Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/18—Applying electric currents by contact electrodes
  • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/02—Details
  • A61N1/04—Electrodes
  • A61N1/0404—Electrodes for external use
  • A61N1/0408—Use-related aspects
  • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
  • A61N1/0432—Anode and cathode
  • A61N1/044—Shape of the electrode
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/02—Details
  • A61N1/04—Electrodes
  • A61N1/0404—Electrodes for external use
  • A61N1/0408—Use-related aspects
  • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
  • A61N1/0448—Drug reservoir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/18—Applying electric currents by contact electrodes
  • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
  • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body

Definitions

• the present invention relates to transdermal and/or intradermal drug delivery devices, kits and methods and, more particularly, to a dermal path which is capable of delivering an electric current for electrically including transdermal and intradermal delivery of a wide variety of substances or for enhancement of wound healing, scar prevention, scar reduction, tissue repair and/or tissue regeneration via electrical stimulation.
• iontophoresis is in wide use today in the administration of drugs as it effectively delivers electrically charged medicaments through the skin, and into the capillary structure and lymphatic system. This technique avoids the gastrointestinal side effects sometimes associated with orally ingested drugs and is preferable to subcutaneous injection because of its relatively benign and painless nature.
• electroporation facilitates the transdermal or intradermal delivery of uncharged substances by electrically inducing the formation of transient dermal micropores that allow mobilization of the uncharged substances by diffusion.
• iontophoresis as well as other electrically induced techniques, such as electroporation, has been incorporated into many transdermal delivery devices, including the popular dermal patch. Therefore, there are many dermal patches known in the art today which incorporate a power source and electrical circuitry for aiding transdermal delivery.
• Bioelectrodes come in many sizes, shapes and configurations such as following assigned to Ioimed, Inc., which produces iontophoretic delivery devices. 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. Accordingly, those that are incorporated into dermal patches cause the patches to be large and relatively expensive. Moreover, such dermal patches must be charged, or loaded, by clinician and not by the subject.
• a versatile dermal patch that incorporates a power source that may be used to transdermally or intradermally deliver a range of different substances. It is a further object of the present invention to provide a versatile dermal patch that incorporates a power source that may be used to introduce an electric current to a skin portion for a variety of purposes.
• kits for transdermal or intradermal delivery of at least one substance comprising (a) a dermal patch which comprises an electrochemical cell having at least two electrodes positioned on one side of the dermal patch for forming electrical contact with a skin portion of a subject; and (b) at least one retainer for retaining a conductive fluid containing the substance, the conductive fluid being for deposition on at least one of the electrodes and/or topical application onto the skin portion of the subject; the patch being designed and configured for delivering an electric current for transdermal or intradermal delivery of the substance through the conductive fluid and the skin of the subject.
• kits for introduction of current and/or voltage to a skin portion of a subject comprising (a) a dermal patch which comprises an electrochemical cell having at least two electrodes positioned on one side of the dermal patch for forming electrical contact with the skin portion of the subject; and (b) at least one retainer for retaining a conductive fluid for deposition on at least one of the electrodes and/or topical application onto the skin portion of the subject; the patch being designed and configured for delivering an electric current for introduction of current and/or voltage to the skin portion of the subject through the conductive fluid.
• a dermal patch consisting essentially of an electrochemical cell having at least two electrodes positioned on one side of the dermal patch for forming electrical contact with a skin portion of a subject, the dermal path being designed and configured for delivering an electric current through a conductive fluid being deposited on at least one of the electrodes and/or being topically applied onto the skin portion of the subject.
• a method of transdermal or intradermal delivery of a substance comprising (a) topically applying a conductive fluid containing the substance into a skin portion of the subject and/or depositing the conductive fluid containing the substance on at least one electrode of a dermal patch which comprises an electrochemical cell having at least two electrodes positioned on one side of the dermal patch; (b) positioning the dermal patch such that the electrodes are in electrical contact with the skin portion of the subject; and (c) delivering an electric current through the conductive fluid and the skin portion so as to transdermally or intradermally deliver the substance.
• a method of introducing current and/or voltage to a skin portion of a subject comprising (a) topically applying a conductive fluid onto a skin portion of the subject and/or depositing the conductive fluid on at least one electrode of a dermal patch which comprises an electrochemical cell having at least two electrodes positioned on one side of the dermal patch; (b) positioning the dermal patch such that the electrodes are in electrical contact with the skin portion of a subject; and (c) delivering an electric current through the conductive fluid so as to introduce current and/or voltage to the skin portion of the subject.
• the conductive fluid is an aqueous based fluid.
• the conductive fluid is hydrogel. According to features in the described preferred embodiments the conductive fluid is selected from the group consisting of a gel, a cream, a paste, a lotion, a suspension, an emulsion and a solution.
• the conductive fluid is for deposition on at least one of the two electrodes.
• the conductive fluid is for topical application to the skin portion of a subject.
• the substance is a charged substance. According to features in the described preferred embodiments the substance is an uncharged substance.
• the substance is selected from the group consisting of a pharmaceutical, a cosmetic and a cosmeceutical.
• the pharmaceutical is selected from the group consisting of a therapeutic and an anesthetic.
• the electric current serves for causing iontophoresis, electrophoresip, electroporation or any combination thereof.
• the electric current is for causing wound healing, scar prevention, scar reduction, body tissue repair and/or tissue regeneration.
• the retainer is selected from the group consisting of a vessel, a tube, ajar, a container, a dispenser and an ampoule.
• the retainer is a separator for deposition upon at least one of the two electrodes.
• the electric current delivers the substance from the separator.
• Such separator is intended to prevent contact between the electrode and the skin and to provide an even distribution of the electric current over the entire surface of the patch.
• Such separator being either an integral part of the electrode or attached thereto.
• the separator is contained in a removable cover.
• the electrochemical cell is a flexible thin layer electrochemical cell.
• the electrochemical cell is a flexible thin layer open liquid state electrochemical cell which comprises a first layer of insoluble negative pole, a second layer of insoluble positive pole and a third layer of aqueous electrolyte, the third layer being disposed between the first and second layers and including (a) a deliquescent material for keeping the open cell wet at all times; (b) an electroactive soluble material for obtaining required ionic conductivity; and (c) a water-soluble polymer for obtaining a required viscosity for adhering the first and second layers to the third layer.
• one of the two electrodes is for mobilizing the at least one substance.
• 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 are the sole constituents of the patch.
• the dermal patch further comprises an attachment mechanism for attaching to the skin portion of the subject.
• the dermal patch further comprises a circuitry for controlling the electric current.
• the kit is packaged and identified for a wound healing application, a scar prevention application, a scar reduction application, a tissue repair application, a tissue regeneration application, a transdermal delivery application and an intradermal delivery application.
• the present invention successfully addresses the shortcomings of the presently known configurations by providing a versatile dermal patch, operable in transdermal and/or intradermal delivery with any number of substances and dosages.
• FIG. 1 is a sectional view of a dermal patch constructed in accordance with a preferred embodiment of the present invention
• FIGS. 2a-g are illustrations of retainers according to different embodiments of the present invention
• FIGS. 3a-d illustrate a first foolproof embodiment according to the present invention
• FIGS. 4a-d illustrate a second foolproof embodiment according to the present invention
• FIGS. 5a-c illustrate a third foolproof embodiment according to the present invention.
• FIG. 6 is a sectional view of a different configuration of a dermal patch according to the present invention. DESCRIPTION OF THE PREFERRED EMBODIMENTS
• the present invention is of kits, dermal patches and methods which can be used for transdermal and/or intradermal delivery of a variety of substances, such as pharmaceuticals, cosmetics and cosmeceuticals, by means of iontophoresis, electrophoresis and/or electroporation.
• a dermal patch of the present invention is advantageously versatile in the sense that single patch is operative for transdermal and/or intradermal delivery of a versatile range of substances and/or dosages and that the patch may be simply charged and administered by the subject.
• Patch 10 includes a top surface 12 and a skin contacting bottom surface 13, which together form patch body 11.
• Patch 10 is preferably fabricated from flexible materials, which enable surface 12 and/or 13 to conform to the contours of a subject's skin portion when path 10 is applied thereon. It is understood that patch body 11 may be of any size and shape necessary according to the relevant application.
• Patch 10 preferably further includes a skin attachment mechanism, which is preferably an adhesive layer 28 which serves for attaching patch 10 to a skin portion of the subject.
• Adhesive layer 28 covers at least a portion of bottom surface 13 of patch 10.
• Adhesive layer 28 preferably includes 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. Adhesive layer 28 may be useful for either a single attachment or repeated attachments.
• Patch 10 includes therein an electrochemical cell 14, which is preferably a flexible thin electrochemical cell, most preferably an open, liquid state electrochemical cell. It is appreciated that patch 10 may employ any other electrochemical cell or power generating device that serves to provide the needed electric current for the relevant application. Numerous types of miniature power sources, both disposable and rechargeable, which can be incorporated into patch body 11 are known in the art.
• electrochemical cell 14 is a thin flexible electrochemical cell, which engages most of the entire volume of patch body 11.
• electrochemical cell 14 includes a positive pole layer 16, a negative pole layer 18 and an electrolyte layer 20 interposed therebetween.
• An example of a suitable thin and flexible electrochemical cell is described, for example, in U.S. Patent Nos. 5,652,043, 5,897,522 and 5,811,204, which are incorporated herein by reference. 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.
• the cell comprises a first layer of insoluble negative pole, a second layer of insoluble positive pole and a third layer of aqueous electrolyte being disposed between the first and second layers and including (a) a deliquescent material for keeping the open cell wet at all times; (b) an electroactive soluble material for obtaining required ionic conductivity; and, (c) a water-soluble polymer for obtaining a required viscosity for adhering the first and second layers to the first layer.
• a porous substance such as, but not limited to, a filter paper, a plastic membrane, a cellulose membrane and a cloth
• having the first layer of insoluble positive pole include manganese-dioxide powder and the second layer of insoluble negative pole include zinc powder
• having the first layer of insoluble negative pole and/or the second layer of insoluble positive pole further include carbon powder
• 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
• 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
• 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
• Electrochemical cell 14 includes terminals serving as electrodes referred to hereinafter as positive electrode 22 and negative electrode 24 each of which being in electrical contact with positive pole layer 16 and negative pole layer 18, respectively. Electrodes 22 and 24 are electrically connected to electrochemical cell 14 using well known means, e.g., printed flexible circuits, metal foils, wires, electrically conductive adhesives or by direct contact. It is understood that measures are taken to avoid contact between the electrodes and between each of the electrodes and the opposite pole layer. In figure 1 , the measure taken is the interposition of insulating element 17 formed of a dielectric material.
• Electrodes 22 and 24 are electrically conductive and may be formed of a metal, e.g., a metal foil or metal deposited or painted on a suitable backing. Examples of suitable metals include aluminum, platinum, stainless steel, gold and titanium. Alternatively, electrodes 22 and 24 may be formed of a hydrophobic polymer matrix containing a conductive filler such as a metal powder/flakes, powdered graphite, carbon fibers or other known electrically conductive filler material. Electrodes 22 and 24 can be applied to the cell and the entire cell can be manufactured by, for example, a suitable printing technology such as, but not limited to, silk print, offset print, jet printing, lamination, materials evaporation or powder dispersion.
• a suitable printing technology such as, but not limited to, silk print, offset print, jet printing, lamination, materials evaporation or powder dispersion.
• electrochemical cell 14 as described hereinabove is among the simplest of power sources. It is appreciated that each of electrodes 22 and 24 may be of any size and shape, and located with respect to one another, in any arrangement, as may be required to cover the skin portion under treatment. Indeed, in accordance with a preferred embodiment of the present invention, electrochemical cell 14, in conjunction with electrodes 22 and 24, constitute the sole internal elements of patch 10. Accordingly, patch 10 is among the smallest and thinnest active practice and delivers the maximum power per unit of surface area.
• Patch 10 of the present invention is preferably supplied within a protective removable or reusable package, or liner, or cover 19, so as to provide physical protection and prolong shelf life prior to use.
• Patch 10 is designed and configured to be used with at least one, and preferably many, external substances. Such substances, described in detail hereinafter, are designed to be contained in a conductive fluid, also described in detail hereinafter.
• the conductive fluid is designed to be retained in at least one, preferably many, retainers.
• the combination of patch 10 and the retainer form a kit that may be retained by a patient for use for a variety of applications.
• the formation of such conductive fluid will generally be “pharmaceutically acceptable” or “physiologically acceptable” formulations for cosmetic or therapeutic use.
• pharmaceutically acceptable and “physiologically acceptably” refer to substances that can be administered to a subject, preferably without excessive adverse side effects (e.g., for a topically applied formulation, skin rash, irritation, etc.).
• the conductive fluid 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 are cationic acrylates and may be, for example, preferably made from acrylic esters of quatemry chlorides and/or sulfates or acrylic amides of quaternary chlorides. They can be formed by free radical polymerization in the presence of water, preferably by ultra-violet curing with initiator and multi-functional cross-linking agent.
• the hydrogel may preferably 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, humectant plasticizers, etc.) depending on intended end-use.
• An additive that is preferably added to the hydrogel is a conductive adhesive matter (additive) that serves to allow the conductive fluid to both attach patch 10 to the skin of the subject and to serve as the conductive interface between the electrode and the skin.
• the adhesive additive is preferably a polymeric adhesive and may be pressure or temperature activatable or it may be activated by the exposure to the ambient atmosphere.
• an aqueous conductive fluid in accordance with the teachings of the present invention will typically comprise water, alcoholic/aqueous solutions, at least one salt or any other charged agent and preferably a buffering medium.
• non-aqueous conductive fluids may also be employed.
• the conductive fluids used in conjunction with patch 10 preferably administered by deposition on one or both electrodes. It is appreciated that the conductive fluid may alternatively or in addition be administered by topical application to the skin.
• topical is used herein to refer to administration of a substance on the surface of the skin or mucosal tissue, which can be applied via direct application (e.g., spreading), via an impregnated porous material or object or by spraying or misting.
• topical application of the fluid to the skin of the subject is typically less precise and, if not done carefully, may inadvertently cause an electrical connection between the electrodes directly through the conductive fluid such that the electric current and the mobilized ions would not pass through the skin.
• the retainers will vary in shape, size and method of dispensing according to the quantity, application and location relevant to the treatment. Shown in Figures 2b-g are retainers in the form of a vessel 31 tube 32, jar 33, a container 34, a dispenser 35 and an ampoule 36. It will be appreciated that the present invention contemplates all such retainers as well as others in any shape, size or configuration that serve to retain the conductive fluid and dispense it for use as needed on either the electrodes or upon the skin of a subject.
• retainer 30 Shown in Figure 2a is retainer 30 which is a separator.
• separator is intended to describe a retainer made of a porous non-conductive material, such as a sponge, paper, etc., that serves to retain the conductive fluid therein. Separators offer advantages over other retainers in that they allow precise positioning of the conductive fluid, they are not messy, and they permit a precise dosage to be administered.
• Fluid is retained in a separator in such a manner that objects that are in contact with the separator are also in contact with the fluid contained therein.
• separators are preferably designed and configured to fit between one or both of electrodes 22 and 24 and the skin of the subject, thus providing a simple, clean and convenient electrode/skin interface through which electricity may flow via the conductive fluid to the area of treatment.
• separators are constructed so that their non-conductive structure does not impede the electrical contact between electrodes 22 or 24 and the conductive fluid therein. It is understood that a separator will not be positioned such that it or its contents create an electrical contact between electrodes 22 and 24. Such positioning will form an electric circuit that does not include the skin of the subject and will frustrate the purpose of the electrical application.
• Separators may be fabricated in the form of plugs, cartridges or tablets and the like which are designed to be compatible with different shapes, sizes and configurations of electrodes 22 and/or 24.
• retainer 30, in its embodiment as a separator is preferably a thin waferlike container, which may be of a desired shape to be compatible with both the area of treatment and the electrode in use.
• Such separators may preferably be protected by a thin film layer, which will be peeled off immediately prior to use.
• Separators may be packaged for storage or use as may be compatible with the preferred embodiment of the kit of the present invention. Separators will preferably be individually packaged in order to preserve shelf life and to avoid evaporation of the conducting fluid and/or to substance contained therein.
• retainers particularly separator 30, are intended to render patch 10 extremely user friendly and almost foolproof in its employment.
• the wide variation in the designs and configurations of retainers shown are for the purpose of the precise application of the conductive fluid either on the appropriate electrode or topically upon the skin of the subject.
• a retainer in the form of tube 32 will permit the simple deposition of a dab of conductive fluid precisely on the electrode.
• a retainer in the form of ampoule 36 will assure correct dosing of the medicament.
• Dispenser 35 will permit careful and accurate application of conductive fluid to the exact skin portion of the subject.
• the preferred embodiment of the invention will have separator 30 as the vehicle for the conductive fluid, which can be positioned with precision on either the electrode or on the skin of the subject.
• the kit comprising patch 10 and one or more of retainers 30 through 36 will preferably also contain any other implements, instruction, markings, aids or devices that will serve to assist a user to properly apply and position the conductive fluid as required.
• FIGS 3a-5c Several foolproof embodiments with respect to patch 10 of the present invention are shown in Figures 3a-5c.
• a strip 100 is placed over the skin 102 and a conductive lotion, gel, cream or the like 104 is applied over the skin 102, such that upon removal of strip 100, two non-contacting zones 106 receptive of a patch 108 constructed and operative in accordance with the teachings of the present invention are formed and patch 108 is applied onto the skin 102, such that the electrodes 110 thereof each being in contact with one of zones 106 so as to avoid a shortcut.
• a patterning device 200 having two openings 201 is placed over the skin 202 and a conductive lotion, gel, cream or the like 204 is applied over the skin 202, such that upon removal of patterning device 200, two non-contacting zones 206 receptive of a patch 208 constructed and operative in accordance with the teachings of the present invention are formed and patch 208 is applied onto the skin 202, such that the electrodes 210 thereof each being in contact with one of zones 206, so as to avoid a shortcut.
• a foldable patch 308 is placed, in its folded configuration, over the skin 302 and a conductive lotion, gel, cream or the like 304 is applied over the skin 302 on both sides thereof, such that upon flattening patch 308, two non-contacting zones 306 receptive of patch 308 are formed and patch 308 is contacting the skin 302, such that the electrodes 310 thereof each being in contact with one of zones 306, so as to avoid a shortcut.
• Figure 6 shows an embodiment of patch 10 of the present invention in which electrode 22 is not integral to electrochemical cell 14 but is connected by a conductive connector, hereinafter referred to as connector 21.
• Connector 21 may be printed or may be of any conductive material known in the art.
• the retainer which is a separator, is deposited on electrode 24 of electrochemical cell 14.
• electrode 24 may be referred to as the medical electrode and electrode 22 as the conductive adhesive electrode.
• simultaneous contact with the skin of a subject by electrode 22 and separator 30 will form an electrical circuit which includes the skin of the subject as part of the conductive path.
• electrochemical cell 14 will produce an electric current which will be delivered through the conductive fluid held by retainer 30 which is in contact with the skin.
• patch 10 transdermally or intradermally deliver a pharmaceutical substance, a cosmetic substance or a cosmeceutical substance.
• transdermal and “intradermal” and grammatical variations thereof, respectively refer to the delivery of a composition through across the skin or into the skin.
• pharmaceutical refers to therapeutic and anesthetic substances.
• Therapeutic as used herein, is understood to include any substance serving to cure, heal, treat medically or preserve health.
• Anesthetic as used herein, is understood to include any substance serving to cause a loss of tactile sensation, particularly pain.
• Such substances in order to be delivered electrically, will preferably be in the form of charged molecules which will respond to an electric current. It is appreciated that any pharmaceutical substance, cosmetic substance or cosmeceutical substance may be delivered by the invention described herein, as long as the substance is charged or can be charged.
• the substance In cases where the substance is not naturally charged it is preferably combined with a charging agent, or subjected to environmental conditions, such as a specific pH environment, which induces charge formation.
• a charging agent or subjected to environmental conditions, such as a specific pH environment, which induces charge formation.
• Methods of charging molecules are well known in the art and as such no further description is given herein.
• the substance to be delivered may be charged prior to or concomitant with its delivery. Therefore, where used herein the term "substance” refers to active substances which are preferably in the form of charged ions or charged molecules and which are able to be electrically delivered transdermally or intradermally.
• 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, sympathornimetics, xanthine derivatives, cardiovascular preparations including calcium channel blockers such as nifedipine, an
• the invention is also useful for the delivery of cosmetic and cosmeceutical substances.
• 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), 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 such as aminophyllines and others, skin bleaching agents such as retinoic acid, hydroquinone and peroxides and others, botanical preparations such as extracts of aloe-vera, wild yam, hamamelitanin, ginseng, green tea and others.
• skin acting anti-oxidants such as caretenoids, ascorbic acid (vitamin C) and vitamin E, as
• 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.
• the delivery of the substance transdermally or intradermally preferably occurs by a process of iontophoresis and/or electrophoresis.
• Iontophoresis refers to the-movement of ions caused by the application of an electrical potential.
• Electrophoresis refers to the movement of charged colloidal particles or macromolecules caused by the application of an electrical field.
• the electric current caused by the electric potential between electrodes 22 and 24 serves to release the charged substance from the conductive fluid and to deliver the molecules/ions of the charged substance from the conductive fluid and to deliver the molecules into the adjacent skin tissue.
• the charged substance within the conductive fluid which is deposited between one or both of electrodes 22 and 24 and the skin of the subject, would be attracted to or repelled by electrode 22 and electrode 24 as appropriate to their charge.
• electrode 22 would repel the substance, thus mobilizing it into or through the skin.
• the charged substance is driven across the conductive fluid/skin interface into the skin.
• reverse iontophoresis may also be used in a process of transdermal or intradermal recovery of substances from the body. Such a technique employs the same electrical principles applied in reverse. Techniques of transdermal, or intradermal recovery of substances are well known in the art. The movement of substances transdermally or intradermally may also be aided by a process of electroporation. Electroporation is typically carried out by high voltage pulses applied to a pair of electrodes which are applied to a tissue surface. The electric pulses cause the passing ions to perforate the tissue layer, providing new pathways for the passage of substances, both charged and not charged. It must be noted that electroporation does not deliver a charged substance, but rather reduces the resistance to passage of substances into the adjacent tissue.
• patch 10 Another preferred purpose of patch 10 is to promote wound healing, scar reduction, scar prevention, tissue repair and/or tissue regeneration by direct application of currents through the skin.
• Electric current has long been known and utilized therapeutically to force excitable cells (nerve, muscles and receptors of nerve ends) of the human body, by electrical stimuli externally supplied in the form of electrical pulses, to generate an electrical response, the so-called action potentials.
• action potentials are cell-intrinsic electrical pulses with a defined amplitude and duration for the relevant cell type.
• a pulse width of about 1ms and an amplitude of about 80 mV to 100 mV is typical.
• the cell reverts to its cell membrane voltage, which at rest, depending on cell type, has a value between 60 mV and 120 mV. This voltage is caused by different ion concentrations in the extracellular and intracellular spaces separated by the cell membrane. More positive ions are found outside the cell. According to definition, the potential outside the cell is set to 0 V, so that a negative potential is given in the cell.
• the action potentials are generated by the body itself and utilized for information transfer and to trigger cellular processes.
• electrotherapy therapeutic effects are induced by specific generation of action potentials (defined number and at specific loci).
• Apparatuses for electrotherapy use a plurality of various electrical currents, or pulse forms. Aiming to choose the electrotherapy best suited for a specific indication, the therapist should be able to revert to criteria of maximally clear definition. These criteria derive from the replies, to questions about the effectiveness and tolerance of the various current form.
• the spectrum of effects includes, e.g., the areas of pain alleviation, stimulation of striated and nonstriated muscles, of influencing perfusion, the detumescent mechanisms, of the areas of checking inflammatory processes and of promoting regeneration (wounds, accelerated healing of bones, etc.,)
• the aim in the application should always be achieving the desired effect in the affected area by proper selection of the current form, either distal or, proximal to the electrode or in the depth of the body.
• electrotherapeutic apparatuses are based on two stimulus current methods, the polarity-dependent "polar stimulation principle” and the polarity-independent “apolar stimulation principle".
• Low-frequency alternating currents (LF current) ranging from 0 to 200 Hz are used in the "polar stimulation principle”.
• Hyperpolarization rise in membrane voltage
• the anode makes the spacing between the potential in the cell and the stimulus threshold greater.
• the membrane voltage drops beneath the negative electrode, the cathode.
• the cell triggers automatically an action potential.
• Stimulant current apparatuses employ different pulse shapes in the low-frequency spectrum of about >0 to 200 Hz (LF current). Applicable are, e.g., the so-called delta currents, rectangular currents, diadynamic currents, high-voltage currents, ultrastimulant currents, faraday currents - to name but a few. Some alternating currents have a direct current component, which additionally backs the polar effects. There are two frequency-dependent methods of using action potential's therapeutically:
• the number of action potentials generated by the excitable cell e.g., nerve or muscle
• the same number of pulses are then generated in the relevant cell by stimulation, thereby backing the cell in performing its tasks.
• a stimulation frequency of up to 6 Hz is applied to generate up to 6 individual contractions per second.
• Fatigue principle In contrast, when forcing the cell (nerve or muscle) to generate action potentials, by stimulation at higher frequency and appreciably more often than the cell would be required to do so to perform its tasks, it fatigues after a short time. The opposite effect occurs.
• the cell fatigue can be explained by energy-consuming processes in the formation of action potentials. For instance, a sclerosed muscle can be relaxed according to this fatigue principle by stimulating it with a "higher" frequency of, e.g., 100 Hz or 200 Hz.
• the intensity must be chosen sufficiently high to exceed the stimulus threshold.
• the level of intensity to be set depends on the following factors: the position (depth) of the cell to be stimulated in the tissue (distance from the electrode), the size of the electrodes and the tissue resistances in the region penetrated by the electric potential, which, in turn, is influenced by the parameters of the current form.
• MF currents medium-frequency alternating currents
• Meant by MF currents are sinusoidal alternating currents with a frequency of > 5 Hz to 100,000 Hz.
• a single cycle (alternating pulse) with sufficient intensity has a polar effect which is able to trigger an action potential in a nerve or muscle cell.
• MF pulses are applied at a low-frequency repetition rate of >0 to about 200 Hz and MF carrier frequencies of > 5 Hz to 100,000 Hz. In practice, this is mostly a sinusoidal, amplitude-modulated MF current (AM-MF current).
• AM-MF current amplitude-modulated MF current
• Fatigue principle To fatigue excitable cells, MF pulses with higher amplitudes are used.
• Muscle training in voluntary innervation insufficiency and muscle distention With the nerve muscle apparatus intact, the striated muscle (skeletal muscle) is stimulated directly by permanent depolarization. This results in muscle contraction, which is used, e.g., in voluntary innervation insufficiency of the muscles or to stretch the antagonists of spastic muscles.
• the intensity should be interrupted by pauses in short intervals. The intensity also may be increased and decreased between 100% and about 50% of the adjusted value.
• Very strong muscle contractions may be induced without fatigue phenomena.
• tetanic contraction which can be induced with stimulation current of about 50 Hz and up, a rapid decrease of the muscle contraction force occurs contrarily, due to fatigue of the myokinetic units.
• Permanent depolarization induces cell division in healthy cells. Wound healing may be promoted thereby, bone healing accelerated in fractures. Moreover, MF currents induce under the effect of the electrical alternating field reciprocal movement (shaking effect) of charged molecules in the current penetrated tissue, accompanied by rotation movements of the charged molecule shares. Achieved thereby is a greater probability of a "correct" meeting position of enzyme and substrate, which in metabolic processes interact chemically (metabolic facilitation). This shaking effect tends to level differences in concentration, in that diffusion processes which on account of existing concentration gradients proceed in certain directions are accelerated due to the kinetic energy that is additionally imparted (MF iontophoresis, inhibition of inflammation, alleviation of pain).
• the shaking effect is especially effective at high intensities.
• Distribution of inflammatory and pain mediators :
• the concentration of an important messenger substance of the cell, the cyclic AMP can also be influenced by alternating current, depending on MF current and/or voltage (Dertinger, 1989, Kemabastechnik Düsseldorf, Nagy Nemectron GmbH Düsseldorf).
• threshold dissociation occurs from 8 kHz, that is, the threshold amperage for muscle contraction goes below that of the sensible threshold (Edel, H.: Fibel der Elektrodiagnostik and Elektrotherapie [Primer of Electrodiagnostics and Electrotherapy, Muller & Steinicke Munchen 1983, p. 193). Strong muscle contractions can be induced without pain.
• threshold dissociation is of particular interest in utilizing the reversible process of muscle contraction, which is caused by the permanent depolarization of the MF current.
• iontophoresis can be accomplished with MF current, i.e., the administration of medications with the aid of current through the skin into the body. Owing to the physical circumstances, iontophoresis with MF current requires a longer treatment time and higher intensities as compared to galvanic current.
• patch 10 preferably includes electrical circuitry for controlling the level or duration of current produced by electrochemical cell 14.
• Such circuitry may take the form of an on-off switch for "on-demand" drug delivery (e.g., patient controlled delivery of an analgesic for pain relief), a timer, a fixed or variable electrical resistor, a controller which automatically turns the device on and off at some desired periodicity to match the natural or circadian patterns of the body, or other more sophisticated electronic control devices known in the art.
• an on-off switch for "on-demand" drug delivery e.g., patient controlled delivery of an analgesic for pain relief
• a timer e.g., patient controlled delivery of an analgesic for pain relief
• a fixed or variable electrical resistor e.g., a controller which automatically turns the device on and off at some desired periodicity to match the natural or circadian patterns of the body, or other more sophisticated electronic control devices known in the art.
• the level of current can be controlled by a variety of known
• the circuitry may also include an integrated circuit which could be designed to control the dosage of active agent delivered, or even to respond to sensor signals in order to regulate the dosage to maintain a predetermined dosage regimen.
• a relatively simple circuit can control the current as a function of time, and if desired, generate complex current waveforms such as pulses or sinusoidal waves as is further described above.
• the circuitry may employ a bio-feedback system which monitors a biosignal, provides an assessment of the therapy, and adjusts the active agent delivery accordingly.
• a typical example is the monitoring of the blood sugar level for controlled administration of insulin to a diabetic patient.
• a simple yet important use of a controlling circuit is the avoidance of heat buildup and resultant tissue damage.
• the delivery of ions causes heat due to the movement of the ions and that the greater the delivery, the greater will be the heat buildup at the site of the delivery.
• the current used for treatment could be patient-controlled such that a balance may be found between maximizing the delivery of substance and minimizing the discomfort of temperature increase.
• a kit according to the present invention will therefore include a dermal patch-for the transdermal and/or intradermal delivery of at least one substance, and at least one retainer for retaining the substance(s) away from the patch prior to use.
• This construction allows the versatile use of substances/dosages with a single dermal patch.
• a method of transdermal or intradermal delivery of at least one substance according to the present invention is hence effected by (a) topically applying a conductive fluid containing the substance onto a skin portion of the subject and/or depositing the conductive fluid containing the substance on at least one electrode of a dermal patch which, comprises an, electrochemical cell having at least two electrodes positioned on one side of the dermal patch; (b) positioning the dermal patch such that the electrodes are in electrical contact with the skin portion of the subject; and (c) delivering an electric current through the conductive fluid and the skin portion so as to transdermally or intradermally deliver the substance.
• a method of introducing current and/or voltage to a skin portion of a subject according to the present invention is hence effected by (a) topically applying a conductive fluid onto a skin portion of the subject and/or depositing the conductive fluid on at least one electrode of a dermal patch which comprises an electrochemical cell having at least two electrodes positioned on one side of the dermal patch; (b) positioning the dermal patch such that the electrodes are in electrical contact with the skin portion of a subject; and (c) delivering an electric current through the conductive fluid so as to introduce current and/or voltage to the skin portion of the subject.
• the conductive fluid may be deposited onto one or both electrodes either being retained within the retainer or by being: dispensed from any of the other retainers described. It is further understood that the above applications of the present invention may also be effected by topically applying the conductive fluid to the skin at the location that the electrode will be placed.
• the present invention offers numerous advantages over existing patches which inherently include substances to be transdermally or intradermally delivered as a single dermal patch can be used to deliver any number of different substances/doses as long as it is powered, it need not be discarded as it is never depleted.
• Mild rosacea characterized by redness of parts of the face and telangectasia, is a common disorder, afflicting many individuals, mainly from the aging population. Unfortunately the treatments for mild rosacea are 5 limited.
• Patient has mild to moderate redness in both sides of the face.
• Patient is between 20 and 65 years of age.
• the study objectives were to detect the therapeutic effects on the redness phenomenon, during and following treatment and to detect side effects.
• an "Active Patch” linked by thin cords to a power supply so that the large part of the patch (Main Patch) was linked to the Positive pole of the power supply and the small part of the patch (Counter-Patch) was linked to the negative pole of the power supply.
• Each patch was coated by a Test Preparation (aqueous gel, containing witch hazel extract). 0.4 ml of the Test Preparation was evenly applied onto the Main Patch and 0.1 ml to the Counter Patch, using a spatula. The patches were then applied onto the skin of the study subjects for a 5 period of 7-20 minutes (the Treatment Period). Observations were taken immediately after removal of the patches and 10, 25 and 40 minutes thereafter, including subjective assessment by the patient and blinded assessment by a trained observer. Photographs were taken prior to treatment and at all observation points. In all three patients, there was a pronounced reduction in the degree of redness and the extent of telangectasia at the Active Patch sites. This improvement was first observed immediately after patch removal and further documented for the rest of the observation period. The Passive Patch sites exhibited very slight improvements, which were not considered by the patients or the observer as significant.

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