HK1074808B - Dermal patch - Google Patents

Description

Skin patch

[0001] This application claims priority from the filing date of application No.60/330526 filed 24/10/2001, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to transdermal and/or intradermal drug delivery devices, kits and methods, and more particularly, to dermal patches capable of delivering electrical current for the electrical delivery of a wide variety of substances, including transdermal and intradermal, or by electrical stimulation for improved wound healing, scar prevention, scar reduction, tissue repair and/or tissue regeneration.

Background

Recently, great attention has been paid in the technical and patent literature to the delivery of substances such as drugs and other beneficial agents, drugs and cosmetics, into or through intact skin surfaces by passive processes such as diffusion and osmosis, and by active processes such as electro-inductive iontophoresis, electrophoresis, electroosmosis and/or electroporation. The ubiquitous nicotine patch designed to aid smoking cessation has made such forms of transdermal drug delivery widely known. (hereinafter, the term "iontophoresis" will collectively mean any of the terms iontophoresis, electrophoresis, electroosmosis, and/or electroporation, and the term "iontophoretic" includes the respective adjective forms.)

In fact, there is currently a particularly long list of drug substances conventionally administered transdermally and/or intradermally, and similar long lists of devices and methods for drug administration known in the art. Short but varied samples include the following: us patent No.6294582, which discloses a device for the transdermal treatment of asthma; U.S. patent No.5899856, which discloses a skin patch for detecting alcohol consumption; U.S. patent No.6291677, which teaches transdermal administration of antiviral protease inhibitors; us patent No.6266560, which discloses transdermal treatment of erectile dysfunction; U.S. patent No.6238381, which discloses transdermal delivery of antiviral, antibacterial and anti-aging substances; and U.S. patent No.6288104, which discloses transdermal administration of a substance for the treatment of congestive heart failure.

While many substances are passively administered via a dermal patch, there are also many substances that are electrically delivered either within the skin or transdermally.

The use of electrical stimulation of body parts is well known and has a history of equal length and colour. In the alternating period of the approximately 20 th century, there are a plethora of "electrodes" used to apply "electrotherapy" to the human body. These electrodes are placed on the body with respect to the organ to be treated. Such early "electrotherapy" included general electrical stimulation which caused ionized molecules to be driven, usually superficially, into the body. This early form of iontophoresis or iontophoresis was used, the postulated beneficial effect for local stimulation and often simple wetness to introduce drugs into the patient's skin.

Iontophoresis technology is currently widely used in drug delivery because it efficiently electrically transports charged drugs into the skin, and into the capillary structures and lymphatic system. This technique avoids gastrointestinal side effects sometimes associated with orally ingested drugs and is preferred over subcutaneous injections because of its relatively benign and painless nature.

Another technique known as electroporation facilitates transdermal or intradermal delivery of uncharged substances by electrically inducing the formation of transient skin pores that allow migration of the uncharged substance by diffusion.

Therefore, iontophoresis, as well as other electrically induced techniques such as electroporation, have been incorporated into many transdermal delivery devices, including common skin patches. Thus, there are many skin patches currently known in the art that include a power source and circuitry for assisting transdermal delivery.

Most current dermal patches, including those that are passive and electrically active, include substances for transdermal delivery. Such patches are specifically designed and/or shaped to deliver a predetermined dose of a particular substance and this substance forms an integral part of the patch, i.e. the "nicotine patch". One disadvantage of such skin patches manufactured in a predetermined type and with a predetermined amount of substance therein is that once the substance is exhausted, the entire device is useless and must be discarded. This is disadvantageous because patches using electrically induced delivery techniques necessarily have components, such as batteries, electrodes, circuitry, and other components, which may be expensive and/or harmful to the environment when discarded in large quantities. Furthermore, in order to change the dosage, patches of different dosages must be provided.

A range of reusable skin patches are also currently known in the art, these patches comprising a container for holding a drug substance prior to administration. These skin patches typically include a reservoir that is part of one or both electrodes that deliver current to the skin of the subject. Such electrodes are commonly referred to as bioelectrodes.

Bioelectrodes come in many sizes, shapes and configurations, such as those assigned to Iomed, Inc., below, which produce iontophoretic delivery devices. Examples of such bioelectrodes include those described in U.S. patent nos. 5037380 and 5248295, which teach patches with refillable containers; U.S. patent No.5846217, which teaches a patch having a small access window for refilling; and U.S. patent nos. 537424, 5730716, and 6223075, which teach patches that hold dry drugs and must be hydrated. All such bioelectrodes are complex and comprise many parts and are therefore relatively bulky. Thus, those parts included in the skin patch make the patch large and relatively expensive. Furthermore, such skin patches must be charged or loaded by the clinician rather than by the subject.

Thus, there is a widely recognized need for, and highly advantageous for, a thin, flexible, and simple electroactive skin patch that is simple to administer to a subject, versatile in use, and capable of applying a range of substances and/or doses, as well as for various purposes, and that is simple in design and inexpensive to manufacture.

Disclosure of Invention

It is therefore an object of the present invention to provide a multi-purpose skin patch including a power source that can be used to deliver a range of different substances either transdermally or intradermally.

It is yet another object of the present invention to provide a multi-purpose skin patch including a power source that can be used to introduce electrical current into a portion of the skin for various purposes.

It is yet another object of the present invention to provide a multi-purpose dermal patch including a thin and flexible power source which can be used to introduce electrical current into a portion of the skin for various purposes and/or which can be used to deliver a range of different substances either transdermally or intradermally.

According to one aspect of the present invention, there is provided a kit for transdermal or intradermal delivery of at least one substance, the kit comprising (a) a dermal patch comprising an electrochemical cell having at least two electrodes positioned on one side of the dermal patch for making electrical contact with a skin portion of a subject; and (b) at least one holder for holding a conductive fluid containing a substance for deposition on the at least one electrode and/or topical application to a skin portion of a subject; the patch is designed and shaped for delivering an electrical current for transdermal or intradermal delivery of a substance through a conductive fluid and the skin of a subject.

According to another aspect of the invention, there is provided a kit for introducing an electric current and/or voltage to a skin portion of a subject, the kit comprising (a) a skin patch comprising an electrochemical cell having at least two electrodes positioned on one side of the skin patch for making electrical contact with the skin portion of the subject; and (b) at least one holder for holding an electrically conductive fluid for deposition on the at least one electrode and/or topical application to a skin portion of a subject; the patch is designed and shaped for delivering an electrical current for introducing the electrical current and/or voltage to a skin portion of a subject via a conductive fluid.

According to a further aspect of the present invention there is provided a skin patch consisting essentially of an electrochemical cell having at least two electrodes positioned on one side of the skin patch for making electrical contact with a skin portion of a subject, the skin patch being designed and shaped for delivering an electrical current through a conductive fluid deposited on the at least one electrode and/or topically applied to the skin portion of the subject.

According to a further aspect of the present invention there is provided a method of transdermal or intradermal delivery of a substance comprising (a) topically applying a substance-containing conductive fluid to a skin portion of a subject and/or depositing the substance-containing conductive fluid on at least one electrode of a dermal patch comprising an electrochemical cell having at least two electrodes positioned on one side of the dermal patch; (b) positioning the skin patch such that the electrode is in electrical contact with a skin portion of the subject; and (c) delivering an electrical current through the electrically conductive fluid and the portion of the skin to deliver the substance transdermally or intradermally.

According to a further aspect of the present invention there is provided a method of introducing an electrical current and/or voltage to a skin portion of a subject, comprising (a) topically applying a conductive fluid to the skin portion of the subject, and/or depositing the conductive fluid on at least one electrode of a skin patch comprising an electrochemical cell having at least two electrodes positioned on one side of the skin patch; (b) positioning the skin patch such that the electrode is in electrical contact with a skin portion of the subject; and (c) delivering an electrical current through the electrically conductive fluid so as to introduce an electrical current and/or voltage to the skin portion of the subject.

According to features in the described preferred embodiments, the electrically conductive fluid is a water-based fluid.

According to features in the described preferred embodiments, the electrically conductive fluid is a hydrogel.

According to features in the described preferred embodiments, the conductive fluid is selected from the group consisting of a gel, a paste, a lotion, a suspension, an emulsion, and a solution.

According to features in the described preferred embodiments, the electrically conductive fluid is for deposition on at least one of the two electrodes.

According to features in the described preferred embodiments, the electrically conductive fluid is for topical application to a skin portion of a subject.

According to features in the described preferred embodiments, the species is a charged species.

According to features in the described preferred embodiments, the species is an uncharged species.

According to features in the described preferred embodiments, the substance is selected from the group consisting of a drug, a cosmetic and a cosmeceutical.

According to features in the described preferred embodiments, the drug is selected from the group consisting of a therapeutic agent and an anesthetic agent.

According to features in the described preferred embodiments, the current is used to induce iontophoresis, electrophoresis, electroporation, or any combination thereof.

According to features in the described preferred embodiments, the electrical current is used to induce wound healing, scar prevention, scar reduction, body tissue repair and/or tissue regeneration.

According to features in the described preferred embodiments, the holder is selected from the group consisting of a barrel, a tube, a canister, a container, a dispenser, and an ampoule.

According to features in the described preferred embodiments, the holder is a spacer for deposition on at least one of the two electrodes.

According to features in the described preferred embodiments, the current transports the substance from the separator. Such separators tend to prevent contact between the electrodes and the skin and provide an even distribution of current across the surface of the patch. Such a separator is an integral part of the electrode or attached to the electrode.

According to features in the described preferred embodiments, the spacer is contained in a removable cover.

According to features in the described preferred embodiments, the electrochemical cell is a flexible thin layer electrochemical cell.

According to features in the described preferred embodiments, the electrochemical cell is a flexible, thin-layer, open liquid electrochemical cell comprising a first layer of insoluble negative electrode, a second layer of insoluble positive electrode, and a third layer of aqueous electrolyte, the third layer being disposed between the first and second layers and comprising (a) a deliquescent material for always keeping the open cell moist; (b) an electroactive soluble material for obtaining a desired ionic conductivity; and (c) a water-soluble polymer for obtaining a desired viscosity to adhere the first and second layers to the third layer.

According to features in the described preferred embodiments, at least one of the two electrodes is used to move at least one substance.

According to features in the described preferred embodiments, the at least two electrodes are integrally formed with the electrochemical cell.

According to features in the described preferred embodiments, the electrochemical cell and the at least two electrodes individually constitute a patch.

According to features in the described preferred embodiments, the skin patch further comprises an attachment mechanism for attaching to a skin portion of the subject.

According to features in the described preferred embodiments, the skin patch further comprises a circuit for controlling the current.

According to features in the described preferred embodiments, the packaging and determination kit is applied for wound healing applications, scar prevention applications, scar reduction applications, tissue repair applications, tissue regeneration applications, transdermal delivery applications, and intradermal delivery.

The present invention successfully addresses the shortcomings of the presently known structures by providing a multi-purpose dermal patch operable in delivering any number of substances and doses transdermally or intradermally.

Drawings

With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this respect, 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.

In the drawings:

FIG. 1 is a cross-sectional view of a dermal patch constructed in accordance with a preferred embodiment of the invention;

FIGS. 2a-g are views of a holder according to various embodiments of the invention;

3a-d show a first very simple embodiment according to the invention;

figures 4a-d show a second very simple embodiment according to the invention;

5a-c show a third very simple embodiment according to the invention; and

fig. 6 is a cross-sectional view of a different configuration of a skin patch according to the present invention.

Detailed Description

The present invention relates to a kit, skin patch and method for transdermal and/or intradermal delivery of a variety of substances such as drugs, cosmetics and cosmeceuticals by iontophoresis, electrophoresis and/or electroporation. The dermal patch of the present invention is advantageously versatile in the sense that a single patch is operable to deliver a range of versatile substances and/or doses transdermally and/or intradermally, and the patch can be simply charged and administered by a subject.

Before explaining at least one embodiment in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

The principles and operation of a kit for transdermal and intradermal delivery of substances and a kit for introducing an electrical current and/or voltage to a skin portion of a subject in accordance with the present invention may be better understood with reference to the drawings and the accompanying description.

Referring now to fig. 1, there is shown a dermal patch according to the teachings of the present invention, referred to herein below as patch 10. The patch 10 includes a top surface 12 and a skin-contacting bottom surface 13, which together form a patch body 11. Patch 10 is preferably made of a flexible material and conforms surfaces 12 and/or 13 to the contour of the skin portion of the subject when patch 10 is applied to the skin portion of the subject. It will be appreciated that patch body 11 may be of any size and shape necessary according to the respective application.

The patch 10 also preferably includes a skin attachment mechanism, which is preferably an adhesive layer 28, for attaching the patch 10 to a portion of the subject's skin. Adhesive layer 28 covers at least a portion of bottom surface 13 of patch 10. Adhesive layer 28 preferably comprises a biocompatible, permeable pressure sensitive adhesive, such as Bio-PSA from Dow Corning. Other examples of biocompatible adhesives will be readily apparent to those of ordinary skill in the art. The adhesive layer 28 may be used for one-time attachment or for repeated attachment.

The patch 10 includes, among other things, an electrochemical cell 14, which is preferably a flexible, thin electrochemical cell, most preferably an open liquid electrochemical cell. It will be appreciated that any other electrochemical cell, or power generation device, may be used with the patch 10 to provide the current required for the relevant application. Various types of miniature power sources, disposable and rechargeable, are known in the art, and may be incorporated into patch body 11.

According to a preferred embodiment of the present invention, electrochemical cell 14 is a thin, flexible electrochemical cell that engages a majority of the entire volume of patch body 11. In the preferred embodiment, electrochemical cell 14 includes a positive electrode layer 16, a negative electrode layer 18, and an electrolyte layer 20 interposed therebetween. One example of a suitable thin and flexible electrochemical cell is described, for example, in U.S. patent nos. 5652043, 5897522, and 5811204, which are incorporated herein by reference. Briefly, the electrochemical cells described in the above-identified U.S. patents are open liquid electrochemical cells that can be used as disposable or rechargeable power sources for various miniaturized and portable electrically activated devices of compact design. The cell comprises a first layer of insoluble negative electrode, a second layer of insoluble positive electrode, and a third layer of aqueous electrolyte disposed between the first and second layers, and comprises (a) a deliquescent material for always keeping the open cell moist; (b) an electroactive soluble material for obtaining a desired ionic conductivity; and (c) a water-soluble polymer for obtaining a desired viscosity to adhere the first and second layers to the first layer.

Some preferred embodiments of the disclosed electrochemical cell include (i) engaging an electrolyte layer in a porous substance such as, but not limited to, filter paper, plastic film, cellulose film, and cloth; (ii) making the first layer insoluble positive electrode comprise manganese dioxide powder and the second layer insoluble negative electrode comprise zinc powder; (iii) making the first layer insoluble negative electrode and/or the second layer insoluble positive electrode further comprise carbon powder; (iv) selecting an electroactive soluble from zinc chloride, zinc bromide, zinc fluoride and potassium hydroxide; (v) the negative electrode insolubilizing the first layer comprises a silver oxide powder and the positive electrode insolubilizing the second layer comprises a zinc powder, and the electroactive dissolvable material is potassium hydroxide; (vi) making the first layer insoluble negative electrode include cadmium powder and the second layer insoluble positive electrode include nickel oxide powder, and selecting the electroactive dissolvable material to be potassium hydroxide; (vii) making the first layer insoluble negative electrode comprise iron powder and the second layer insoluble positive electrode comprise nickel oxide powder, and selecting the electroactive dissolvable material to be potassium hydroxide; (viii) causing the first layer of insoluble negative electrode and the second layer of insoluble positive electrode to comprise lead oxide powder, the battery then being charged by a voltage applied to these electrodes, and the electroactive soluble material in such case being selected to be thiosulfonic acid; (ix) the deliquescent material and the electroactive dissolvable material may 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 chloride, calcium bromide, potassium hydrogen phosphate and potassium acetate; (xi) The water-soluble polymer can be polyvinyl alcohol, polyacrylamide, polyacrylic acid, polyvinylpyrrolidone, polyethylene oxide, agar, agarose, starch, hydroxyethyl cellulose, and combinations and copolymers thereof; (xii) The water-soluble polymer and the deliquescent material may be the same material, such as dextran, dextran sulfate, and combinations and copolymers thereof. The electrochemical cell 14 preferably includes any one or more of the embodiments described above. Preferred constructions of the electrochemical cell 14 according to the invention include such combinations, which are free of toxic compounds.

Electrochemical cell 14 includes terminals that serve as electrodes, hereinafter referred to as positive electrode 22 and negative electrode 24, each of which is in electrical contact with positive electrode layer 16 and negative electrode layer 18, respectively. Electrodes 22 and 24 are electrically connected to electrochemical cell 14 using known means, such as printed flexible circuits, metal foils, wires, conductive adhesives, or by direct contact. It will be appreciated that measures are taken to avoid contact between the electrodes and between each electrode and the opposing pole layer. In fig. 1, a measure is taken to insert an insulating member 17 formed of a dielectric material.

Electrodes 22 and 24 are electrically conductive and may be formed of a metal, such as a metal foil or a metal deposited or coated on a suitable backing. Examples of suitable metals include aluminum, platinum, stainless steel, gold, and titanium. Alternatively, the electrodes 22 and 24 may be formed from a hydrophobic polymer containing conductive fillers such as metal powder/chips, powdered graphite, carbon fiber, or other known conductive filler materials.

Electrodes 22 and 24 may be applied to the cell and the entire unit may be fabricated, for example, by suitable printing techniques such as, but not limited to, screen printing, offset printing, jet printing, lamination, material evaporation, or powder diffusion. Thus, the electrochemical cell 14 as described hereinabove is one of the simplest power sources.

It will be appreciated that each of the electrodes 22 and 24 may be of any size and shape and positioned relative to each other in any configuration, as may be desired to cover the portion of skin being treated. In fact, electrochemical cell 14, in conjunction with electrodes 22 and 24, constitute separate internal elements of patch 10, in accordance with a preferred embodiment of the present invention. Thus, the patch 10 is one of the smallest and thinnest active practices and delivers the greatest power per unit surface area.

The patch 10 of the present invention is preferably provided in a protective removable or reusable package or liner or cover 19 to provide physical protection prior to use and to extend shelf life.

The patch 10 is designed and configured for use with at least one, and preferably a plurality of, foreign substances. Such substances, described in detail below, are designed to be contained in an electrically conductive fluid, also described in detail below.

The electrically conductive fluid is designed to be held in at least one, and preferably a plurality of, holders. The combination of patch 10 and holder form a kit that can be held by a patient for a variety of applications.

Reference is now made to fig. 2a-g, which illustrate a series of holders for holding an electrically conductive fluid. The formation of such conductive fluids is often a "pharmaceutically acceptable" and "physiologically acceptable" formulation for cosmetic or therapeutic use. As used herein, the terms "pharmaceutically acceptable" and "physiologically acceptable" refer to substances that can be administered to a subject, preferably without undue adverse side effects (e.g., for topically applied preparations, rashes, inflammation, etc.). Specific formulations include aqueous gels, pastes, lotions, suspensions, emulsions and solutions, or other liquid formulations suitable for topical application as known in the art.

In the preferred embodiment, the electrically conductive fluid is electrically conductive and is an adhesive hydrogel suitable for use as a skin contact adhesive, particularly suitable for use as an electrical interface for an electrode of a medical device. The hydrogel is a cationic acrylic acid and may, for example, preferably be made of ammonium chloride and/or ammonium sulfate acrylates or ammonium chloride acrylamides. They may be formed by free radical polymerization in water, preferably by ultraviolet curing, using initiators and multifunctional crosslinking agents. The hydrogel preferably includes a buffering system to help prevent discoloration of the hydrogel, and/or hydrolysis of the hydrogel, and/or to improve shelf life.

Other additives may be incorporated into the present hydrogels either before or after curing depending on the intended end use (e.g., conductivity enhancers, drugs, wetting agents, plasticizers, etc.). The additive preferably incorporated into the hydrogel is a conductive adhesive substance (additive) that serves to allow the conductive fluid to both attach the patch 10 to the skin of the subject and to serve as a conductive interface between the electrodes and the skin. The adhesive additive is preferably a polymeric adhesive and may be pressure or temperature activatable, or it may be activated by exposure to the ambient atmosphere.

Preferred hydrogels are sufficiently adherent but remain easily separable. Further details pertaining to hydrogels suitable for use in the context of the present invention are described, for example, in U.S. patent No.5800685, which is incorporated herein by reference.

In any case, the aqueous conductive fluid according to the teachings of the present invention generally comprises water, an alcoholic/aqueous solution, at least one salt or any other charged agent, and preferably a buffer medium.

It will be appreciated that non-aqueous conductive fluids may also be used.

The conductive fluid used in conjunction with patch 10 is preferably administered by deposition on one or both of the electrodes. It will be appreciated that the conductive fluid may be replaced by or otherwise administered by topical application to the skin. The term "topical" is used herein to refer to the administration of a substance onto the surface of skin or mucosal tissue, which may be applied via direct application (e.g., diffusion), via a filled porous material or object, or by spraying or nebulization. It will be appreciated that topical application of a fluid to the skin of a subject is generally less accurate and, if not done carefully, may inadvertently cause the electrical connection between the electrodes to pass directly through the conductive fluid, so that the current and mobile ions do not pass through the skin.

Thus, the shape, size and distribution method of the holders may vary depending on the number, application and location associated with the treatment. Shown in fig. 2b-2g are holders in the form of a barrel 31, a tube 32, a canister 33, a container 34, a dispenser 35 and an ampoule 36. It is to be understood that the present invention contemplates all such holders, as well as other holders of any shape, size or configuration, that serve to hold the conductive fluid and dispense the conductive fluid as desired for application to the electrodes or the skin of the subject.

Shown in fig. 2a is a retainer 30, which is a spacer. The use of the term "separator" is intended to describe a holder made of a porous, electrically non-conductive material, such as sponge, paper, or the like, which serves to hold an electrically conductive fluid therein. Spacers offer advantages over other holders in that they allow precise positioning of the conductive fluid, they are not messy, and they allow precise dosing.

The fluid is held in the spacer in such a way that objects in contact with the spacer also contact the fluid contained therein. Thus, by establishing physical contact between the electrode and the separator, electrical contact can be established with the electrically conductive fluid held in the separator.

Preferably, the separator is designed and shaped to fit between one or both of the electrodes 22 and 24 and the subject's skin, thus providing a simple, clean and convenient electrode/skin interface through which current can flow to the treatment area via the conductive fluid. As noted above, the spacers are configured such that their non-conductive structure does not impede electrical contact between the electrodes 22 or 24 and the conductive fluid therein. It will be appreciated that the separator is not positioned such that it or its contents create an electrical contact between electrodes 22 and 24. Such positioning would create an electrical circuit that does not include the subject's skin and would defeat the purpose of the electrical application.

The separator may be manufactured in the form of a plug, box, or pellet, etc., designed to be compatible with the different shapes, sizes, and configurations of the electrodes 22 and/or 24.

According to a preferred embodiment, the holder 30, which in its embodiment is a spacer, is preferably a thin sheet-shaped holder, which may be of a desired shape to be compatible with the area to be treated and the electrodes used. Such spacers are preferably protected by a film layer, which is peeled off before use.

The spacer may be packaged for storage or use, as may be compatible with the preferred embodiment of the kit of the present invention. The spacers are preferably individually packaged in order to preserve shelf life and avoid evaporation of the conductive fluid and/or the substances contained therein.

The use of the above-described retainer, and particularly the spacer 30, is intended to make the patch 10 very user-friendly and almost very simple in its use. The wide variation in the design and shape of the holder shown is for precise application of the conductive fluid on the appropriate electrodes or topically on the skin of the subject. For example, a holder in the form of a tube 32 allows for simple deposition of small amounts of conductive fluid on the electrode with precision. A holder in the form of an ampoule 36 ensures the correct dose of medicament. The dispenser 35 allows for careful and precise application of the conductive fluid to the precise skin portion of the subject. The preferred embodiment of the present invention allows the separator 30 to act as a vehicle for the conductive fluid, which can be precisely positioned on the electrode or the subject's skin.

It will be appreciated that the precise location of the electrically conductive fluid on the associated electrode or the skin of the subject is important for the effective conduction of electrical current through the skin of the subject. Thus, the kit comprising patch 10 and one or more holders 30 through 36 preferably also includes any other means, instructions, indicia, aids or devices for assisting the user in properly applying and positioning the conductive fluid as desired.

Several very simple embodiments of the patch 10 relating to the present invention are shown in figures 3a-5 c. In the embodiment of fig. 3a-d, strip 100 is placed on skin 102 and a conductive lotion, gel, paste or the like 104 is applied to skin 102 such that when strip 100 is removed, two non-contacting areas 106 are formed that receive patch 108 constructed and operative according to the teachings of the present invention, and patch 108 is applied to skin 102 such that each of its electrodes 110 contacts one of areas 106 so as to avoid a short circuit.

In the embodiment of fig. 4a-d, a patterning device 200 having two openings 201 is placed on skin 202 and a conductive lotion, gel, paste or the like 204 is applied to skin 202 such that when patterning device 200 is removed, two non-contacting areas 206 are formed that receive a patch 208 constructed and operative according to the teachings of the present invention, and patch 208 is applied to skin 202 such that each of its electrodes 210 contacts one of the areas 206 so as to avoid a short circuit.

In the embodiment of fig. 5a-c, a foldable patch 308 is placed on the skin 302 in its folded shape, and a conductive lotion, gel, paste or the like 304 is applied to the skin 302 on both sides thereof, such that when the patch 308 is flattened, two non-contacting areas 306 receiving the patch 308 are formed, and the patch 308 contacts the skin 302 such that each of its electrodes 310 contacts one of the areas 306, so as to avoid short circuits.

Referring now to fig. 6, an embodiment of the patch 10 of the present invention is shown in which the electrodes 22 are not integrated with the electrochemical cells 14, but are connected by a conductive connection, hereinafter referred to as connection 21. The components of an embodiment according to the present invention and which are similar to the patch 10 described above are not further described and are identified by the same reference numerals as described above. The connector 21 may be printed or may be any conductive material known in the art. According to the embodiment shown, the retainer, which is a separator, is deposited on the electrodes 24 of the electrochemical cells 14. Thus, in this configuration, electrode 24 may be referred to as a medical electrode and electrode 22 as a conductive adhesive electrode. According to this embodiment, simultaneous contact with the subject's skin through the electrodes 22 and the separator 30 forms an electrical circuit that includes the subject's skin as part of the conductive path. In such a configuration, the electrochemical cell 14 will generate an electrical current that is delivered by the electrically conductive fluid held by the retainer 30 in contact with the skin. An electric current is passed through the skin, which suitably moves charged ions or molecules in a conductive fluid contained therein to pass through the skin.

One purpose of the patch 10 is to deliver a pharmaceutical, cosmetic or cosmeceutical substance transdermally or intradermally. As used herein, the terms "transdermal" and "intradermal" and grammatical variations thereof refer to the delivery of an ingredient through/across or into the skin, respectively. As used herein, the term "drug" refers to both therapeutic agents and anesthetic agents. As used herein, a therapeutic agent is understood to include any substance used in medical treatment, healing, treatment, or maintenance of health. As used herein, anesthetic agents are understood to include substances used to cause loss of tactile sensation, particularly pain. For electrotransport, such substances preferably employ charged molecules, which will respond to an electric current. It is to be understood that any pharmaceutical, cosmetic or cosmeceutical substance may be delivered by the invention described herein, so long as the substance is or can be charged.

In the case where the substance is not naturally charged, it is best to combine it with a charging agent, or to experience environmental conditions, such as a particular pH environment, which induces charge formation. Methods of charging molecules are well known in the art and are not described further herein. In any case, it will be appreciated that the substance to be delivered may be charged prior to or concomitantly with its delivery.

Thus, as used herein, the term "substance" refers to an active substance, which is preferably in the form of a charged ion or charged molecule, and which can be delivered electrically, either transdermally or intradermally. Generally, this includes therapeutic substances in all major therapeutic areas including, but not limited to, anti-infective drugs such as antibiotics and antivirals, analgesics including fentanyl, sufentanil, buprenorphine and analgesic combinations, anesthetics, anorectics, antiarthritics, antiasthmatic agents such as terbutaline, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, migraine-inhibiting agents, antihalation agents, agents such as scopolamine and ondansetron, antineoplastics, antiparkinson agents, cardiac stimulants such as dobutamine, antipruritics, antipsychotics, antipyretics, spasmolytics including gastrointestinal and urinary, anticholinergics, sympathetic nerve stimulators, xanthine derivatives, cardiovascular agents including calcium channel blockers such as nifedipine, and the like, Beta blockers, beta agonists such as albuterol and ritodrine, antiarrhythmics, antihypertensives such as atenolol, ACE inhibitors, diuretics, vasodilators including normal, coronary, peripheral and cerebral, central nervous system stimulants, cough and cold preparations, decongestants, diagnostic agents, hormones such as parathyroid hormone, auxin and insulin, hypnotics, immunosuppressors, muscle relaxants, parasympathetic blockers, parasympathomimetics, antioxidants, nicotine, prostaglandins, psychostimulants, analgesics, and sedatives. The present invention is also useful for delivering cosmetic and cosmeceutical substances. For example, such materials include skin-acting and other antioxidants such as carotenoids, ascorbic acid (vitamin C) and vitamin E, as well as other vitamin preparations, anti-wrinkle agents such as retinoids, including vitamin a (retinol), alpha hydroxy acids, beta hydroxy acids (well known as salicylic acid), combination hydroxy acids and polyhydroxy acids, as well as hydrolyzed and soluble collagen and others, moisturizers such as hyaluronic acid and others, anti-cellulite agents such as aminophylline and others, skin bleaching agents such as retinoic acid, hydroquinone and peroxides and others, botanical preparations such as aloe vera, wild yam, hamamelis tannin, ginseng, green tea, and other extracts.

It will be appreciated that the present invention may be used to deliver a wide range of doses of the above and other substances over a desired period of time.

Transdermal and intradermal delivery of substances preferably occurs by iontophoretic and/or electrophoretic processes. Iontophoresis refers to the movement of ions induced by the application of an electrical potential. Electrophoresis refers to the movement of charged colloidal particles or macromolecules induced by the application of an electric field. The current caused by the potential between electrodes 22 and 24 is used to release the charged species from the conductive fluid, transport molecules/ions of the charged species from the conductive fluid, and transport molecules to adjacent skin tissue. Charged species in the conductive fluid deposited between one or both of the electrodes 22 and 24 and the subject's skin will either be attracted to the electrodes 22 and 24 or repelled by the electrodes 22 and 24, depending on their charge. For example, if the substance is positively charged, the electrode 22 repels the substance, thus moving it into or through the skin. In such a configuration, when current flows from positive electrode 22 in a direction toward the skin, the charged species are driven through the conductive fluid/skin interface into the skin.

It must be noted that reverse iontophoresis may also be used in the process of transdermal or intradermal recovery of substances from the body. Such techniques use the same electrical principles applied in reverse. Techniques for transdermal or intradermal recovery of substances are well known in the art.

Percutaneous or intradermal movement of substances may also be assisted by an electroporation procedure. Electroporation is typically performed by high voltage pulses applied to a pair of electrodes applied to the tissue surface. The electrical pulse causes ions to pass through the tissue layers, providing a new pathway for charged and uncharged species to pass through. It must be noted that electroporation does not transport charged species, but rather reduces the resistance of the species to passage into adjacent tissue. Since it does not provide the required driving force, electroporation needs to be combined with transport techniques such as iontophoresis or electrophoresis in order to obtain good permeation.

Another preferred purpose of patch 10 is to promote wound healing, reduce scarring, prevent scarring, tissue repair, and/or tissue regeneration by applying an electrical current directly through the skin. Electrical currents have long been known and are used therapeutically to promote electrical responses, so-called action potentials, by excitable cells of the human body (receptors for nerves, muscles and nerve endings) by means of electrical stimulation provided externally in the form of electrical pulses. These action potentials are intracellular electrical pulses of defined amplitude and duration for the relevant cell type. For example, for nerves, a pulse width of about 1ms and an amplitude of about 80mV to 100mV is typical. The cell returns to its cell membrane voltage, which at rest has a value between 60mV and 120mV depending on the cell type. The voltage is generated by different ion concentrations in the extracellular space and the intracellular space separated by the cell membrane. There are more positive ions outside the cell. By definition, the potential outside the cell is set to 0V, so that a negative potential is given in the cell.

In healthy persons, action potentials are generated by the body itself and are used for information transfer and to trigger cellular processes.

In electrotherapy, the therapeutic effect is caused by the specific generation (in defined numbers and at specific sites) of action potentials.

Devices for electrotherapy use a variety of different current or pulse forms. In order to select the electrotherapy best suited for a particular condition, the therapist should be able to return to the maximum well-defined criteria. These criteria are derived from the responses to analyze the efficacy and tolerances of the various current patterns.

The range of effects includes, for example, areas of pain relief, striated and non-striated muscles, stimuli affecting perfusion, areas examined for inflammatory processes, and detumescence mechanisms (accelerated healing of wounds, bones, etc.) that promote regeneration. The aim of this application should always be to obtain the desired effect at the distal or proximal end of the electrode, or in the affected area deep in the body, by the correct choice of current form.

Basically, electrotherapy devices are based on two stimulation current methods, the "polar stimulation principle" which relies on polarity and the "non-polar stimulation principle" which does not rely on polarity.

Low frequency alternating current (LF current) ranging from 0 to 200Hz is used for "extreme stimulation principle". Hyperpolarization (a rise in membrane voltage) occurs below the positive electrode (anode), allowing greater separation of the potential in the cell from the stimulation threshold. Conversely, the membrane voltage under the negative electrode (cathode) drops. When the stimulation threshold is reached, the cell automatically triggers an action potential.

The stimulation current device uses different pulse shapes in the low frequency spectrum (LF current) of about > 0 to 200 Hz. Applicable are for example so-called triangular currents, rectangular currents, alternating currents, high voltage currents, over-excited stimulation currents, faraday currents, etc. Some alternating currents have a direct current component, which additionally supports the polarization effect.

There are two methods of using action potentials therapeutically, frequency dependent:

functional simulation principle:

the number of action potentials generated by an excitable cell (e.g., nerve or muscle) to perform its task is determined. In therapy, the same number of pulses is then generated in the respective cells by stimulation, thereby supporting the cells to perform their tasks.

For example, a stimulation frequency of up to 6Hz is applied to produce contractions up to 6 times per second.

Fatigue principle:

conversely, when a cell (nerve or muscle) is caused to produce an action potential by stimulation at a higher frequency and slightly faster than the frequency required by the cell to produce the action potential in order to perform its task, it fatigues after a short time. The opposite effect occurs. Cell fatigue can be explained by the process of energy consumption in forming action potentials.

For example, according to the fatigue principle, the hardened muscle can be relaxed by stimulating it with a "higher" frequency of, for example, 100Hz or 200 Hz.

In order to fully generate any action potential, of course the intensity must be chosen high enough to exceed the stimulation threshold. The level of intensity to be set depends on the following factors: the position (depth) of the cells to be stimulated in the tissue (distance from the electrode), the size of the electrode and the resistance of the tissue in the region penetrated by the potential, which in turn is influenced by parameters in the form of currents.

In practice, the current form and electrode size are specified. Now to stimulate a population of cells at a distance from the electrode (e.g., deep in the tissue), the current and/or voltage intensity continues to increase until an action potential is generated.

Cells located deeper and deeper or further away from the electrodes are successfully stimulated with increasing intensity. By the principle of electrodeless stimulation, only so-called medium frequency alternating currents (MF currents) without any direct current component are used. The significance of MF current is a sinusoidal alternating current with a frequency > 5Hz to 100000 Hz. A single cycle (ac pulse) of sufficient intensity has a polarization effect that can trigger an action potential in a nerve or muscle cell.

Typically, a "product sum effect" occurs. At increasing frequencies, increasingly higher intensities are also required in order to be able to trigger action potentials in the cells. Wys has proven undoubtedly that the action potentials generated with MF pulses proceed completely independently of polarization effects. This means that wherever the intensity and the number of oscillations are sufficiently large, an action potential is generated, independent of the instantaneous polarity of the MF current (Wys, Oscar A.M.; Prinzipien der elektrischen Reizung, [ Prinliple of electric Stimulation ], Neujahrs-Blatt, published 1976 by Natural Research Society in Zurich, Kommissoverlag Leeman AG, Zurich, 1976, 28-34).

The MF pulses are applied at a low frequency repetition rate of > 0 to about 200Hz and a carrier frequency of > 5Hz to 100000 Hz. In practice, this is mostly a sinusoidal, amplitude modulated MF current (AM-MF current). The following principle is consistent with what is described in connection with the "polar stimulation principle".

Functional simulation principle:

in synchronism with MF pulsing (amplitude modulation), action potentials appear in excitable cells. Causing the cell to perform its natural function, which emanates from that frequency.

Fatigue principle:

to fatigue excitable cells, MF pulses with higher amplitudes are used.

As the current intensity increases, cells located deeper and deeper (farther from the electrodes) are successfully stimulated.

With increasing frequency, greater intensity is required to generate the action potential.

Based on a medium frequency alternating current, the following additional options for treatment are given:

when stimulated with MF current of sufficient intensity (constant amplitude), action potentials are first generated. As the MF current flows for a longer time, the decaying side of the action potential remains at a level of depolarization (permanent depolarization) that is equal to about half of the equilibrium potential. When the NM current is turned off, the membrane voltage drops and then decays to the level of the equilibrium potential.

The following clauses describe the therapeutic use of permanent depolarization.

Pain relief and effect perfusion:

high intensity within tolerance limits, depending on the nature of the area being treated, causes the blocking of the nerve transmission channel due to permanent depolarization. This true nerve block (evidence established by the BOWMAN of e.k. university of ljubilijana, Rancho Los agidos Hospital, Downey, Calif, u.s.a., burrow r.1981) is used for example for pain blocking in phantom limb pain, or for Stellatum blocking in blood flow disorders.

Muscle contraction:

muscle training and muscle stretching in hypoinnervation.

The striated muscle (skeletal muscle) is directly stimulated by permanent depolarization due to the intact neuromuscular organ. This results in muscle contraction, which is used, for example, in the spontaneous innervation of muscles, or in the antagonism of stretch-spasm muscles. During treatment, the intensity should be interrupted by a short interval of pause. The intensity may also increase and decrease between 100% and about 50% of the adjustment value.

Producing strong muscle contraction force:

strong muscle contractions can be caused without the phenomenon of fatigue. In tonic contractions, which can be caused by a stimulation current of about 50Hz and higher, a rapid decrease of the muscle contraction force occurs on the contrary due to fatigue of the muscle motor unit.

Cell division

Wound healing and accelerated bone healing:

permanent depolarization causes cell division of healthy cells. Thereby promoting wound healing and accelerating bone healing in fracture. Furthermore, under the effect of the alternating current field, the MF current causes a reciprocating motion (oscillatory action) of the charged molecules in the tissue penetrated by the current, accompanied by a rotational motion of the charged molecular fraction. Thus, a greater possible "correct" meeting position of the enzyme with the substrate is obtained, which chemically reacts during the metabolism (metabolic facilitation). This oscillatory action tends to create level differences in concentration, so that the diffusion process proceeding in a certain direction due to the existing concentration gradient is accelerated by the additionally imparted kinetic energy (MF iontophoresis, inhibition of inflammation, alleviation of pain).

The oscillatory action is particularly effective at high intensities.

Distribution of inflammatory and pain mediators:

inhibition of inflammation and alleviation of pain:

during pain, inflammation, high concentrations of inflammation and pain mediators are often found in diseased tissue. This high concentration is reduced (dispersed) by the action of shaking. This "oscillation intensity" with the same frequency, caused by the high current intensity, has a greater significance for the therapeutic effect (Hans-Jurgens, May, Elektrische Difference-therapeutic [ electric Difference Therapy ], Karlsruhe 1990).

Effects of metabolism (diffusion, mitochondria, cyclic AMP):

facilitation and promotion of metabolic processes:

as described above, biochemical metabolic processes are promoted.

Also during the penetration of cell cultures with MF currents, it has been found that the number of mitochondria (the "energy factories" of cells) and their size greatly increase.

Depending on the MF current and/or voltage, the concentration of important messenger substances of the cells, cyclic AMP, can also be influenced by an alternating current (Dertinger, 1989, Kemforchungszentrum Karlsruhe, Nagy Nemectron GmbH Karlsruhe).

Furthermore, painless and strong muscle contractions can be induced by MF currents.

The so-called "threshold splitting" occurs from 8kHz, i.e., the threshold amperage for muscle contraction is lower than the amperage for the sensory threshold (Edel, H.: Fibel der Elektro diagnostic and Elektrotherie [ Primer of electronics and Electrothery, Muller & Steinicke Munchen 1983, p.193 ]). Strong muscle contractions may not be caused by pain. From a therapeutic point of view, threshold splitting is of particular interest in using the reversible process of muscle contraction caused by permanent depolarization of MF currents.

Due to the high intensity of the MF current, heat is generated in the tissue through which the current penetrates. But a prerequisite is that the patient is not uncomfortable (feeling, muscle, tolerance, pain) beyond the threshold.

Similar to the improvement of metabolic processes, iontophoresis may also be accompanied by MF current, i.e. the administration of a drug through the skin into the body with the help of an electric current. Iontophoresis with MF currents requires longer treatment times and higher intensities compared to galvanic currents, due to the specific circumstances.

As mentioned above, and also in the scope of the attached trade literature (reference "ElektrischeDifferencel-Therapie" [ electric Differencel Therapy ] by A. Handgsjuorgens and H.U.May, 1990; Nemectron GmbH, Karlsruhe), it has been found that, depending on the diagnosis, existing electrotherapy devices use low-frequency currents at frequencies > 0 to 200Hz or amplitude-modulated medium-frequency currents, or medium-frequency currents at frequencies > 5Hz to 100000Hz, each with a constant amplitude (intensity).

Because any one or more of the above uses contemplate the skin patch of the present invention, the patch 10 preferably includes circuitry for controlling the level or duration of current produced by the electrochemical cell 14. Such circuitry may take the form of an on-off switch for "on-demand" drug delivery (e.g., the patient controls the delivery of an analgesic for pain relief), a timer, a fixed or variable resistance, a controller that automatically turns the device on and off at a desired cycle to match the body's natural or circadian pattern, or other more sophisticated electronic control devices known in the art. For example, a predetermined constant level of delivery current is desirable since a constant current level ensures a constant rate of substance delivery. The level of the current may be controlled by a variety of known means, such as a resistor or a simple circuit using a resistor and a field effect transistor. The circuit may also include an integrated circuit that may be designed to control the dose of active agent delivered, or even respond to sensor signals, in order to adjust the dose to maintain a predetermined dose regimen. A relatively simple circuit can control the current as a function of time and, if desired, produce complex current waveforms, such as pulses or sine waves, as further described above. In addition, the circuit may use a biofeedback system that monitors biological signals, provides an assessment of treatment, and modulates active agent delivery. A typical example is the monitoring of blood glucose levels for controlled administration of insulin to diabetic patients. A simple but important use of the control circuit is to avoid heat build-up and eventual tissue damage. It will be appreciated that ion transport generates heat due to ion motion, and that the more transport, the more heat accumulates at the location of transport. Also, the current used for treatment may be patient controlled in order to find a balance between maximum delivered substance and discomfort of minimum temperature increase.

Thus, a kit according to the invention comprises a dermal patch for transdermal and/or intradermal delivery of at least one substance, and at least one holder for holding the substance away from the patch prior to use. This configuration allows for multiple use of substances/doses through a single skin patch.

Thus, a method of transdermal or intradermal delivery of at least one substance in accordance with the present invention is achieved by (a) topically applying a conductive fluid containing the substance to a skin portion of a subject and/or depositing the conductive fluid containing the substance on at least one electrode of a dermal patch comprising an electrochemical cell having at least two electrodes positioned on one side of the dermal patch; (b) positioning the skin patch such that the electrode is in electrical contact with a skin portion of the subject; and (c) delivering an electrical current through the electrically conductive fluid and the skin portion for transdermal or intradermal delivery of the substance.

Thus, a method of introducing current and/or voltage to a skin portion of a subject according to the present invention is achieved by (a) topically applying a conductive fluid to the skin portion of the subject and/or depositing the conductive fluid on at least one electrode of a skin patch comprising an electrochemical cell having at least two electrodes positioned on one side of the skin patch; (b) positioning the skin patch such that the electrode is in electrical contact with a skin portion of the subject; and (c) delivering an electrical current through the electrically conductive fluid so as to introduce an electrical current and/or voltage to the skin portion of the subject.

It will be appreciated that the conductive fluid may be deposited on one or both electrodes held in the holder or dispensed from any of the other holders described. It will also be appreciated that the above-described application of the invention may also be achieved by the topical application of a conductive fluid to the skin at the location where the electrodes are placed.

The present invention provides a number of advantages over prior patches that inherently include a substance to be delivered transdermally or intradermally, in that a single dermal patch can be used to deliver any number of different substances/doses, so long as it is powered, it need not be discarded, as it will never be exhausted.

Additional objects, advantages and novel features of the present invention will become apparent to one of ordinary skill in the art upon examination of the following examples, which are not intended to be limiting. Furthermore, each of the various embodiments and aspects of the present invention as described hereinabove, and claimed in the claims below finds experimental support in the following examples.

Examples of the present invention

Reference is now made to the following examples, which together with the above description illustrate the invention in a non-limiting manner.

Treatment of mild rosacea

Mild rosacea, characterized by partial hyperemia and telangiectasia of the face, is a common condition that afflicts many people, mainly from the elderly population. Unfortunately, treatment of mild rosacea is limited.

Three patients with mild rosacea participated in the pilot study, meeting the following inclusion criteria:

patients have mild rosacea and need to alleviate congestion on both sides of the face; and

patients are between 20 and 65 years of age.

The aim of the study was to detect the therapeutic effect of congestion during and after treatment, as well as to detect side effects.

Each study subject received treatment on both sides of the face.

On one side of the face, the "active patch" is connected to the power supply by a thin wire so that a large portion of the patch (the main patch) is connected to the positive pole of the power supply and a small portion of the patch (the opposite patch) is connected to the negative pole of the power supply.

A "passive patch" of the same shape, not connected to a power source, was used on the other side of the face of each test subject.

Each patch was coated with the test formulation (aqueous gel, containing witch hazel extract). 0.4ml of the test formulation was applied uniformly to the main patch and 0.1ml of the test formulation was applied uniformly to the opposite patch using a spatula. The patch was then applied to the skin of the study subject for 5 periods of 7 to 20 minutes (treatment period).

Observations were made immediately after removal of the patch, and at 10, 25 and 40 minutes thereafter, including subjective evaluation by the patient and unbiased evaluation by a trained observer. Photographs were taken before treatment and at all observation points.

In all three patients, there was a significant reduction in the degree of congestion and the extent of capillary dilation at the active patch area. The improvement was first observed immediately after patch removal and was further demonstrated for the remaining observation period. The passive patch area represents a slight improvement that is not considered meaningful by the patient and observer.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for clarity, described in the context of separate embodiments, may also be provided separately or in any suitable subcombination.

It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention is defined by the appended claims and includes both combinations and subcombinations of the various features described hereinabove as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

Claims (42)

1. A kit for transdermal or intradermal delivery of at least one substance, comprising:

(a) a dermal patch that conforms to the contour of a dermal surface, the dermal patch comprising an electrochemical cell and at least two electrodes electrically connected to the electrochemical cell, the electrodes comprising a negative electrode and a positive electrode, the electrodes being electrically coupled to a portion of the subject's skin;

(b) at least one holder for holding a conductive fluid containing the at least one substance for deposition on at least one of the at least two electrodes and/or topical application to a skin portion of a subject;

the dermal patch is designed and shaped to facilitate delivery of an electrical current through the skin and the electrically conductive fluid, the electrical current for delivery of the at least one substance through or within the skin;

wherein the skin patch is foldable along two adjacent lines such that the electrode can be folded away from or flattened onto a skin portion.

2. The kit of claim 1, wherein: the electrically conductive fluid is a water-based fluid.

3. The kit of claim 1, wherein: the electrically conductive fluid is a hydrogel.

4. The kit of claim 1, wherein: the current is used to induce iontophoresis, electrophoresis, electroporation, or any combination thereof.

5. The kit of claim 1, wherein: at least one of the at least two electrodes is integrally formed with the electrochemical cell.

6. The kit of claim 1, wherein: the electrochemical cell and the at least two electrodes are individually configured as the skin patch.

7. The kit of claim 1, wherein: the skin patch further includes an attachment mechanism for attaching the skin patch to a skin portion of a subject.

8. The kit of claim 1, wherein: the skin patch also includes circuitry for controlling the current.

9. The kit of claim 1, wherein: the electrochemical cell is a flexible thin layer electrochemical cell.

10. The kit of claim 1, wherein: the electrochemical cell is a flexible, thin layer, open liquid electrochemical cell comprising a first layer of insoluble negative electrode, a second layer of insoluble positive electrode, and a third layer of aqueous electrolyte, the third layer disposed between the first and second layers and comprising:

(a) a deliquescent material for keeping the open cell wet at all times;

(b) an electroactive soluble material for obtaining a desired ionic conductivity; and

(c) a water soluble polymer for obtaining a desired viscosity to adhere the first and the second layers to the third layer.

11. The kit of claim 1, wherein: for use selected from the group consisting of wound healing applications, anti-scarring applications, scar reduction applications, tissue repair applications, tissue regeneration applications, and treatment of rosacea.

12. The kit of claim 1, wherein: the electrically conductive fluid comprises the at least one substance.

13. The kit of claim 1, wherein: the at least one substance is selected from the group consisting of pharmaceuticals, cosmetics and cosmeceuticals.

14. The kit of claim 1, wherein: the retainer is a barrier for deposition on a skin portion such that the electrical current causes the transdermal or intradermal delivery of the at least one substance when contacted by the barrier with at least one of the at least two electrodes.

15. The kit of claim 1, wherein: the retainer is a separator for deposition on at least one of the at least two electrodes such that when contacted by the separator with a skin portion, the electrical current causes the transdermal or intradermal delivery of the at least one substance.

16. The kit of claim 1 or 14, wherein: the spacer is contained in a removable cover.

17. The kit of claim 1, wherein: the skin patch is a flexible patch.

18. The kit of claim 1, wherein: the dermal patch further includes a patch body, and the electrochemical cell and the at least two electrodes are disposed on the patch body to avoid contact between the at least two electrodes.

19. A dermal patch comprising an electrochemical cell for supplying power to the dermal patch and at least two electrodes in electrical connection with the electrochemical cell, the electrodes being electrically coupled to a portion of the skin of a subject, wherein at least one of the at least two electrodes is integrally formed with the electrochemical cell; wherein at least one of the at least two electrodes is a terminal of an electrochemical cell.

20. The patch of claim 19, wherein: for at least one of delivering current and/or voltage to a skin portion of the subject, delivering at least one substance to the skin portion of the subject, transdermal delivery, and intradermal delivery.

21. The patch of claim 19, wherein: the skin patch is a flexible patch.

22. The patch of claim 19, wherein: the dermal patch further includes a patch body, and the electrochemical cell and the at least two electrodes are disposed on the patch body to avoid contact between the at least two electrodes.

23. The patch of claim 19, wherein: at least one of the at least two electrodes is a terminal of an electrochemical cell.

24. The patch of claim 19, wherein: the at least two electrodes are terminals of an electrochemical cell.

25. The patch of claim 19, wherein: the electrochemical cell is a flexible thin layer electrochemical cell.

26. The patch of claim 25, wherein: the electrochemical cell is an open liquid electrochemical cell comprising a first layer of insoluble negative electrode, a second layer of insoluble positive electrode, and a third layer of aqueous electrolyte, the third layer disposed between the first and second layers and comprising:

(a) a deliquescent material for keeping the open cell wet at all times;

(b) an electroactive soluble material for obtaining a desired ionic conductivity; and

(c) a water soluble polymer for obtaining a desired viscosity to adhere the first and the second layers to the third layer.

27. The patch of claim 19, wherein: for use selected from the group consisting of wound healing applications, anti-scarring applications, scar reduction applications, tissue repair applications, tissue regeneration applications, and treatment of rosacea.

28. The patch of claim 19, wherein: also included is a conductive fluid.

29. The patch of claim 28, wherein: the conductive fluid comprises at least one substance and is pre-applied to the at least two electrodes and, when contacted by the patch with the skin, delivers an electrical current through the conductive fluid and the skin of the subject for transdermal or intradermal delivery of the at least one substance.

30. The patch of claim 28, wherein: the electrically conductive fluid is an aqueous hydrogel.

31. The patch of claim 20, wherein: the at least one substance is selected from the group consisting of pharmaceuticals, cosmetics and cosmeceuticals, and moisture.

32. A skin patch that conforms to the contours of a skin surface, comprising:

at least two electrodes for electrically coupling with a portion of the skin of a subject, the electrodes comprising a negative electrode and a positive electrode;

an electrochemical cell electrically coupled to the at least two electrodes, wherein the electrochemical cell provides power to the dermal patch; and

wherein the skin patch is foldable along two adjacent lines such that the electrode can be folded away from or flattened onto the skin portion.

33. A skin patch according to claim 32 wherein: the at least one negative electrode, the at least one positive electrode, and the electrochemical cell are disposed on the patch body, avoiding contact between each electrode.

34. A skin patch according to claim 33 wherein: the at least one negative electrode and the at least one positive electrode are applied to the patch body by using a printing technique.

35. A skin patch according to claim 32 wherein: further comprising at least one substance selected from the group consisting of pharmaceuticals, cosmetics, cosmeceuticals, and moisture, and combinations thereof.

36. A skin patch according to claim 32 wherein: which is used to facilitate delivery of the active substance into a skin portion of a subject.

37. A skin patch according to claim 32 wherein: for delivering a current/voltage to a skin portion of a subject.

38. A skin patch according to claim 32 wherein: at least one electrode is a medical electrode and at least one electrode is an adhesive electrode.

39. A skin patch according to claim 38 wherein: a conductive fluid or conductive composition is disposed on the medical electrode.

40. A skin patch according to claim 32 wherein: the electrochemical cell comprises a flexible electrochemical cell, and the flexible electrochemical cell is a flexible thin layer open liquid electrochemical cell comprising a first layer of insoluble negative electrode, a second layer of insoluble positive electrode, and a third layer of aqueous electrolyte, the third layer disposed between the first and second layers and comprising:

(a) a deliquescent material for keeping the open cell wet at all times;

(b) an electroactive soluble material for obtaining a desired ionic conductivity; and

(c) a water soluble polymer for obtaining a desired viscosity to adhere the first and the second layers to the third layer.

41. A skin patch according to claim 32 wherein: the dermal patch is adapted for delivery of an active substance to a portion of the skin.

42. A kit for introducing current and/or voltage to a skin portion of a subject, the kit comprising:

(a) a dermal patch that conforms to the contour of a dermal surface, the dermal patch comprising an electrochemical cell and at least two electrodes electrically connected to the electrochemical cell, the electrodes comprising a negative electrode and a positive electrode, the electrodes being electrically coupled to a portion of the subject's skin; and

(b) at least one holder for holding an electrically conductive fluid for deposition on at least one of the at least two electrodes and/or topical application to a skin portion of a subject;

the skin patch is designed and shaped to facilitate the delivery of electrical current through the skin and the electrically conductive fluid;

wherein the skin patch is foldable along two adjacent lines such that the electrode can be folded away from or flattened onto a skin portion.