital image to record the baseline. Thereafter, subjects were instructed to apply the dermal patch for 20 minutes.

Following the 20-minute treatment a trained expert graded the wrinkles. In addition digital imaging was taken immediately following the dermal patch removal, and at hourly intervals at 1, 2, 3, and 4 hours thereafter. End-points included both expert grading, Visual Photo Scores (VPS) by visual image analysis for fine lines and wrinkles as well as self-grading by the subjects.

The following parameters for efficacy were measured during and following the course of the treatment. Skin hydration

Skin moisturization was measured via a Corneometer (CM 825, Courage- Khazaka). The Corneometer data serves as surrogate measurements for skin hydration by measuring the skin's electrical capacitance.

Evaluation of the appearance of fine line and wrinkles 1. Clinical evaluations of fine lines and wrinkles

Clinical evaluations were conducted by a trained investigator. Grading was according to the following scale: Wrinkle grades: 0 = No evidence of lines or wrinkles

I = A few, short barely perceptible fine lines just below eye and/or very slight lines in the corners.

2 = A few shallow lines that are discreetly visible below the eye, no real deep lines or wrinkles in the corners. 3 = Shallow, easily visible lines further below eye with one or two shorter, deeper lines/wrinkles in the corners

4 = A moderate number of fine lines in close proximity covering the entire area below the eye, with wrinkles that are deeper and longer in length in the corners and that extend slightly into the cheek area. 5 = Several deeper lines below the eye that are densely packed, with coarse wrinkles that extend above the eye and into the cheek area.

The change (δ) between baseline grades and each time interval after treatment were calculated. Thereafter the recorded values were interpreted according to the following scale:

0 = δ=0: No improvement 1 = 0<δ<0.5: Slight improvement

2 = δ=0.5: Moderate improvement

3 = δ=l : Good improvement

4 = δ>2: Excellent improvement

* A score equal or greater than 2 is considered as a significant improvement

2. Visual Photos Score (VPS)

The appearance of fine lines and wrinkles on the subject's eye contour area were further assessed by a calibrated digital images of the right and left sides of the face taken at baseline and at each designated time point. Changes in wrinkles appearance were graded as follows:

0 = No difference

1 = Very slight, extremely small change in at least one area, following careful observation

2 = Slight, changes are easier to notice in at least one or two areas, scrutinizing is unnecessary and minor changes are noticeable.

3 = Moderate, changes are noticeable quickly in two or more areas.

4 = Marked significant change that is noticeable immediately.

* A score value from -1 to 1 is interpreted as not significant while score values of 2 or more represented a significant improvement in wrinkle condition.

Data analysis between data points and within data was performed using a one-sided T test with a confidence level of 0.05.

Results Skin Hydration

Corneometer measurements based on skin capacitance were taken at baseline, immediately after treatment (Time = 0) and every hour thereafter for four hours thereafter.

As shown in the graph in FIG. 21, for 4 hours and at all time intervals the Corneometer measurements demonstrated a significant improvement versus baseline (considered 100%). Hydration as measured by the Corneometer peaked at two hours and had only slightly decreased at four hours.

Appearance of fine line and wrinkles

1. Clinical assessment of fine line and wrinkles

Clinical assessment by expert grading after 20-minute dermal patch treatment was used to evaluate the improvement in the appearance of wrinkles. Changes in the baseline scores were recoded, as described in the Methods section. Briefly, a score equal or greater than 2 is considered as a significant improvement As shown in the graph in FIG. 22, 28% out of the 36 subjects treated with dermal patch 1.5V had a moderate to marked improvement after 20-minute treatment.

2. Visual Photos Score (VPSl

Calibrated facial photographs were taken before, immediately after and at hourly intervals up to four hours after treatment, where a score value from -1 to 1 is interpreted as not significant while score values of 2 or more represent a significant improvement in wrinkle condition.

As is shown in the Graph in FIG. 23, 12% of 34 subjects had an immediate improvement (value of 2 or more), however after an hour and peaking at two hours post treatment, 26% and 50% of subjects, respectively, had VPS values greater than 2. This indicates a Bell shaped distribution, possibly due to other biological effects, as the DC current was operative for only 20 minutes.

Conclusions

A 1.5 V dermal patch, which included water stable/resistant electrodes, a 1.5 V Power Paper electrochemical cell and hydrogel according to an embodiment of the present invention demonstrated an effect on skin appearance. Skin hydration was significantly improved versus the baseline. Visual photo scores demonstrated that 50% of subjects had a significant improvement (moderate to marked improvement) in wrinkle appearance for at least two hours following treatment. Subjective

assessments indicated a significant improvement in wrinkle appearance, with 81% and 75% of subjects reporting a marked improvement immediately after treatment and 4 hours post treatment, respectively. The treatment was well tolerated without any side effects. The results indicated that a single 20-minute treatment with dermal patch (1.5V) configured according to an embodiment of the present invention significantly improved wrinkle appearance.

Example 4: Evaluation of Efficacy of a 3 V dermal patch configured with at least one water resistant electrode according to one embodiment of the present invention

40 female subjects with Caucasian skin and wrinkles graded 2 or greater on a 1-5 grade scale (shallow fine lines to deep wrinkles) on both sides of the face were used in a randomized, split facial study. Prior to and following the 20-minute treatment, and at hourly intervals during four hours following treatment, the following assessments were performed:Skin moisturization; Wrinkle grading;Facial images: Subjective assessments.

3 V dermal patches according to one embodiment of the present invention as described in FIGS. 5a and 5b, which include a water resistant main electrode, a water resistant counter electrode, a 3 V power source comprising a thin and flexible electrochemical cell and hydrogel disposed on the electrodesThe average current density was about 9.2 μA/cm ² .The dermal patch was shaped to fit the under-eye contour and crow's feet area, covering a total surface area of about 10 cm ² . The interface between the dermal patch and the skin was a hydrogel.

The study protocol was identical to that described in Example 3, for evaluation of a 1.5 V dermal patch of the present invention.

The parameters and evaluation methods were the same as described in Example 3 for evaluation of a 1.5 V dermal patch of the present invention.

Results Skin Hydration

Corneometer measurements based on skin capacitance were taken at baseline, immediately after treatment (Time = 0) and every hour thereafter for three hours.

As shown in Table 2, when comparing Corneometer measurements at any point in time to the Corneometer measurements at the baseline, a statistically significant difference between the two groups was noted, indicating that the 3V dermal patch treatment had added a substantial amount of moisture to the stratum corneum. This phenomenon lasted for at least three consecutive hours.

Table 2 - Corneometer measurements

Appearance of fine line and wrinkles 1. Clinical assessment of fine line and wrinkles

As shown in the Graph in FIG 24, 60% of subjects treated for 20 minutes with 3 V dermal patch according to the present invention had a significant improvement (moderate to excellent) at t=0, an improvement that lasted for 4 hours for a smaller part of the studied population.

2. Visual Photos Score CVPS)

Calibrated facial photographs were taken before, immediately after and at hourly intervals up to four hours after treatment, where a score value from -1 to 1 is interpreted as not significant while score values of 2 or more represent a significant improvement in wrinkle condition.

As seen in the graph in FIG. 25, 45% out of 40 subjects had an immediate significant improvement (2 grades or more), which was retained by 29% and 21% of subjects for two and four hours respectively.

Conclusions

In this clinical study using a 3V dermal patch with a main water stable/resistant electrode and a counter water stable/resistant electrode according to one embodiment of the present invention, improvement in skin appearance was demonstrated by all methods. Skin hydration was significantly improved versus the

baseline. Expert grades demonstrated that 60% of subjects had a significant improvement (moderate to marked improvement) in wrinkle appearance immediately following treatment. This improvement was maintained for up to four hours. Subjective assessment demonstrated highly significant improvement in wrinkle appearance, with 80% and 60% of subjects reporting a marked improvement, immediately after treatment and five hours post treatment, respectively. The treatment was well tolerated without any side effects. The results indicated that a single 20-minute treatment with a 3 V dermal patch according to the present invention rapidly and immediately improved the appearance of wrinkles.

Example 5: In vitro experiment to show effect of iontophoresis on skin penetration of caffeine with a water resistant electrode system according to the present invention

Caffeine is an ingredient of many cellulite-reducing products since it is known to increase fat reduction of subcutaneous adipose sites. Caffeine and other Xanthine analogs increase lipolysis by blocking the antilipolytic action of adenosine, a potent endogenous inhibitor of lipolysis and by inhibiting the activity of phosphodiesterase, which destroys cyclic AMP a lipolysis activator. The enhancing effect of iontophoretic induction on Caffeine skin penetration was assessed as a function of current densities. All tests included 30-60 minutes of topical application, followed by analysis. The amounts of Caffeine were determined in the receiving compartment of a modified Franz cell system, using dermatomized porcine skin. The amount in the receiving compartment served as the primary measure for the enhancing effect.

Materials and Methods

Caffeine was obtained from Sigma-Aldrich (Lot-02206HA). The test formulation was a Caffeine solution- caffeine 2%, NaCl 0.5% and water 97.5%.A11 other chemicals used are analytical grade, obtained from standard supply houses (Sigma, VWR, etc.). The skin membrane was obtained from porcine ear, obtained at a local abattoir. The skin was full thickness skin. The tissue was removed from the ear within a few hours of sacrifice, and was stored frozen for a period of no longer than one month.

Prior to each experiment, the viability of skin barrier function was checked via a measurement of trans-epidermal water loss (TEWL). Perturbation of the skin barrier, either by physical disruption, chemical attack or because of disease, can severely compromise the role of the SC. The porcine skin samples, before mounting in the diffusion cell, were measured for TEWL (DermaLab ^® , Cortex Technology) to assess whether skin barrier function was intact.

Passive and iontophoretic experiments were performed in vertical diffusion cells (LGA, Berkeley), in which the skin membrane separates the physically- and electrically-isolated anode and cathode chambers from the receiving compartment phase. Li the experiments, the formulation (2% Caffeine in ddw) was placed in one of the donor chambers and physiologically buffered saline (PBS) at pH 7.4 was placed in the second donor chamber and in the receiving compartment. The exposed area of skin in each donor chamber was 0.64 cm ² .

Power supply attached to two electrodes (active electrode Ag/ AgCl, counter electrode Ag/ AgCl), wherein each electrode was a water resistant electrode according to the present invention and as described herein above was used and current and voltage were recorded manually. LGA Franz cells adjusted for iontophoresis were used.

For passive experiments, the diffusion cell was assembled and the compartments loaded as described above. Transport, in the absence of electrical current, was allowed to proceed for the designated application time, at the end of which, the entire content of the receiving compartment was drained and the solution reserved for subsequent analysis of Caffeine (see below). hi the iontophoresis studies, the diffusion cell was assembled and the compartments loaded as above. Transport, assisted by electrical current, was allowed to proceed for the designated application time. The electrodes used were Ag/ AgCl, prepared as described in Example 2. A pre-determined constant electrical current, ranging from 0.04 to 0.30 niA/cm ² was then passed between the electrodes for 30-60 minutes.At the end of the treatment period, the entire content of the receiving compartment was drained and the solutions were reserved for subsequent analysis of Caffeine (see below).

Quantitative analysis of Caffeine was done in Analyst research laboratories. The HPLC analytical method used was Kromasil 100 C18 5m, 15Ox 4.6 mm, P.N.KSOD1050S1505.

Results

Table 3 shows the amount of Caffeine found in the receiving compartment following 30-60 minutes application of 2% caffeine, with and without electrical current. FIGS. 26 and 27 show graphical representation of caffeine skin penetration. After 30-60 minutes of application, Caffeine was found only in the receiving compartment of the active cells (with electric charge). No Caffeine was found in the passive receiving compartments.

The amount of Caffeine that was found in the receiving compartment after iontophoresis application was proportional to the current intensity. Even at low current level caffeine was found in the receiving compartment. In the iontophoresis experiments no difference was found between the _; enhancing effect of the anode electrode and the enhancing effect of the cathode electrode on Caffeine skin penetration.

Table 3 — μg of Caffeine found in the receiving compartment after 30-60 minutes of current application

Conclusions

Iontophoresis using water resistant electrodes with a non- water absorbing binder according to the present invention, at 40-300 mA/cm ² significantly enhanced the skin penetration of Caffeine. There is a strong correlation between the currents intensity and the degree of Caffeine skin penetration. Since Caffeine is an uncharged

molecule it can be delivered by the Cathode electrode or by the anode electrode, preferably by the anode electrode, depending on the skin charge and the pH of the formulation.

Example 6: Quantitative assessment of iontophoresis on skin penetration of arbutin using a water stable/resistant electrode system according to the present invention

An in vitro skin penetration test system was employed in order to quantitatively assess the enhancing effect of iontophoresis on skin penetration of the cosmetic active ingredient Arbutin using an electrode system of water stable/resistant electrodes (active electrode Ag/ AgCl, counter electrode Ag/ AgCl) according to the present invention.

Arbutin is found in many de-pigmentation products since it is known as a skin whitening agent, and inhibits the formation of melanin by inhibiting Tyrosinase activity. Arbutin also protects the skin against damage caused by free radicals. The enhancing effect of iontophoretic induction on Arbutin skin penetration was _r assessed as function of current densities. AU tests were determined in the receiving compartment of a modified Franz cell system, using dermatomized porcine skin. The amount in the receiving compartment served as the primary measure for the enhancing effect.

Results

Table 4 shows the amount of Arbutin found in the receiving compartment following 30 minutes application of 5% Arbutin, with and without electrical current. FIG. 28 shows graphical representation of arbutin skin penetration. At pH 8-9 Arbutin is negatively charged, and therefore in the current assay the effect of iontophoresis on Arbutin skin penetration was studied only under the cathode electrode. After 30 minutes of application, Arbutin was found only in the receiving compartment of the active cells (with electric charge). No Arbutin was found in the passive receiving compartments. Increasing the current intensity increased the amount of Arbutin that was found in the receiving compartment after iontophoresis application.

Therefore, an iontophoretic device including a power source and a water resistant/stable electrode system according to the present invention promoted delivery of arbutin into the skin.

Table 4 - μg of Arbutin found in the receiving compartment after 30 min of current application

It is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the description. The invention includes other embodiments and can be practiced or implemented in various ways. Also it is to be understood that the phraseology and terminology employed herein is for the purpose of description only and should not be regarded as limiting.