Device for treatment of human or animal barrier membranes

ES 2 372 050 T3

DESCRIPTION

Procedures to treat acne and acne rosacea with electrochemically generated zinc ions

Background of the invention

Transdermal devices have been widely prescribed for decades for the treatment of systemic diseases and local disorders. During passive transdermal administration, an active agent is delivered to a mammal using a concentration gradient across a barrier membrane (eg, by passive diffusion through the skin). For example, a patch containing the drug in high concentration is fixed on the skin of a patient.

Electricity can be used to facilitate drug transport across the skin barrier. In electrically assisted devices, an electrical potential (voltage) is applied to the membrane to facilitate drug transport. In transdermal ionotophoresis, an ionized drug migrates into the skin directed by an applied electrical potential gradient. Anionic drugs are transported into the skin under the cathode (negatively charged electrode), while cationic drugs are transported under the anode (positively charged electrode). Iontophoresis allows an enhanced permeation rate, as well as better control of the ionic species into the skin.

The most common design of an iontophoresis device includes a power source (eg, a battery), an electrical control mechanism, and two different conductive electrodes. Each conductive electrode is in contact with a different electrolyte composition (with or without an active agent). The electrolyte or ionic active composition is, in general, an aqueous solution contained in a chamber for liquids, or a semisolid. The assembly of the conductive electrode and electrolyte composition is often referred to as an "electrode assembly" or simply "an electrode." Usually two electrode assemblies are attached to the skin separated by electrical insulation between them.

Alternatively, the two electrode assemblies can be constructed into a single iontophoresis device with an electrical insulating material formed between the two electrode assemblies for electrical isolation to prevent short circuit. An example of such an iontophoresis device is described in US Patent No. 5,387,189.

In another variation on common iontophoresis device designs, the electrolyte composition in one of the two electrode assemblies, and the conductive electrode is placed directly in contact with the skin to complete the electrical circuit. An example of such an iontophoresis device is described in US Patent No. 6,385,487.

During a typical iontophoresis operation (monopolar operation), one of the two electrodes (ie, the active electrode) leads the active agent into the skin. The other electrode (that is, the scattered electrode) acts to close the electrical circuit through the skin. Sometimes a second active agent of opposite electrical charge can be placed in the electrolyte composition in contact with the second electrode, and thus is transported into the skin under the second electrode. Alternatively, the electrical polarity of the first and second electrodes can be periodically reversed to drive ionic species under both electrodes (bipolar operation). A bipolar iontophoresis device for transdermal drug delivery is described in US Patent No. 4,406,658. The use of a galvanic couple as a power source in an iontophoresis device is well known in the art. See, for example, US Patent Nos. 5,147,297, 5,162,043, 5,298,017, 5,326,341, 5,405,317, 5,685,837, 6,584,349, 6,421,561, and 6,653,014. Typical materials from which a galvanic couple is made include a zinc donor electrode and a silver chloride counter electrode. This combination produces an electrical potential of approximately one volt. This galvanic couple actuated iontophoresis system, which has no means of control, is automatically activated when tissue and / or body fluids form a complete circuit with the system to generate electricity. German patent document DE 198 31 798 A1 describes an acne treatment by applying zinc oxide to the skin to treat acne.

Summary of the invention

In one aspect, the present invention includes a method of exfoliating the skin by applying to the skin in need of such exfoliation a device that includes a cover having a skin-contacting surface, a first conductive electrode, a second conductive electrode, and a carrier including an agent selected from an alpha-hydroxy acid, a beta-hydroxy acid, and their salts; wherein the first conductive electrode is in electrical communication with the second conductive electrode, wherein the first conductive electrode is in ionic communication with the vehicle, wherein the vehicle is in communication with the skin-contacting surface, and in which the

ES 2 372 050 T3 skin contact surface is placed in contact with the skin.

In another aspect, the present invention includes a method of exfoliating the skin, by topical application of a composition that includes a first particulate conductive electrode, a second conductive particulate electrode, and an agent selected from an alpha- hydroxy acid, a beta-hydroxy acid, and its salts, in which the difference of the standard potentials of the first conductive electrode and the second conductive electrode is at least 0.2 V.

In another aspect, the present invention includes a method for stimulating a composition that includes a first particulate conductive electrode and a second particulate conductive electrode, wherein the difference of the standard potentials of the first and second conductive electrodes conductive electrode is at least 0.2 V, said procedure including stimulating the topical application of said composition for treating a wound on a barrier membrane.

In another aspect, the present invention includes a method of treating pores in the skin by applying to the skin in need of such treatment a device that includes a cover having a skin contacting surface, a first conductive electrode, a second conductive electrode, and a vehicle; wherein the first conductive electrode is in electrical communication with the second conductive electrode, wherein the first conductive electrode is in ionic communication with the vehicle, wherein the vehicle is in communication with the skin-contacting surface, in wherein the skin contacting surface is placed in contact with the skin, and wherein said procedure for treating pores on the skin is selected from the group of cleaning pores on the skin, reduce sebum on the skin, reduce the appearance of blackheads on the skin, and reduce the appearance of pores on the skin.

In another aspect, the present invention includes a method of treating pores in the skin by topical application of a composition that includes a first particulate conductive electrode and a second particulate conductive electrode, wherein the difference of the Standard potentials of the first conductive electrode and the second conductive electrode is at least 0.2 V.

In another aspect, the present invention includes a method of stimulating a composition that includes a first particulate conductive electrode and a second particulate conductive electrode, wherein the difference of the standard potentials of the first and second conductive electrodes conductive electrode is at least 0.2 V, said procedure including stimulating the topical application of said composition for the treatment of pores in the skin, wherein the procedure for treating pores on the skin is selected from the group of cleaning pores on the skin, reducing sebum on the skin, reducing the appearance of blackheads on the skin, and reducing the appearance of pores on the skin.

In one aspect, the present invention includes a method of treating skin infections including, but not limited to, acne or acne rosacea, by applying electrochemically generated zinc ions to the skin. In one embodiment, the method includes topical application of a device that includes a zinc-containing anode. In another embodiment, the device includes a cover having a skin-contacting surface; a first conductive electrode containing zinc; a second conductive electrode; and a vehicle; wherein the first conductive electrode is in electrical communication with the second conductive electrode, wherein the first conductive electrode is in ionic communication with the vehicle, and wherein the vehicle is in communication with said skin-contacting surface.

In another aspect, the present invention includes a device having a barrier membrane contact surface, said device containing: a power source; a first conductive electrode; a second conductive electrode; and a vehicle; wherein the power source is in electrical communication with the first conductive electrode and the second conductive electrode, wherein the first conductive electrode and the second conductive electrode are in ionic communication with the vehicle, and wherein the vehicle is in communication with the contact surface with the barrier membrane. In another aspect, the present invention includes a method of delivering electricity to a human barrier membrane by applying such a device to the membrane. In another aspect, the present invention includes a method of treating a skin disorder by applying such a device to the skin.

In another aspect, the present invention includes a device having a barrier membrane contact surface, said device containing: a power source; a first conductive electrode; a second conductive electrode; and a vehicle containing an active agent; wherein the power source is in electrical communication with the first conductive electrode and the second conductive electrode, wherein the first conductive electrode and the second conductive electrode are in ionic communication with the vehicle, and wherein the vehicle is in communication with the contact surface with the barrier membrane. In another aspect, the present invention includes a method of delivering electricity to a human barrier membrane by applying such a device to the membrane. In another aspect, the present invention includes a

ES 2 372 050 T3 method of treating a skin disorder by applying said device to the skin.

In another aspect, the present invention includes a device having a barrier membrane contact surface, said device containing: a power source; a first conductive electrode; a second conductive electrode; a first light emitting diode; and a vehicle containing an active agent; wherein the power source is in electrical communication with the first conductive electrode, the second conductive electrode, and the light-emitting diode, and wherein the device is arranged such that the light from the first light-emitting diode and the vehicle are in communication with the interface with the barrier membrane. In another aspect, the present invention includes a method of delivering an active agent to a human barrier membrane by applying such a device to the membrane. In another aspect, the present invention includes a method of treating a skin disorder by applying such a device to the skin.

In another aspect, the present invention includes a method of treating a skin disorder by applying to the skin a device having a barrier membrane contacting surface that delivers an oxidizing agent to the barrier membrane, in the that the device contains: a power source; a first conductive electrode, wherein the first conductive electrode is an inert anode; a second conductive electrode, wherein the second conductive electrode is a cathode; and a vehicle containing water; wherein the power source is in electrical communication with the first conductive electrode and the second conductive electrode, wherein the first conductive electrode is in ionic communication with the vehicle, wherein the oxidizing agent is generated by an electrical current that passes from the first conductive electrode through the vehicle, and wherein the vehicle is in communication with the contact surface with the barrier membrane. In another aspect, the present invention includes a method of delivering an oxidizing agent to a barrier membrane by applying such a device to the membrane.

In another aspect, the present invention includes a method of treating a skin disorder by applying to the skin a device having a barrier membrane contact surface that delivers a reducing agent to the barrier membrane, in the that the device contains: a power source; a first conductive electrode, wherein the first conductive electrode is an inert cathode; a second conductive electrode, wherein the second conductive electrode is an anode; and a vehicle containing water; wherein the power source is in electrical communication with the first conductive electrode and the second conductive electrode, wherein the first conductive electrode is in ionic communication with the vehicle, wherein the reducing agent is generated by an electrical current that passes from the first conductive electrode through the vehicle, and wherein the vehicle is in communication with the contact surface with the barrier membrane. In another aspect, the present invention includes a method of delivering a reducing agent to a barrier membrane by applying such a device to the membrane.

Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.

Brief description of the drawings

FIGURE 1 is a cross section of one embodiment of the device suitable for practicing the invention. Conductive electrodes 140 and 240 are respectively connected by lead wires 110 and 210 to an electrically insulated connecting wire 350 located at the rear of device 500.

FIGURE 2 is a cross section of one embodiment of the device suitable for practicing the invention. Conductive electrodes 140 and 240 are respectively connected by lead wires 110 and 210 to an electrically insulated connector wire 350 inserted within vehicle layer 120 of device 500.

FIGURE 3 is a cross section of one embodiment of the device suitable for practicing the invention. Conductive electrodes 140 and 240 are respectively connected by lead wires 110 and 210 to an electrically insulated connector wire 350 inserted within vehicle layer 120.

FIGURE 4 is a cross section of one embodiment of the device suitable for practicing the invention. The conductive electrodes 140 and 240 are in electrical communication with each other through a direct connection.

FIGURE 5 is a cross section of an embodiment according to the invention. Device 800 contains two electrode assemblies 200 and 600.

FIGURE 6 is a top view of an embodiment according to the invention showing conductive electrodes 140 and 240 connected by electrically insulated connector wire 350 inserted within vehicle layer 120. Conductive electrodes 140 and 240 are arranged in an interdigital configuration .

FIGURE 7 is a top view of an embodiment according to the invention showing the conductive electrodes 4

ES 2 372 050 T3

140 and 240 connected by an electrically insulated connector wire 350 inserted within the vehicle layer 120. The conductive electrodes 140 and 240 are arranged in a concentric configuration.

FIGURE 8 is a top view of an embodiment according to the invention showing a plurality of assemblies of conductive electrodes 140 and 240 connected together by a connector cable 350 to form a plurality of galvanic pair power sources, which are in contact with vehicle layer 120. Conductive electrodes 140 and 240 are arranged in a parallel configuration.

FIGURE 9 is a top view of an embodiment according to the invention showing a plurality of conductive electrode assemblies 140 and 240 connected together by direct physical contact at intersections 370 to form a plurality of galvanic pair power sources, which they are in contact with the carrier layer 120. The conductive electrodes 140 and 240 are arranged in a perpendicular configuration.

FIGURE 10 is a top view of an embodiment according to the invention showing the conductive electrodes 140 and 240 connected to an electrically insulated connector wire 350 inserted into the vehicle shell 120.

FIGURE 11 is a top view of an embodiment according to the invention showing conductive electrodes 140 and 240 inserted within vehicle layer 120.

Detailed description of the invention

It is believed that those skilled in the art, based on the description herein, can utilize the present invention to its fullest extent. The following specific embodiments are to be considered merely illustrative and not limiting of the remainder of the description in any way.

Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Furthermore, all publications, patent applications, patents and other references mentioned herein are incorporated by reference. Unless otherwise indicated, a "percent" refers to a percent by weight (ie,% (w / w)).

A "product" means a product that contains the device in its final packaged form. In one embodiment, the product contains instructions directed to the user to apply the device to the barrier membrane (eg, to treat a skin disorder). Said instructions may be printed on the device, be an insert, or be printed on any additional packaging.

In one aspect, the present invention includes promoting a device of the present invention for its intended use. "Promote" means promotion, advertising or marketing. Promotional examples include, but are not limited to, written, visual, or oral statements made about the product or in stores, magazines, print, radio, television, the internet, and the like.

As used herein, "pharmaceutically acceptable" means that the ingredients the term describes are suitable for use in contact with the barrier membrane (eg, skin or mucosa) without toxicity, incompatibility, instability, irritation, allergic responses and the like, undue.

As used herein, a "safe and effective amount" means an amount of the ingredient or composition sufficient to provide the desired benefit at a desired level, but low enough to avoid serious side effects. The safe and effective amount of the ingredient or composition varies with the area being treated, the age and skin type of the end user, the duration and nature of the treatment, the specific ingredient or composition being used, the particular pharmaceutically acceptable vehicle being used, and the like.

As used herein, the term "treat" or "treatment" means treatment (eg, relief or elimination of symptoms and / or cure) and / or prevention or inhibition of the disorder (eg , a skin disorder). A "skin disorder" means a dermatological disease or disorder (including, but not limited to acne, acne rosacea, or skin infections) or skin characteristics (including, but not limited to pigmentation, growth regulation of hair, skin texture, skin firmness, skin elasticity, skin vasculature, dark circles, cellulite, sebum regulation, and skin shine). Examples of skin infections include, but are not limited to, those due to susceptible pathogens, such as acne, acne rosacea, impetigo, folliculitis, furunculosis, ecthyma, eczema, psoriasis, atopic dermatitis, herpes, epidermolysis bullosa, ichthyosis, and infected traumatic injuries (eg, ulcers, minor burns, cuts, abrasions, lacerations, wounds, biopsy sites, surgical incisions, and insect bites).

The present invention relates to a device for supplying electricity (for example, to induce a

ES 2 372 050 T3 desirable biological response) and / or an active agent to a barrier membrane. In one embodiment, the device of the present invention is a self-contained device that contains a battery as a power source, and two conductive electrodes in electrical communication with the positive and negative poles of the battery. In one embodiment, the device of the present invention is a self-contained device that contains at least one pair of two different conductive electrodes in electrical communication as a power source. An "electrical communication" means that electrons can pass directly between the elements of the device (for example, between the conductive electrodes of the device). In one embodiment, the two conductive electrodes are in electrical communication through direct contact with each other.

An “ionic communication” means that electrons can pass between elements (for example, the conductive electrode, the vehicle and / or the conductive electrode and the skin) through ion migration as “electron transporters” in contact with said elements (for example, electrons pass between the conductive electrode and the skin through the ionic transport of electrolytes (for example, in the vehicle) in contact with the conductive electrode and the skin).

In one embodiment, the two conductive electrodes are in ionic communication with the electrolyte-containing vehicle (e.g., ions from one or more electrolytes in the vehicle are in contact with the conductive electrode) and the vehicle is in ionic communication with the skin. This electrode configuration is different from conventional iontophoresis devices, in which each conductive electrode is in contact with a different vehicle (for example, each electrode is contained in a separate compartment and is attached to the skin with electrical insulation control them so that all electrical current travels through the skin to complete the electrical circuit). An advantage of this embodiment of the present invention includes the ability to simultaneously deliver active agents of opposite charges from the same vehicle into substantially the same site on the skin under the conductive electrodes. Another advantage is that the devices of the present invention are much easier to manufacture than conventional iontophoresis devices and therefore allow substantial savings.

The device contains a barrier membrane contacting surface (eg, a skin contacting surface) that is applied to the membrane (eg, the user applies it to their skin). The device is arranged such that the vehicle is in communication with the barrier membrane interface (for example, so that electricity and / or active agent can be delivered from the vehicle into the barrier membrane). barrier). In one embodiment, the vehicle is the interface with the barrier membrane (eg, the vehicle is a hydrogel). In one embodiment, the device contains a light-emitting diode, such that the light from the light-emitting diode is in communication with the interface with the barrier membrane (for example, so that light can be delivered to the membrane barrier).

In one embodiment, the device of the present invention delivers an active agent into the barrier membrane. Active agents to be delivered by the device of the present invention include active agents initially incorporated into the vehicle or generated electrochemically by electrical current passing from a conductive electrode through the vehicle during use. "Electrochemically generated" means that the chemical species is created as a result of an electrochemical reaction that occurs by the flow of electrical current through an electrode, such as a chemical species released from a reactive electrode (for example, an ion of electrochemically generated zinc), an electrochemically generated chemical species on the surface of an inert electrode, or a chemical species that is a post-reaction product of said electrochemically generated species.

Power source

In one embodiment, the device of the present invention includes a power source. The power source can be a conventional direct current (DC) or a pulsed DC, such as that described in US Patent No. 5,042,975. In one embodiment, the current density to be used by the device of the present invention (current intensity per unit area of ​​the barrier membrane) is generally less than about 0.5 mA / cm², such as less than about 0.1 mA / cm², or less than about 0.05 mA / cm². In one embodiment, the power source produces a voltage of about 0.1 volts to about 9 volts, such as about 1 to about 3 volts, such as about 1.5 volts.

In one embodiment, the power source is a battery (eg, a rechargeable or disposable battery). In one embodiment, the battery is a small disposable battery suitable for a wearable patch or face mask type adhesive device. Examples of suitable batteries include, but are not limited to, coin or button cells, such as lithium, silver oxide, and zinc air cells (generally used in small electronic devices). A zinc air cell is preferred for its small size and high energy density, as well as its better environmental characteristics. Examples of zinc air cells include, but are not limited to, the Energizer ™ AC5 and AC10 / 230 (Eveready Battery Co. Inc., St. Louis, MO). Another favorite stack for the

The ES 2 372 050 T3 device is a stack of flexible thin layer open liquid state electrochemical cells, such as the cell described in US Patent No. 5,897,522.

Galvanic torque

In one embodiment, the device / composition of the present invention has a galvanic couple as a power source, in which the electrons passing between the first conductive electrode and the second conductive electrode are generated as a result of the difference in standard potentials between the electrodes (for example, electricity is not generated by an external battery or other power source, such as an AC power source). Examples of such galvanic couples include, but are not limited to, zinc-copper, zinc-copper / copper halide, zinc-copper / copper oxide, magnesium-copper, magnesium-copper / copper halide, zinc-silver, zinc-silver. / silver oxide, zinc silver / silver halide, zinc-silver / silver chloride, zinc-silver / silver bromide, zinc-silver / silver iodide, zinc-silver / silver fluoride, zinc-gold, magnesium-gold, aluminum -gold, magnesium-silver, magnesium-silver / silver oxide, magnesium-silver / silver halide, magnesium-silver / silver chloride, magnesium-silver / silver bromide, magnesium-silver / silver iodide, magnesium-silver / silver fluoride, magnesium-gold, aluminum-copper, aluminum-silver, aluminum-silver / silver oxide, aluminum- silver / silver halide, aluminum-silver / silver chloride, aluminum-silver / silver bromide, aluminum-silver / silver iodide, aluminum-silver / silver fluoride, copper-silver / silver halide, copper-silver / silver chloride, copper-silver / silver bromide, copper-silver / silver iodide, copper-silver / silver fluoride, iron-copper, iron-copper / copper oxide, iron-copper / copper halide, iron-silver, iron-silver / silver oxide, iron-silver / silver halide, iron-silver / silver chloride, iron-silver / silver bromide, iron-silver / silver iodide, iron-silver / silver fluoride, iron-gold, iron-conductive carbon, zinc-conductive carbon, copper-conductive carbon, magnesium-conductive carbon, and aluminum-carbon. The materials that act to build the galvanic couple can also act as the conductive electrodes of the device, for example, zinc as the conductive anode and silver / silver chloride as the conductive cathode, or zinc as the conductive anode and copper as the conductive cathode. Metals act as the galvanic couple, and conductive electrodes can also be alloys. Non-limiting examples of alloys include zinc, copper, aluminum, magnesium alloys as anode materials, and silver, copper, and gold alloys as cathode materials.

In one embodiment, the materials that make up the galvanic pair have a standard potential difference equal to or greater than about 0.1 volts, such as greater than about 0.2 volts, such as greater than about 0.5 volts. In one embodiment, the materials that make up the galvanic couple have a standard potential difference equal to or less than about 3 volts.

In one embodiment, the device or composition of the present invention generates and / or is capable of generating a current into the barrier membrane of approximately 1 nano-A / cm² at about 400 micro-A / cm² of electricity, such as about 100 A / cm² at about 50 micro-A / cm².

In one embodiment, one of the conductive electrodes is in the form of a metal foil, a metal wire, or a metal coated on a substrate, and the other conductive electrode is bonded or deposited on the first conductive electrode. In another embodiment, the metal sheet is perforated. In one embodiment, said perforated metal sheet is in the form of a mesh, such as a mesh of zinc, magnesium, aluminum, copper or their alloys. In one embodiment, the second conductive electrode is in the form of a fabric coated with a metal, and its oxide, halide, and sulfide, such as a coated fabric with silver, silver / silver oxide, silver / silver halide, zinc, magnesium, copper, copper / copper halide, copper / copper oxide. In another embodiment, the second conductive electrode is deposited on the first conductive electrode by chemical or electrochemical deposition, such as electroless plating for chemical deposition and electrolytic plating for electrochemical deposition, as is known in the art. In another embodiment, the second conductive electrode is deposited onto the first conductive electrode by physical deposit, such as spray coating, plasma coating, conductive ink coating, screen printing, dip coating, or vacuum deposition.

In one embodiment, the device is a single compartment treatment device. A "single compartment treatment device" means a device in which both conductive electrodes of the device are in contact with the same vehicle. Examples of such devices are shown in Figures 1-4 and 6-11.

Vehicle

The vehicle of the present invention is a liquid (for example, a solution, a suspension, or an emulsion that may be immobilized within an absorbent material, such as gauze or a non-woven pad), a semisolid (for example, a gel , a cream, a lotion, a microemulsion, or a hydrogel), or a solid (for example, a lyophilized composition containing active agents, which can be reconstituted by adding a liquid before use) which during use is capable of conducting electricity from a conductive electrode (eg, the vehicle contains one or more electrolytes, organic solvents, and water). In one embodiment, the vehicle

ES 2 372 050 T3 (eg, a liquid or a semisolid) is added to the device by the user prior to applying the device to the barrier membrane.

Examples of electrolytes include, but are not limited to, pharmaceutically acceptable organic and inorganic salts and buffers. Examples of salts include, but are not limited to, chloride salts (such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, strontium chloride, magnesium chloride, or other chloride salts), as well as salts of sodium, potassium, lithium, calcium, magnesium, strontium, fluoride, iodide, bromide. Examples of buffers include, but are not limited to, phosphates, citrates, acetates, lactates, and borates.

In one embodiment, the electrolyte is an active agent, or is transformed into an active agent upon passage of electrical current through the vehicle. Examples of such electrolyte-active agents include, but are not limited to, salicylic acid, salicylates, and other weak acid or weak base active agents.

In one embodiment, the vehicle contains water. In another embodiment, the vehicle can also contain one or more organic solvents. Examples of organic solvents include, but are not limited to, dimethylisosorbide; isopropylmyristate; surfactants of a cationic, anionic and non-ionic nature; vegetable oils; mineral oils; waxes; rubbers; synthetic and natural gelling agents; alkanols; glycols; and polyols.

Examples of glycols include, but are not limited to, glycerin, propylene glycol, butylene glycol, pentalene glycol, hexylene glycol, polyethylene glycol, polypropylene glycol, diethylene glycol, triethylene glycol, glycerol, and hexantriol, and their copolymers or mixtures. Examples of alkanols include, but are not limited to, those having from about 2 carbon atoms to about 12 carbon atoms (eg, from about 2 carbon atoms to about 4 carbon atoms), such as isopropanol and ethanol. Examples of polyols include, but are not limited to, those having from about 2 carbon atoms to about 15 carbon atoms (eg, from about 2 carbon atoms to about 10 carbon atoms), such as propylene glycol.

Organic solvents can be present in the vehicle in an amount, based on the total weight of the vehicle, from about 1% to about 90% (eg, from about 5% to about 50%). Water may be present in the vehicle (before use) in an amount, based on the total weight of the vehicle, from about 5% to about 95% (eg, from about 50% to about 90%).

The vehicle may also contain preservatives (such as cresol, chlorocresol, benzyl alcohol, methyl phhydroxybenzoate, propyl p-hydroxybenzoate, phenol, thimerosal, benzalkonium chloride, benzethonium chloride, and phenylmercuric nitrate); stabilizing or antioxidant agents (such as ascorbic acid, ascorbic acid esters, butylhydroxyanisole, butylhydroxytoluene, cysteine, N-acetylcysteine, sodium bisulfite, sodium metabisulfite, sodium formaldehyde sulfoxylate, acetone, sodium bisulfite, ntocopherols); chelating agents (such as ethylenediaminetetraacetic acid and its salts); buffers (such as acetic acid, citric acid, phosphoric acid, glutamic acid, and their salts); and agents to adjust tonicity (such as sodium chloride, sodium sulfate, dextrose, and glycerin).

In one embodiment, the carrier may also contain a suspending material and / or fluid absorbent material (eg, to physically stabilize the carrier ingredients). Examples of suspender materials include, but are not limited to, cotton-based gauze; non-woven pads made from rayon or a blend of rayon, polyester, and / or other polymeric fibers; sponge-like and open-cell foam materials made of polyurethane, polyester, and / or other polymers; and cross-linked and non-cross-linked gelling materials, such as polyacrylamide, polyvinyl alcohol, gelatin, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and carboxymethyl cellulose.

Examples of fluid absorbent materials include, but are not limited to, cross-linked and non-cross-linked polymers; swellable polymers, such as water-swollen cellulose derivatives (e.g., methylcellulose (MC), hydroxyethylmethylcellulose (HEMA), hydroxypropylmethylcellulose (HPMC), ethylhydroxyethylcellulose (EHEC), hydroxyethylcellulose (HEC), hydroxypropylCmethyl), and carboxycarbonate (CM) and its salts); polyvinyl alcohol (PVA); polyvinylpyrrolidone (PVP); poly (ethylene oxide) (PEO); polymers made from monomers, such as hydroxyethyl methacrylate (HEMA), hydroxyethoxyethyl methacrylate (HEEMA), hydroxydiethoxyethyl methacrylate (HDEEMA), methoxyethyl methacrylate (MEMA), methoxyethoxyethyl methacrylate (MEEMA), dimethacrylate MDE (methyl methacrylate) ethylene glycol (EGDMA), n-vinyl-2-pyrrolidone (NVP), methacrylic acid (MA), and vinyl acetate (VAC); polyacrylamide; jelly; gums and polysaccharides, such as acacia, karaya gum, tragacanth gum, guar gum, benzoin gum, and alginic acid and its salts; polyethylene glycol (PEG); polypropylene glycol (PPG); and clays or other swellable materials, such as bentonite and montmorillonite. The amount of fluid absorbent material in the vehicle can range from about 0.1% to about 95%.

ES 2 372 050 T3 by weight, such as from about 1% to about 20% by weight of the vehicle.

Another embodiment of the present invention is directed at pairing one or more inert conductive electrodes to electrochemically generate oxidizing or reducing agents from electrochemically reactive materials in situ in the vehicle. These oxidizing or reducing agents can be used as active agents to treat barrier membrane disorders.

Examples of electrochemically reactive materials in the vehicle according to the present invention include, but are not limited to, water and compounds containing selected elements from the Periodic Table of Elements VIB and VIIB (such as oxygen, sulfur, fluorine, chlorine, bromine , and iodine).

In one embodiment, the reactive material reacts with the inert anode to form an oxidizing agent. Examples of this reactive material include, but are not limited to, OH ions^-, Cl^-, I^-, Br^-, SO3^2-, and HCO3^-. Thus, the present device allows the generation of oxidizing agents, such as nascent oxygen gases (eg, singlet oxygen), chlorine, and chlorine dioxide, which are difficult to formulate into a conventional topical product.

In one embodiment, the reactive material reacts with the inert cathode to form a reducing agent. Examples of such a reactive material include, but are not limited to, oxidized or disulfide forms of thio compounds with one or more sulfhydryl functional groups, amino acids containing a thio group and their salts or esters, and sulfides. Examples of such thio compounds include, but are not limited to, thioglycolic acid and its salts, such as thioglycolates of calcium, sodium, strontium, potassium, ammonium, lithium, magnesium, and other metal salts; thioethylene glycol; thioglycerol; thioethanol; thioacetic acid; and thiosalicylic acid; and its salts. Examples of amino acids containing a thio group include, but are not limited to L-cysteine, D-cysteine, DL-cysteine, N-acetyl-L-cysteine, DL-homocysteine, L-cysteine ​​methyl ester, L-cysteine ​​ethyl ester, N-carbamoylcysteine, glutathione, and cysteamine. Examples of sulfides include, but are not limited to, calcium, sodium, potassium, lithium, and strontium sulfides, and glutathione disulfide. The inert cathode converts the aforementioned reactive disulfide or oxidized form of a sulfur-containing compound to a compound containing a thio group, or a sulfhydryl-containing compound. Examples of such conversion are the conversion of cystine to cysteine, and the conversion of the oxidized form of glutathione to glutathione.

In one embodiment, the concentration of the reactive material in the vehicle can range from about 0.01% to about 25% by weight, such as from about 0.1% to about 10% by weight, of the vehicle. The pH value of the vehicle can range from about pH 1.5 to about pH 9, preferably from pH 2 to pH 7, and most preferably from about pH 3 to pH 5.

In one embodiment, the vehicle contains an adhesive. The adhesive is used to fix the device to the barrier membrane. Examples of hydrophobic adhesives include, but are not limited to, silicones, polysiobutylenes and their derivatives, acrylics, natural gums, and combinations thereof. Examples of silicone adhesives include, but are not limited to, Dow Corning 355, available from Dow Corning of Midland, MI; Dow Corning X7-2920; Dow Corning X7-2960; and GE 6574, available from General Electric Company of Waterford, NY. Examples of acrylic adhesives include, but are not limited to, multipolymers of vinyl (D-acetate acrylate), such as Gelva 7371, available from Monsanto Company of St. Louis, MO; Gelva 7881; Gelva 2943; and 1780 medical grade adhesive, available from Avery Dennison of Painesville, OH. Examples of hydrophilic adhesives include, but are not limited to, papaya gum and other natural gums, MC, HEMA, HPMC, EHEC, HEC, HPC, CMC, PVA, PVP, PEO, HEMA, HEEMA, HDEEMA, MEMA, MEEMA, MDEEMA, EGDMA, NVP, MA, VAC, polyacrylamide, getatins, acacia, gum karaya, gum tragacanth, guar gum, benzoin gum, and alginic acid and its salts, polyethylene glycol (PEG), and polypropylene glycol (PPG) .

In one embodiment, the concentration of the adhesive in the vehicle can range from about 0.1% to about 95% by weight, such as from about 1% to about 20% by weight, of the vehicle.

Electrodes

The conductive electrodes of the present invention can be reactive conductive electrodes or inert conductive electrodes. A "reactive conductive electrode" means that the conductive electrode itself undergoes a change in its chemical composition during electrode chemical reactions that occur when electrical current passes through the electrode during the procedure. In one embodiment, the reactive conductive electrode is an anode made from reactive materials, such as a pure metal or metal alloy including, but not limited to, zinc, aluminum, copper, magnesium, manganese, silver, titanium, tin, iron and its alloys. The materials that act to make up the galvanic couple described above can also act as the reactive conductive electrode. After the passage of an electric current, metal ions, such as zinc, copper, magnesium, manganese and / or aluminum cations, are released from the anode towards the vehicle and are transported into the barrier membrane. These ions may have therapeutic benefits, such

ES 2 372 050 T3 as antimicrobial effects, carry out immunological modulation, enzymatic regulation and / or have anti-inflammatory effects.

In one embodiment, the reactive conductive electrode is made of reactive materials, such as metal halides (eg, silver-silver chloride (Ag / AgCl), silver-silver bromide, and silver-silver iodide). In this case, the main electrochemical reaction at the cathode surface is the conversion of solid silver halide to metallic silver with little unwanted consumption of the oxidizing agents generated by the anode. The halide ions released can be further oxidized to produce oxidizing agents, such as chloride ions to chlorine (Cl2), hypochlorous acid (HClO), and hypochlorite ions (ClO^-), and iodide to iodine ions.

An "inert conductive electrode" means that the conductive electrode itself does not undergo a change in its chemical composition. In one embodiment, the anode is made with an inert conductive electrode, such that the electrochemical process at the surface of the anode generates oxidizing agents, such as nascent oxygen (for example, by electrolysis of water) and / or oxidizing agents that contain chlorine, such as chlorine, hypochlorite, chlorate and perchlorate, and chlorine dioxide. Nascent oxygen is an oxidizing agent that inhibits P. acnes, and chlorine-containing oxidizing agents are potent antimicrobial agents with bactericidal activity.

In one embodiment, the conductive electrode is made of or coated on its surface with inert materials, such as noble metals (eg, gold, platinum, or gold-coated conductive metals), conductive carbon (eg, glassy carbon or graphite) , carbon-surrounded polymers (for example, carbon silicone rubbers), a sponge or foam of conductive carbon polymers, silver halide coated silver (for example, silver coated with silver chloride, silver bromide coated silver, and silver iodide coated silver), and corrosion resistant alloys.

In one embodiment, the anode of the device, which acts as a conductive electrode, is made of the aforementioned reactive conductive oxidizable metals, such as zinc, calcium, magnesium, aluminum, iron, tin, copper or their alloys, while the cathode, which also acts as a conductive electrode, is made with the reactive reducible conductive materials mentioned above, such as more chemically stable metals and their halides, oxides, sulfides or other salts of metals, such as silver and silver halides (eg, silver chloride, silver bromide, silver iodide, silver fluoride), silver oxide, silver sulfide. In one embodiment, the reducible conductive material is in direct contact with a good electrical conductor, such as a thin layer of silver chloride, silver oxide, or silver sulfide on metallic silver; silver chloride powder with a binder (for example, a silver chloride ink); and / or silver chloride powder mixed with silver or a conductive carbon powder bound by a binder in the form of a matrix (eg, silver-silver chloride ink, and silver-carbon chloride ink).

In another embodiment, the anode of the device in the present invention is made from the aforementioned reactive conductive oxidizable metals, while the cathode is made from the aforementioned more chemically stable electrode materials, such as conductive carbon, metallic silver, gold or platinum, or a mixture of powders of conductive carbon and the noble metal in the form of a matrix, as described in US Patent No. 5,162,043.

In one embodiment, the device of the present invention enables the targeted transport of beneficial zinc through hair follicles to the pilosebaceous unit (i.e., a sebaceous gland and associated hair follicle) to treat acne or acne rosacea. Zinc is a fundamental metal for the human body because it participates in various biological activities in the body (for example, the body of a 70 kg person contains approximately 2.3 grams of zinc). It is known that a lack of zinc in the body can lead to skin diseases, such as acne.

In another embodiment, the device of the present invention allows for the targeted transport of other beneficial metals into hair follicles and pilosebaceous glands using an anode made from a zinc alloy containing small amounts of other beneficial metals. These beneficial metals include, without limitation, certain metals fundamental to the human body, such as iron, copper, magnesium, manganese, calcium, potassium, aluminum, and selenium. As the zinc alloy anode oxidizes, it releases zinc ions and other beneficial metals in the zinc alloy into the vehicle, these ingredients subsequently migrating into the hair follicles under the electrical potential applied to the skin. In one embodiment, the zinc alloy content at the anode is greater than about 50% by weight, such as greater than 90% by weight.

In one embodiment, the measured conductance ratio between the first conductive electrode and the second conductive electrode of (i) the vehicle, and (ii) the skin hydrated with said vehicle (in which substantially all of the current passes between the electrodes through skin) is in the range of about 10,000: 1 to about 1: 100. In other words, the distribution of electric current between Vehicle and Ip¡el is such that the value of Vehicle / Ipiel is between about 10,000 and about 0.01. Ivehicle is the portion of the current

ES 2 372 050 T3 total that passes through the device (Itotai) that only passes through the vehicle layer between the anode and cathode without traveling through the skin, while Ipiel is the portion of Itotal that passes through through the skin, specifically, Itotal - ^Ivehicle ^{+ I}skin.

Decreasing the ratio of vehicle conductance to skin conductance will result in a greater percentage of current passing through the skin, thereby enhancing iontophoretic transport of any active agent being administered to the skin. Decreasing the conductivity of the vehicle can be achieved, non-exclusively, by adding less conductive materials to the vehicle. Examples of such less conductive materials include, but are not limited to, oils, such as silicone or hydrocarbon oils, air pockets, such as air bubbles or air pockets in a semi-solid vehicle, or polymeric or clay spheres. In an embodiment where the primary intention is to generate species electrochemically in the vehicle, the Vehicle / Skin value is between about 10,000 and about 1. In another embodiment, where the primary intention is to conduct electricity and / or active agents into the skin, the Vehicle / Skin value is between about 10 and about 0.01. Adjusting the Vehicle / Skin value for a particular application can also be achieved by changing the distance between the first and second electrodes, or the distance between the two conductive electrodes and the skin. For example, as the distance between the two conductive electrodes decreases, the measured conductance between the two electrodes increases and so does Vehicle, which leads to a higher Vehicle / Skin value. On the other hand, if the distance between the two conductive electrodes and the skin increases, Ipiel increases, which leads to a lower Ivehicle / Ipiel value.

Electrochemically Generated Zinc Ions

In one embodiment, the zinc ions are electrochemically generated by a zinc anode in a topical composition or are subsequently added thereto. The topical composition is then applied to the user's barrier membrane to achieve the anticipated beneficial effects from the zinc ions and other active agents present in the topical composition. Active agents in the topical composition may contain anti-acne agents, such as salicylic acid or benzoyl peroxide. One method of producing such electrochemically generated zinc ions is to incorporate an electrochemical device for the generation of zinc into a container and / or dispensing container of the topical composition (for example, a bottle equipped with a dispensing pump for a skin cream to treat / prevent acne). In one embodiment, an electrochemical device that includes a zinc anode, a silver / silver chloride cathode, and a power source (eg, a battery) in electrical communication with each other, is included within the dispensing pump. As the topical composition (such as a cream) passes through the dispensing pump, it comes into contact with the zinc anode and the cathode, and completes the electrical circuit (i.e., an electrical current passes from the anode towards the cream and returns to the energy source through the cathode), and the zinc anode begins to release zinc ions towards the cream. Alternatively, the electrochemical device for generating zinc does not contain a battery. Instead, the zinc anode and cathode are connected to form a galvanic couple to generate zinc ions when both electrodes come into contact with the cream.

Active agents

In one embodiment, the vehicle contains one or more active agents. An "active agent" means a compound (eg, a synthetic compound or a compound isolated from a natural source) that has a cosmetic or therapeutic effect on the barrier membrane and surrounding tissues (eg, a material capable of exerting a biological effect on a human body), such as therapeutic drugs including, but not limited to, organic and macromolecular compounds. Examples of such therapeutic drugs include peptides, polypeptides, proteins, and nucleic acid materials comprising DNA; and nutrients. Examples of active polypeptide and protein agents include thyrotropin-releasing hormone (TRH), vasopressin, gonadotropin-releasing hormone (GnRH or LHRH), melanotropin-stimulating hormone (MSH), calcitonin, growth hormone-releasing factor (GRF ), insulin, erythropoietin (EPO), interferon-alpha, interferon-beta, oxytocin, captopril, bradykinin, atriopeptin, cholecystokinin, endorphins, nerve growth factor, melanocyte inhibitor-I, gastrin antagonist, somatostatin, enkephalins, melatonin, vaccines, botox (botulinum neurotoxins), cyclosporine and their derivatives (eg, biologically active fragments or analogs). Other active agents include anesthetics; analgesics (eg, fentanyl and its salts, such as fentanyl citrate); drugs to treat psychiatric disorders, epilepsies, and migraine; drugs to stop addictions and drug abuse; anti-inflammatory agents; drugs to treat hypertension, cardiovascular disease, heartburn, and ulcers; contraceptive and hormone replacement therapy drugs, such as estrogens and androgens; antibiotics, antifungals, antivirals, and other antimicrobial agents; antineoplastic agents, immunosuppressive and immunostimulating agents; and drugs that act on the blood and blood-forming organs, including hematopoietic and anticoagulant agents, thrombolytics, and antiplatelet drugs. Other active agents that can be administered to the body using the shear device of the present invention include vaccines for various diseases, such as vaccines for influenza, AIDS,

ES 2 372 050 T3 hepatitis, measles, mumps, rubella, rabies, chickenpox, tetanus, hypogammaglobulinemia, Rh disease, diphtheria, botulism, snake bites, black widow bites and other insect bites / stings, idiopathic thrombocytopenic purpura ( ITP), chronic lymphocytic leukemia, cytomegalovirus (CMV) infection, acute renal rejection, oral polio, tuberculosis, pertussis, Haemophilus b, Pneumococcus, and Staphylococcus aureus.

In one embodiment, the vehicle contains an anti-acne and / or anti-acne rosacea agent. Examples of anti-acne and anti-acne rosacea agents include, but are not limited to, retinoids, such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol; salicylic acid; benzoyl peroxide; resorcinol; sulfur; sulfacetamide; urea; antibiotics, such as tetracycline, clindamycin, metronidazole, and erythromycin; anti-inflammatory agents, such as corticosteroids (eg, hydrocortisone), ibuprofen, naproxane, and hetprofen; and imidazoles, such as ketoconazole and elubiol; and its salts and prodrugs. Other examples of anti-acne active agents include essential oils, alpha-bisabol, dipotassium glycyrrhizinate, camphor, β-glucan, allatoin, feverfew, flavonoids, such as soy isoflavones, Serenoa repens, chelating agents, such as EDTA, lipase inhibitors , such as silver and copper ions, hydrolyzed vegetable proteins, inorganic ions of chloride, iodide, fluoride and their non-ionic derivatives chlorine, iodine, fluorine and other valences, Synthetic phospholipids and natural phospholipids, such as Arlasilk ™ CDM, SV, EFA, PLN, and GLA phospholipids (Uniqema, ICI Group of Companies, Wilton, UK).

In one embodiment, the device of the present invention contains an anti-aging agent. Examples of suitable anti-aging agents include, but are not limited to, inorganic sunscreens, such as titanium dioxide and zinc oxide; organic sunscreens, such as octyl methoxycinnamates; retinoids; dimethylaminoethanol (DMAE), copper-containing peptides, vitamins, such as vitamin E, vitamin A, vitamin C, and vitamin B, and vitamin salts or derivatives, such as ascorbic acid diglycoside and vitamin E acetate or palmitate; alpha-hydroxy acids and their precursors, such as glycolic acid, citric acid, lactic acid, malic acid, mandelic acid, ascorbic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, alpha-hydroxyisocaproic acid, a lactic acid, alpha-hydroxyisovaleric acid, pyruvate ethyl, galacturonic acid, glucoheptonic acid, glucoheptone-1,4-lactone, gluconic acid, gluconolactone, glucuronic acid, glucuronolactone, isopropyl pyruvate, methyl pyruvate, mucic acid, pyruvic acid, sugar acid, 1,4-sugar acid lactone, tartaric acid, and tartronic acid; beta-hydroxy acids, such as beta-hydroxybutyric acid, beta-phenylactic acid, and beta-phenylpyruvic acid; zinc and zinc-containing compounds, such as zinc oxide; and botanical extracts, such as green tea, soy, milk thistle, algae, aloe, angelica, bitter orange, coffee, Coptis chinensis, grapefruit, hoellen, honeysuckle, Job's tears, Lithospermum, blackberry, peony, Pueraria, rice, and safflower ; and its salts and prodrugs.

In one embodiment, the vehicle contains a depigmentation agent. Examples of depigmentation agents include, but are not limited to, soybean extract; soy isoflavones; retinoids, such as retinol; kojic acid; kojic dipalmitate; hydroquinone; arbutin; transexamic acid; vitamins, such as niacin and vitamin C; azelaic acid; linolenic acid and linoleic acid; placertia; licorice; and extracts, such as chamomile and green tea; and its salts and prodrugs.

In one embodiment, the vehicle contains a plant extract. Examples of plant extracts include but are not limited to feverfew, soybeans, soy glycine, oatmeal, wheat, aloe vera, bilberry, witch hazel, Alnus, Arnica, Artemisia capillaris, Asiasarum root, birch, calendula, chamomile, Gnidium, Comfrey, Fennel, Galla rhois, Hawthorn, Houttuynia, Hypericum, Jojoba, Kiwi, Licorice, Magnolia, Olive, Peppermint, Philodendrum, Sage, Sasa Albomarginata, Natural Isoflavones, Soy Isoflavones, and Natural Essential Oils.

In one embodiment, the carrier contains metals, such as metal ions, metal salts, metal complexes, fine metal powders, fibers and fabrics of synthetic or natural origin coated with fine metals, or fine metal fibers. Examples of such metals include, but are not limited to, zinc, copper, aluminum, gold, silver, and titanium. Metal ions provide benefits, such as antimicrobial, anti-inflammatory, and / or sebum-reducing effects. Beneficial metal ions can be released from the metal anode as a result of an electrochemical oxidation reaction that occurs concurrently with the passage of electrical current (eg, zinc ions generated electrochemically from a zinc anode).

In another embodiment, the beneficial ions can be generated indirectly from electrochemical reactions at the electrode surface, such as the generation of hydrogen or hydroxyl ions on an inert electrode, which subsequently leads to a beneficial ion generation process. . For example, a device of the present invention may contain a power source, an inert anode (eg, platinum, a platinum-coated conductive electrode, gold, or a gold-coated conductive electrode), a reactive cathode (eg, a silver / silver chloride electrode), and an aqueous carrier composition containing an oxide (eg, zinc oxide particles), among other active agents. During application to the skin, the electrolysis of the water at the inert anode produces an excess of hydrogen ions that acidify the vehicle towards a pH value.

ES 2 372 050 T3 lower, while the electrochemical reaction at the reactive cathode (for example, the conversion of silver chloride to silver ions) does not affect the pH. As the solution becomes more acidic, the oxide begins to dissolve and release ions (eg, zinc ions) for its beneficial effects on the barrier membrane.

Other active agents include those commonly used for the topical treatment and for the cosmetic treatment of skin tissues, such as topical antibiotics for wounds, topical antifungal drugs to treat fungal infections of the skin and nails, and antipsoriatic drugs. to treat psoriatic lesions of psoriatic skin and nails.

Examples of antifungal drugs include, but are not limited to, miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voriconazole, clioquinol, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, halocylenic acid, undecylenic acid , tolnaphtate, nostatin, cyclopyroxolamine, terbinafine, amorolfine, naphthifine, elubiol, griseofulvin, and their prodrugs and pharmaceutically acceptable salts. In one embodiment, the antifungal drugs are an azole, an allylamine, or mixtures thereof.

Examples of antibiotics (or antiseptics) include, but are not limited to, mupirocin, neomycin sulfate, bacitracin, polymyxin B, 1-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride10, and tetracycline hydrochloride, clindamycin phosphate), Gentamicin sulfate, metronidazole, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, tea tree oil, and their prodrugs and pharmaceutically acceptable salts.

Examples of antimicrobials include, but are not limited to, chlorhexidine salts, such as iodopropynyl butylcarbamate, diazolidinylurea, chlorhexidene digluconate, chlorhexidene acetate, chlorhexidene isethionate, and chlorhexidene hydrochloride. Other cationic antimicrobials can also be used, such as benzalkonium chloride, benzethonium chloride, triclocarbon, polyhexamethylene biguanide, cetylpyridinium chloride, methyl and benzotonium chloride. Other antimicrobials include, but are not limited to, halogenated phenolic compounds, such as 2,4,4'-trichloro-2-hydroxydiphenyl ether (Triclosan); parachloromethaxylenol (PCMX); and short chain alcohols, such as ethanol, propanol, and the like. In one embodiment, the alcohol is preferably at a low concentration (eg, less than about 10% by weight of the vehicle, such as less than 5% by weight of the vehicle), so that it does not unduly dry out the barrier membrane.

Examples of antipsoriatic drugs or drugs for the treatment of seborrheic dermatitis include, but are not limited to, corticosteroids (eg, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, triamcinonide, dexamethasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone verlerate, hydrocortisone butyrate, Aclomethasone dipropionate, flurandrenolide, mometasone furoate, methylprednisolone acetate), methotrexate, cyclosporine, calcipotriene, anthralin, shale oil and its derivatives, elubiol, ketoconazole, mineral tar, salicylic acid, pyrithione zinc, selenium hydrocortiside sulfur, menthol, and pramoxine hydrochloride, and their salts and prodrugs.

Examples of antiviral agents for viral infections, such as herpes and hepatitis, include, but are not limited to, imiquimod and its derivatives, podofilox, podophyllin, interferon-alpha, acyclovir, famciclovir, valciclovir, cross-links, and cidofovir, and their salts and prodrugs. .

Examples of anti-inflammatory agents include, but are not limited to, suitable steroidal anti-inflammatory agents, such as corticosteroids, such as hydrocortisone, hydroxytriamcinolone, alpha-methyldexamethasone, dexamethasone phosphate, beclomethasone dipropionate, chlobetasolimedexychloride valerate, desoxychloride, desoxytonide acetate. , dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclarolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortin butyl ester, fluocortolone, fluprednidene acetate (fluprednylidene), flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisol butyl ester, fluocortolone, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisol butyl ester, fluocortolone diarylonisolone, fluodoxonosolidene corticosteroid, triamudnisolone acetate, fluodoxonosolidene , fluradrenalone acetonide, medrisone, amciafel, amcinafide, betamethasone, chlorprednisone, chlorprednisone acetate, chlocortelone, clescinolone, dichlorisone, difluprednate, fluchloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylproprionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, diphsonolomethazone, diphsonolone, and diphsonomethazone, propionate salts, and diphsonolomethazone, propionate salts and beta-benzenemerioxide. The preferred steroidal anti-inflammatory for use in the present invention is hydrocortisone. A second class of anti-inflammatory agents that are useful in the compositions of the present invention include non-steroidal anti-inflammatory agents.

Other active agents include, but are not limited to, wound healing enhancing agents, such as recombinant human platelet-derived growth factor (PDGF) and other growth factors,

ES 2 372 050 T3 ketanserin, iloprost, prostaglandin E1 and hyaluronic acid, scar reducing agents such as mannose-

6-phosphate, analgesic agents, anesthetics, hair growth enhancing agents, such as minoxadil, agents that delay hair growth, such as eflornithine hydrochloride, antihypertensives, drugs to treat coronary artery diseases, anticancer agents, endocrine medication and metabolic, neurological medications, medication for the suspension of chemical addictions, motion sickness, protein and peptide drugs.

In one embodiment, the vehicle contains a fragrance effective to reduce stress, to calm and / or to affect sleep, such as lavender and chamomile.

The amount of active agent in the vehicle will depend on the active agent and / or the intended use of the device. In one embodiment, the vehicle contains a safe and effective amount of the active agent, for example, from about 0.001% to about 20% by weight, such as from about 0.01% to about 5% by weight, of the vehicle.

Light emitting diode

In one embodiment, the device contains one or more light emitting diodes. Light-emitting diodes (LEDs) of a certain spectrum can be incorporated into the device to emit light towards the barrier membrane (for example, to treat skin disorders such as acne and acne rosacea). The light emitting diode can also provide a signal to the user that the device is working properly.

In one embodiment, the LED periodically emits light (ie, a flashing LED). In another embodiment, said LED also modulates the current that passes through the barrier membrane to form a pulsating DC current. Said pulsatile DC current can enhance the transport of the active agents into the barrier membrane, stimulate biological responses in the barrier membrane, such as enhancing wound healing (for example, in acne lesions) and / or enhancing the sensation on the skin that acts as a signal lets the user know that the device is working. Another potential advantage of using a flashing LED is producing a pulsating DC current without requiring a complex electrical circuit.

The spectrum of LEDs according to the present invention can range from about 300 nm to about 1500 nm, such as from about 350 nm to about 1000 nm. In one embodiment, the range of the LED includes the ranges of violet-blue, green, red, and infrared, for example, from about 400 nm to about 450 nm, such as from about 407 nm to about 420 nm; from about 510 nm to about 550 nm; from about 600 nm to about 700 nm; and from about 1300 nm to about 1500 nm. In one embodiment, the device contains two LEDs, one that emits light that has a wavelength of from about 400 nm to about 500 nm, and another that emits light from about 700 nm to about 1000 nm. Photosensitizing agents, such as 5-aminolevulinic acid (ALA), hypericin, St. John's wort extract or powder, or other synthetic or natural photosensitizing agents, can be incorporated into the vehicle as active agents to be administered and irradiated by the device with the LEDs. of the present invention. The irradiation of light from the LEDs, together with the photosensitizing agent (s) and other active agents mentioned above, electrochemically generated oxidizing agents (e.g., peroxides, nascent oxygen, chlorine dioxide, and chlorine) and / or electrical stimulation of The barrier membrane can act synergistically to achieve better efficacy in treating membrane disorders such as acne and acne rosacea.

General use

In one embodiment, the device is used for the treatment of a barrier membrane disorder (e.g., the transport of an active agent, light, and / or electricity into the membrane, such as the barrier membrane of the skin, eye (cornea, retina, etc.), oral, buccal, nasal, vaginal, gastrointestinal, or rectal mucosa of a human being). In one embodiment, the device is used for the treatment of skin disorders. Examples of such treatments include, but are not limited to, the treatment of acne, acne rosacea, or other microbial skin infections; reducing the visible signs of skin aging (eg, wrinkles, sagging, and age spots); folliculitis and pseudofolliculitis of the beard; treating wounds and injuries (for example, enhancing healing and reducing scarring); sebum regulation (eg, sebum reduction and / or inhibition or control of the oily / shiny appearance of the skin); regulation of pigmentation (for example, reduction of hyperpigmentation or the pigmentation of fair skin); retardation of hair growth (for example, on the skin of the leg) or stimulation of hair growth (for example, on the scalp); and the treatment of dermatitis (eg, atopic, contact, or seborrheic dermatitis) and / or psoriasis.

In another embodiment, the device is used for the treatment of mucosal disorders (e.g., the mucosa of

ES 2 372 050 T3 the oral or vaginal cavities). Examples of such treatments include, but are not limited to the treatment of vaginal yeast infection and vaginosis, oral and genital herpes, cold sores, herpetic angina, oral hygiene, periodontal disease, and other microbial infections of the mucosa.

Another embodiment of the present invention is the device that induces certain desirable biological responses that facilitate the treatment of barrier membrane disorders. These desirable biological responses can be induced by the passage of electrical current through the barrier membrane and / or electrochemically generated oxidizing materials, together with the active agents iontophoresis released from the vehicle, to treat barrier disorders. Examples of desirable barrier membrane responses may include, but are not limited to, regulation of sebum (e.g., reduction of sebaceous gland activity), inhibition of anaerobic microbial growth, and establishment of a microflora of the healthier membrane (for example, reduced growth of P. acnes and the production of irritating fatty acids), blood vasoconstriction (therefore, the stimulation of the local accumulation of active agents or the elimination of dark circles under the eyes due to deoxyhemoglobins), the enhancement of the immunological activity of the tissues (for example, greater elimination of pathogenic microbes in the defense systems of the tissue itself), better tissue repair (for example, enhanced healing and less scarring of lesions, such as acne lesions), and improved keratolytic activity of the vehicle (for example, softening of keratin plugs from pimples in whiteheads and blackheads acne, and thus its elimination is facilitated).

In another aspect, the invention also includes the method of converting an active agent from a less active form to a more active form through oxidation or reduction by an inert electrode (eg, cystine to cysteine, acetyl disulfide -cysteine ​​to acetyl-cysteine, and from retinol to retinoic acid). Thus, an unstable agent can be kept in a more stable form and converted to its active form prior to administration. In another aspect, the generation of reducing agents by the device of the present invention can be used to stabilize oxygen-labile active agents. Examples of such oxygen-labile active agents include, but are not limited to, retinoids, ascorbic acid, and benzoyl peroxide.

In one embodiment, the invention also includes the method of converting an active agent from a less active form to a more active form by oxidation at a reactive anode, such as an anode made of zinc, magnesium, copper, aluminum, an alloy or a mixture of these metals. For example, an anode made of zinc releases zinc ions as an electrical current passes through the electrode. The zinc ions generated by such electrochemical reactions are then transported further by electrical repulsion of the positively charged anode into the barrier membrane. In one embodiment, said ions are deposited in hair follicles and / or sebaceous glands to inhibit the growth of P. acnes and / or suppress inflammation of the skin tissue as a result of P. acnes overgrowth prior to treatment. Similarly, a zinc-copper alloy or other beneficial zinc metal alloy anode releases zinc ions and copper ions or the other beneficial ions, respectively, into the hair follicles and sebaceous glands for the treatment and prevention of acne.

Skin disorders

In one embodiment, the device of the present invention is used to treat skin disorders, such as acne (eg, blackheads and whiteheads) and acne-related skin disorders, such as acne rosacea and cystic nodules; hyperpigmentation, such as freckles, melasma, actinic and senile lentigos, age spots, post-inflammatory hypermelanosis, Becker's nevus, dark circles under the eyes, and facial melanosis; stretch marks; and effects of aging on the skin (such as those caused by photodeterioration), including wrinkles, roughness, pigment alterations, yellowing, fine lines, and laxity, through the administration of active agents that include active agents preformulated in the vehicle and agents electrochemically generated actives (eg, beneficial metal ions) by the electrodes and / or providing electrical stimulation to skin tissues.

In one embodiment, the device of the present invention provides multiple mechanisms of action to treat said disorders, namely (a) the targeted transport of preformulated active agents to the pilosebaceous unit by iontophoresis and electro-osmosis; (b) the electrochemical generation of new active agents (eg, beneficial metal ions from a reactive anode) and the targeted transport of newly generated active agents to the pilosebaceous unit (eg, beneficial ions, such as zinc and copper, enhance the skin's own immune system); and / or (c) the delivery of electrical stimulation to the pilosebaceous unit and surrounding skin tissues to increase blood circulation, and to treat the skin by reducing inflammation, enhancing wound healing, and / or increasing exfoliation of the skin.

ES 2 372 050 T3

Wounds and scars

In one embodiment, the device of the present invention can be incorporated into wound dressings and bandages to provide electrical therapy for enhancing healing and preventing scarring. In one embodiment, the wound exudate fluid and / or a wound cleansing solution acts to activate a galvanic wound dressing / dressing to release the active agents preincorporated in the wound dressing / dressing and / or to generate electrochemically beneficial metal ions, followed by transport of the beneficial metal ions to the wound. The device also treats the wound with a therapeutic electrical current that can increase blood circulation, stimulate the immune response of tissues, and / or suppress tissue inflammation, which can lead to accelerated healing and less scar formation.

Enhancement of chemical peel

Chemical peel treatments are an exercise procedure that involves the application of a chemical agent to the skin to induce the controlled destruction or exfoliation of old skin and the stimulation of new epidermal growth with a more even distribution of melanin. When exfoliating agents reach the dermal layer, important wound healing activities occur causing skin reshaping and skin smoothing, both of which are anti-aging benefits. The release of chemical exfoliating agents contained within the vehicle of the electrically generating composition / device can be used for the treatment of a variety of skin disorders including, but not limited to, acne, post-inflammatory hyperpigmentation, melasma, scarring, photo deterioration, age spots, wrinkles, stretch marks, birthmarks, uneven texture and tone, warts, and pseudofolliculitis of the beard. The composition / device may also have the additional advantage of reducing skin irritation and decreasing the risk of early cancerous and precancerous lesions of the photoaged skin of the face, because iontophoretically administered chemical peel can allow the use of a much higher concentration. Fewer chemical peel agents compared to conventional chemical peel strategy without the use of such a device. Reducing the required chemical peel agents can also minimize the risk of prolonged post-exfoliation erythema, inflammation, and scarring as a result of the chemical peel, while achieving desirable benefits.

Examples of chemical peeling agents include, but are not limited to, hydroxy acids, such as hydroxy acids, such as lactic acid, malic acid, glycolic acid, arginine glycolate, ammonium glycolate, and sodium glycolate; β-hydroxy acids, such as salicylic acid; polyhydric acids (PHA), such as gluconolactone; and non-hydroxylic acids, such as acetic acid, trichloroacetic acid (TCA), pyruvic acid, an alpha-keto acid, phenol, derivatives thereof, or combinations thereof. They can also be combined with sulfur, resorcinol, retinoids, or other active agents, such as Jessner's solution scrub (containing lactic acid, salicylic acid, resorcinol, and ethyl alcohol). The chemical exfoliating agents of the present invention may also include, but are not limited to, protease agents or their derivatives, such as acid protease in the form of apoenzyme, holoenzyme, idoenzyme or zymogen. Examples include pepsin, bromelain, papaya, and cathepsin. Other examples include chemical exfoliating agents from natural extracts, such as fruit extracts, mushroom extracts, and other plant extracts.

In one embodiment, the duration of application of the device to the skin is from about 2 to about 10 minutes, depending on the skin conditions of the individual. In one embodiment, the vehicle contains from about 0.1% to about 70% by weight of said chemical peeling agent, such as from about 0.5% to about 20%, such as from about 2% to about 10%.

Shape

The device includes a cover that can be manufactured in various shapes and sizes to conform to the contours of various anatomical surfaces of the barrier membranes. For example, the cover can be a substrate made in the shape of a full face mask with openings / holes to expose the eyes, eyebrows, nose, and mouth; a partial face mask that covers only the upper or lower half of the face; or a patch that covers only the forehead, or the region under the eyes, the region of the chin and jaw, the neck, the back, wounds, acne lesions or pimples, or other specific areas of the barrier membrane that need treatment.

In one embodiment of the present invention, the jacket is a water insoluble substrate containing a galvanic couple, for example, a fine zinc wire or a fine zinc-coated fiber (for example, a zinc-coated polymeric fiber) connected to a fine copper cable or a fine copper clad fiber (for example, a copper clad polymer fiber). One or more of such fine cables or fibers of the galvanic pair can be incorporated into the substrate to create a device that, when contacted with the vehicle (such as tap water or a

ES 2 372 050 T3 liquid or semi-liquid composition including active agents) generates an electric current. In one embodiment, a substrate containing a galvanic couple may be made of multiple layers, for example a layer of the substrate containing zinc (for example, a fine zinc wire or a fine zinc coated fiber in a flat or non-flat fabric. ) on a layer of copper-containing substrate (for example, a fine copper wire or a fine copper clad fiber in a flat or non-flat fabric). During use, the layers are brought into contact with each other to form a galvanic couple. In another embodiment, the device releases beneficial ions (for example, zinc ions or aluminum ions) that are transported towards the barrier membrane (for example, the skin) when said substrate is applied by the user (for example, used as a wipe to clean the skin or a patch or face mask to treat the skin). Active agents can also be incorporated into the substrate during manufacturing processes or can be subsequently applied to the substrate prior to application to the barrier membrane (eg, in the form of a liquid spray containing electrolytes or active agents to wet the substrate). In one embodiment, the fabric is used as a dry wipe or a dry full or partial face mask, to be moistened immediately prior to use by applying water to the dry wipe or face mask to pre-moisten the skin (e.g., washing with tap water).

"Insoluble in water" means that the substrate, after immersion in distilled water at 25 ° C, does not dissolve easily or disintegrate easily. However, the water insoluble substrate can disintegrate and / or dissolve slowly, that is, over a period of several hours to several days. A wide variety of materials can be used as a water insoluble substrate. Examples of suitable substrates include, but are not limited to, nonwoven substrates, woven substrates, hydro-bonded substrates, air-bonded substrates, natural sponges, synthetic sponges, and polymeric crosslinked meshes.

Water insoluble substrates can be flushed out of the toilet. As used herein, "flush" means that the substrate can pass through at least 3.05 meters of drain pipe in two flushes from the toilet. The material can also be biodegradable.

In one embodiment, the substrates contain a nonwoven material. "Nonwoven" means that the substrate, or a layer of the substrate, is made up of fibers that are not woven to form a fabric, but are in the form of a sheet, mat, or padding layer. The fibers can be randomly arranged (that is, they are randomly aligned) or they can be carded (that is, combed so that they are oriented primarily in one direction; in addition, the nonwoven substrate can be composed of a combination of layers of randomly arranged and carded fibers).

Nonwoven substrates can be formed from a variety of natural and / or synthetic materials. "Natural" means that the materials are derived from plants, animals, insects, or by-products of plants, animals, and insects. "Synthetic" means that the materials are derived primarily from various man-made materials or from natural materials that have been subsequently altered. Non-limiting examples of natural materials useful in the present invention are silk fibers, keratin fibers (such as wool fibers, camel hair fibers), and cellulosic fibers (such as wood pulp fibers, cotton fibers, of hemp, jute fibers, and flax fibers).

Examples of synthetic materials include, but are not limited to those selected from the group containing acetate fibers, acrylic fibers, cellulose ester fibers, cotton fibers, modacrylic fibers, polyamide fibers, polyester fibers, polyolefin fibers, polyvinyl alcohol fibers, rayon fibers, polyurethane foam, and their blends.

Substrates made from one or more of the synthetic and natural materials useful in the present invention can be obtained from a wide variety of commercial sources, such as Freudenberg & Co. (Durham, NC, USA), BBA Nonwovens (Nashville, TN , USA), PGI Nonwovens (North Charleston, SC, USA), Buckeye Technologies / Walkisoft (Memphis, TN, USA), and Fort James Corporation (Deerfield, IL, USA).

Procedures for making nonwoven substrates are also well known in the art. These procedures include, but are not limited to, air flow setting, water flow setting, melt blowing, spun bonding, or carding procedures. The resulting substrate, regardless of the process for its production or its composition, then undergoes at least one of several types of bonding operations to anchor the individual fibers together to form a self-sustaining network. The nonwoven substrate can be prepared by a variety of procedures including hydro-bonding, thermal bonding, and combinations of these procedures. In addition, the substrates can have a single layer or multiple layers. In addition, a multilayer substrate can include a layer or layers of films (eg, apertured or non-apertured film layers) and other non-fibrous materials.

The strength or firmness of the nonwoven can be a desirable attribute. This can be achieved, for example, by adding binder materials, such as moisture resistance resins, or the material can

ES 2 372 050 T3 be made of coatings of polymeric binders, stable fibers, for example based on cotton, wool, linen and the like. Examples of moisture resistance resins include, but are not limited to, Ethylene Vinyl Acetate (VAE) and Ethylene Vinyl Chloride (EVCL), Airflex Emulsions (Air Products, Lehigh, PA), Flexbond Acrylic Polymers ( Air Products, Lehigh, PA), Rhoplex ST-954 acrylic binder (Rohm and Haas, Philadelphia, PA), and ethylene vinyl acetate (EVA) emulsion (DUR-O-SET®, from National Starch Chemicals, Bridgewater, NJ). The amount of binder material on the substrate can range from about 5% to about 20%, by weight, of the substrate.

Higher strength nonwovens can also be obtained using the so-called hydroentangling or hydroentangling technique. In this technique, individual fibers are twisted together to obtain acceptable strength or firmness without the use of binder materials. The advantage of the latter technique is the excellent softness of the non-woven material.

In one embodiment, the nonwoven is made of a superabsorbent polymer. For the purposes of the present invention, the term "superabsorbent polymer" refers to materials that are capable of absorbing and retaining at least about 10 times their weight of body fluid fluids under a pressure of 3.45 kPa. The superabsorbent polymer particles of the invention can be inorganic or organic cross-linked hydrophilic polymers, such as polyvinyl alcohols, polyethylene oxides, cross-linked starches, guar gum, xanthan gum, and other materials known in the art. of the manufacture of absorbent articles.

Additives can also be added to increase the smoothness of the substrates. Examples of such additives include, but are not limited to, polyols, such as glycerol, propylene glycol, and polyethylene glycol, phthalate derivatives, citric esters, surfactants, such as polyoxyethylene (20) sorbitan esters, and acetylated monoglycerides.

Sensory attributes can also be incorporated into insoluble nonwoven substrates. Examples of such sensory attributes include, but are not limited to, color, texture, pattern, and print.

In one embodiment, the device of the present invention is for use as a wipe or cloth (for example, having a specific surface area of ​​approximately 20 cm² at about 10,000 cm²). In another embodiment, the device of the present invention is for use as a mask or a therapeutic patch for application to a portion or substantially the entire face (for example, having a specific surface area of ​​about 1 cm² at about 600 cm²).

In one embodiment, the carrier is present in at least about 50%, such as at least about 75% by weight of the total weight of the water insoluble substrate prior to use. In another embodiment, (i) the liquid carrier is present in an amount of less than about 10%, such as less than about 1% by weight of the total weight of the water-insoluble substrate (for example, the device may not contain any vehicle before usage). In another embodiment, the product contains instructions for users to (i) wet the substrate prior to application, or (ii) wet the barrier membrane (eg, skin) with water and / or other liquid prior to application. .

Devices

An embodiment of the present invention is schematically represented in FIGURE 1. The device 500 contains a movable release paper 100, a vehicle layer 120, a first conductive electrode 140, a second conductive electrode 240, electrical lead wires 110 and 210 that connect the two ends of an electrically insulated connector wire 350 to the two. separate conductive electrodes, an optional power switch 330 located on lead wire 210, a backing layer 160, and a cover layer 340.

The gap "b" represents the distance between the two conductive electrodes 140 and 240 and the release paper (or the membrane after application of the device), and the gap "a" represents the distance between two oppositely charged conductive electrodes. In one embodiment, gap "a" is between 0 and about 20 centimeters, and gap "b" is between 0 and about 1 centimeter. In another embodiment, the ratio of gap "a" to gap "b" is from about 0 to about 20.

In devices that contain a battery as a power source, the electrically insulated connector wire 350 can be replaced by a battery (not shown in the figures). The cell may be encased in a waterproof, polymeric electrical insulation layer (not shown in the figures). Optionally, there may be an electrical circuit (not shown) in device 500 to provide a localized constant current between the cell (not shown) and conductive electrode 140 and / or conductive electrode 240.

When a zinc air cell is used as the power source for device 500, the cell (not shown) is constructed such that the hole in the stainless steel cover faces the opposite side of the layer.

ES 2 372 050 T3 of vehicle 120. A hole is made in the cell cover layer to expose the hole on the zinc air cell which is covered by a movable oxygen impermeable cover. In this case, the power switch 330 is replaced by the movable oxygen impermeable cover. The movable oxygen impermeable cover can be used to start (by removing it) or to stop the electrotransport process of the device (by covering the hole again).

The backing layer 160 may be impermeable to the active agent contained within the carrier layer 120, and is preferably not permeable to water or other solvents in the carrier layer 120. The backing layer 160 and the cover layer 340 may be made of a flexible material that is impermeable to water and electrically insulating, for example polymers, such as polyethylene, polypropylene, poly (vinyl acetate), polyurethane, silicone rubber, or poly (vinyl chloride).

In another embodiment, the backing layer 160 is permeable to electrochemically generated gases (eg, oxygen, chlorine, and hydrogen) to limit excessive build-up of the gases in the vehicle that can cause tissue irritation and / or unwanted deformation of the tissue. device. Examples of this "breathable backing" material include, but are not limited to, a layer of plain and non-flat woven synthetic or cotton, such as the woven materials commonly used for bandages and sports bandages.

Vehicle layer 120 is an adhesive hydrogel containing the active agent. The active agent can be incorporated into carrier layer 120 in the form of dissolved molecules and ions, dispersed solid particles, or liquid droplets, such as cream, lotion, emulsion, multi-emulsion, microemulsion, and / or liposome compositions. Carrier layer 120 may also contain a solid support matrix (eg, gauze, nonwoven, or sponge-like material).

A movable release paper sheet 100 covers the carrier layer 120. The selection of movable release paper 100 depends on the type of adhesive hydrogel used in the carrier layer 120. The movable release paper sheet 100 is generally a polymeric sheet or a polymer coated paper or fabric, which has weak adhesion to the adhesive hydrogel layer 120, thereby allowing it to be easily removed from the carrier layer 120 before of use without damaging the carrier layer 120. Examples of polymers that are generally used for release paper 100 are silicones and polyethylenes. Alternatively, a wax can be used in place of the polymer to coat the release paper 100.

In addition, or instead of using an adhesive on the vehicle layer 120, the device 500 can be attached to the barrier membrane with an adhesive tape, an elastic band, a band with a buckle (similar to a leather watch strap ), or a Velcro® band.

To use the device 500, the movable release paper sheet 100 is peeled off, and the vehicle hydrogel layer 120 of the device 500 is attached to the barrier membrane, such as skin or mucous membranes, such as the barrier membrane. of the vaginal, oral, buccal, nasal, gastrointestinal or rectal mucosa of the user. The device can be attached directly to the barrier membrane if the carrier layer 120 contains an adhesive hydrogel. An electrical potential is applied across the conductive electrodes 140 and 240 by operating the power switch 330.

Another embodiment of the present invention is schematically depicted in FIGURE 2. Electrically insulated connector wire 350 is located within barrier layer 120. The advantage of this arrangement includes less bulk, aesthetics and user comfort. improved.

The light emitting portion of the LED 122 is preferably located in the vehicle layer 120 in close proximity to the skin. Placing the light source on the vehicle layer 120 attached to the barrier membrane has the advantage of minimizing the loss of light energy by reflection from the skin surface. In addition, a light reflective layer can be used as the backing layer 160 (eg, a metallized polymeric film) to further enhance the efficacy of phototherapy, and to achieve more homogeneous irradiation. The backing layer 160 may optionally be perforated at certain points so that the light is visible to the user to act as an indicator that the device is operating normally.

Another embodiment of the present invention is schematically depicted in FIGURE 3. The backing layer 160 (eg, the cover) contains an adhesive layer 130 coated on the outer edge of the backing layer 160 to secure the device 500 to membrane during application. The adhesive in the adhesive layer 130 can be polymeric, pressure sensitive, and / or non-conductive. Suitable adhesive materials include, but are not limited to, silicones, polyisobutylenes and their derivatives, acrylics, natural gums, and combinations thereof. Suitable silicone adhesives include, but are not limited to, Dow Corning 355 (available from Dow Corning of Midland, MI); Dow Corning X7-2920; Dow Corning X7-2960; GE 6574 (available from General Electric Company of Waterford, NY); and silicone pressure sensitive adhesives. Suitable acrylic adhesives include, but are not limited to 19

ES 2 372 050 T3 vinyl acetate acrylate multipolymers, such as Gelva-7371 (available from Monsanto Company of St. Louis, MO); Gelva T 7881; Gelvac 2943; 1-780 medical grade adhesive, available from Avery Dennison of Painesville, OH; and acrylic pressure sensitive adhesives.

One embodiment of the present invention is a dual packaging system, in which the device and the vehicle (or a portion of the vehicle) are packaged separately. A portion of the carrier layer 120 may be an anhydrous liquid immobilizing matrix, such as a dry flat or non-flat tissue, a sponge, or a dehydrated hydrogel layer (eg, lyophilized hydrogel), while the liquid portion of the vehicle, such as a solution, a gel or a cream containing the active agents, is packaged in a separate liquid compartment (not shown in the figures), such as a unit dose bag, a container that can break or a bottle. Before use, the liquid compartment is ruptured and the liquid or semi-solid portion of the vehicle is applied to the immobilizing liquid matrix to activate current generation for application to the skin. The active agents are incorporated into the liquid immobilizing matrix or the liquid / semisolid composition.

An embodiment of the present invention is schematically depicted in FIGURE 4. Conductive electrodes 140 and 240 are in electrical communication with each other through a direct connection, specifically, gap "a" (the distance between two conductive electrodes with opposite charge) equals zero. Two conductive electrodes form a galvanic pair that is in contact with the vehicle layer 120 encased in the backing layer 160 with an opening attached to the release paper 100 with an adhesive layer 130. An important advantage of this configuration is its simplicity and ease of use. manufacturing.

Another embodiment of the present invention is schematically depicted in FIGURE 5. Electrotransport device 800 contains two electrode assemblies 200 and 600, respective adhesive layers 230 and 630, respective vehicle layers 220 and 620, respective conductive electrodes 240 and 640, respective reinforcement layers 270 and 670, respective Lead wire 210 and 610, electrically insulated connecting wire 350, and optional electrical switch 330. Similar to the typical iontophoresis device mentioned above, the two electrode assemblies 200 and 600 have to be attached to the barrier membrane with a gap from each other, after removing the release paper 100 before use.

In one embodiment, the carrier layer 120 contains at least two active agents that have opposite electrical charges. An example of such a composition is a composition containing from about 0.5% to about 2% salicylic acid and from about 0.01% to about 0.2% of a cationic quaternary ammonium antimicrobial agent (such as benzalkonium chloride , benzethonium chloride, methylbenzetonium chloride, and cetylpyridinium chloride), phenol and / or chlorhexidine gluconate. Device 500 of the present invention can simultaneously deliver both oppositely charged active agents into the membrane.

FIGURES 6 and 7 show two examples of different configurations of the various conductive electrodes 140 (shown as a double line) and 240 (shown as a single line) in the vehicle layer 120, connected by electrically insulated cables 350 (shown as a triple line) to form a galvanic torque power source. FIGURE 6 shows conductive electrodes 140 and 240 arranged in an interdigital configuration. FIGURE 7 shows the conductive electrodes in a concentric configuration.

FIGURES 8 and 9 show two examples of other configurations of the various conductive electrodes 140 and 240 in the vehicle layer 120, connected together by a connector wire 350 as in FIGURE 8, or by direct physical contact at each intersection 370 as in FIGURE 9, to form a plurality of galvanic pair power sources, which are in contact with the carrier layer 120. Conductive electrodes 140 and 240 in FIGS. 8 and 9 are arranged in a parallel and perpendicular configuration, respectively.

The alternating parallel arrangement of the conductive electrodes 140 and 240 in FIGURE 8 provides a more uniform distribution of electrical current through the carrier layer 120 and the underlying skin tissue and, therefore, helps to allow more delivery. uniform of the active agents towards the interior of the skin. An example fabrication procedure for the galvanic device shown in FIGURE 8 is weaving a silver-coated polymeric fabric and a zinc-coated polymeric fabric (or zinc wire) to produce a liquid-absorbing fabric layer according to the electrode pattern. parallel, then connect the zinc and silver electrodes by printing the silver and zinc regions with an electrically conductive ink (for example, conductive silver or carbon ink). Covering the electrically conductive ink with another layer of electrical insulating ink will produce the electrically insulated connector wire 350.

Another method of manufacturing the device of FIGURE 8 is by printing: it is printed on a layer of non-conductive polymeric substrate (for example, the polymeric material that forms the reinforcing layer 160)

ES 2 372 050 T3 using a conductive silver or silver-silver chloride ink to produce the first conductive electrode; and the second conductive electrode is printed using a conductive zinc ink. The two different conductive electrodes are then connected by printing over them with the conductive silver or zinc ink (or a different conductive ink, such as carbon ink). A cover ink may then optionally be printed on the connector wire to produce an electrical insulating polymeric layer thereon. If the device is manufactured without insulation with an electrical insulating cover layer, the resulting device is a variation of the one shown in FIGURE 9.

FIGURE 9 is a top view of an embodiment according to the invention showing conductive electrodes 140 and 240 connected together by direct physical contact at intersections 370 to form a galvanic torque power source, which is in contact with the layer of vehicle 120. Conductive electrodes 140 and 240 are arranged in a perpendicular configuration. The manufacturing procedures mentioned above for the device in FIGURE 8 are also suitable for producing this device.

FIGURE 10 is a top view of an embodiment according to the invention showing a device made of zinc mesh having conductive electrodes 140 (shown as bold lines) and conductive electrodes 240 (shown with double lines) connected by insulated connector cables. electrically 350 (shown as single lines) embedded in vehicle layer 120. Conductive electrodes 140 are uncoated regions of the zinc mesh. Conductive electrodes 240 are prepared by coating the indicated portion of the zinc mesh with a silver-silver chloride ink. The electrically insulated connecting wire 350 is prepared by coating the indicated portion of the zinc braid with an electrically insulating paint, ink, or polymeric solution.

FIGURE 11 is a top view of an embodiment according to the invention showing conductive electrodes 140 and 240 within vehicle layer 120. Conductive electrodes 140 are made from a piece of zinc mesh. Conductive electrodes 240 are prepared by coating the indicated portion of the zinc mesh with a silver-silver or silver chloride ink, or by other silver deposition procedures, such as electroless deposition (chemical reduction deposition), plating electrolytic, plasma spray, or vacuum deposit. Elimination of the electrically insulated connecting wire 350 in this design will simplify the manufacturing procedure. The location, pattern, shape, and size of the metallic silver, silver-silver chloride, or silver-silver oxide electrode may vary depending on the need for the particular products.

Zinc mesh (or "expanded zinc" as it is commonly referred to in the anticorrosion and battery fields) can be prepared from a thin sheet of zinc with mechanical perforation and subsequent expansion to form lattice-like patterns. The main advantages of a zinc mesh anode in the galvanic device of the present invention are its ability to form and maintain the shape of the mask / patch desired by the user, which can stretch the mask / patch in any direction so that it takes the desired size; and the fact of being breathable.

It should be noted that although the use of a zinc mesh is described herein as an example of electrode design, other materials mentioned above suitable for galvanic couple formation and for conductive electrodes may also be formed into a mesh or an expanded shape to provide the same function.

Zinc mesh also has the ability to adapt to the shape of the membrane's surface (for example, the shape of an individual's face) by lightly pressing on it, and to maintain this shape. This ability makes it exceptionally suitable for a face mask or certain skin patches to better conform to the contours of certain anatomical features of the face (eg a nose patch) or areas of the body. This exceptional feature also aids in better electrical contact and can also reduce the reliance on using adhesives to secure the device to the skin.

It is also highly desirable and desirable for the consumer to be able to stretch a face mask or patch to different sizes to cover a particular area of ​​skin without compromising its electrical performance. A zinc mesh anode (or other conductive mesh electrode) is uniquely capable of meeting this consumer need. In another embodiment, the mesh is not expanded before use, so the device is smaller and more compact for easy storage and transport. Preferably, the consumer stretches it open to a desired size during application.

Good breathability is important for a relatively large face mask or patch, especially if the device is designed to be worn by a user for a long period of time (for example, more than half an hour, such as during the night). In order for the aforementioned device to be stretchable and / or breathable, the vehicle layer 120 and the backing layer 160 must be capable of being stretchable and

ES 2 372 050 T3 breathable, such as stretch and non-flat woven materials.

In another embodiment, the backing layer 160 in FIGS. 3-5 may be perforated or may be removed entirely for a mask or patch device that is especially suitable for a short duration application, eg, from about 5 to about 30 minutes. As the water in the vehicle composition evaporates, the electrical conductance and electrical current decrease. Ultimately, the electrical current will decrease significantly, essentially providing a self-disabling device to act as a safety measure for the user to prevent any unintentional overexposure of the skin to current and electrical potential causing skin damage.

An example of such a self-disabling device is a galvanic cloth face mask made of a zinc mesh partially coated with silver ink-silver chloride, which is placed between a backing / covering film (for example, a perforated polyethylene film or non-perforated) and a non-flat fabric (for example, a non-woven sheet of polyester and / or rayon) using a bonding process based on heating, ultrasound or other mechanism. Prior to application, a liquid or semi-solid carrier composition containing ionic and non-ionic active agents and other optional electrolytes is applied to the non-woven side of the device to activate the galvanic energy source. The galvanic device is then pressed onto the user's face with the non-woven side in direct contact with the skin. Alternatively, the active agents and other optional electrolytes can be incorporated into the nonwoven layer during the manufacturing process in an anhydrous state. During use, the device can be applied to the face moistened with water, and the water will dissolve the active agents and electrolytes to activate the galvanic current. The anhydrous active agents may be in the form of a dry powder immobilized on the fibers of the nonwoven layer, or first dissolved in an organic solvent (for example, polyethylene glycol, propylene glycol, glycerin and / or alcohol) to form a non-conductive or highly poorly conductive, absorbed into the non-woven layer.

Zinc anode materials can be manufactured by a wide variety of manufacturing procedures including, but not limited to, metal processing, electroless deposition, electroplating, plasma spraying, vacuum deposition, printing procedures, such as screen printing. using a conductive zinc ink, textile or non-woven technologies. Similarly, other conductive metallic materials, such as silver-silver chloride, silver-silver oxide, copper, magnesium, aluminum alloys of zinc, magnesium, copper, and aluminum, can be manufactured to take the shape of the aforementioned electrodes. above using the manufacturing procedures described above.

Topical compositions containing galvanic pairs

In one embodiment, the present invention includes a topical composition containing a first particulate conductive metal (such as fine flakes, wires / fibers, or metal-clad fibers) selected from zinc, aluminum, copper, and their alloys; and a second particulate conductive metal (such as fine flakes, wires / fibers, or metal-clad fibers) selected from silver, copper, gold, and their alloys. The first and second particulate metal can be selected from the above-mentioned electrode materials to form galvanic pairs. Upon contacting, the first conductive metal and the second conductive metal form a galvanic couple, generate an electric current, and generate ions electrochemically. In another embodiment, the difference of the standard potentials of the first conductive metal and the second conductive metal is at least about 0.1 V, such as at least 0.5 V. For example, upon contact with a first zinc-containing conductive metal (such as fine zinc wires, zinc flakes, or zinc-coated polymeric fibers) and a second silver-containing conductive metal (such as fine silver wires / fibers , silver flakes or silver-coated polymeric fibers), the composition generates an electrical current and zinc ions within the topical composition.

The composition may also contain an active agent, such as an anti-acne agent (such as salicylic acid, benzoyl peroxide, retinoic acid, and / or retinol). The topical composition containing the first metal and the second metal is preferably in a semi-solid dosage form (such as a gel, a hydrogel, a water-in-oil emulsion, an oil-in-water emulsion, a cream, a lotion, a ointment, a multiemulsion, a liposome and / or a microcapsule formation), and may contain the aforementioned fluid suspending or fluid absorbent materials. The topical composition can be prepared such that one of the conductive metals is formulated in a different phase from the other conductive metal, for example, the first conductive metal (eg zinc flakes) is formulated in the discontinuous oil phase of a oil-in-water emulsion (eg a cream), while the second conductive metal (eg silver flakes) is formulated in the continuous aqueous phase of the emulsion. The topical composition of the present invention may also contain a humectant (such as glycerin, propylene glycol, polyethylene glycol, sorbitol and / or urea) and the electrolytes mentioned above to maintain a certain level of moisture and conductivity of the skin.

In one embodiment, during storage of said topical composition, the first conductive metal and the second conductive metal are suspended substantially apart in a semi-solid composition (e.g., they are not in

ES 2 372 050 T3 contact each other). Upon application to the membrane (such as the skin or a mucosa) and partial drying of the liquid vehicle, contact between the first conductive metal and the second conductive metal results in the formation of the galvanic couple and the generation of an electric current. and metal ions of the first conductive metal, which provides benefits to the membrane, such as antimicrobial, anti-inflammatory action, wound healing, iontophoretic administration of active agents, stimulation of tissues and / or reduction of sebum.

In one embodiment, the cables / fibers, flakes of the conductive metals, or polymeric fibers coated with the conductive metals are fine enough that they can be suspended in the semi-solid compositions during storage. In another embodiment, they are elongated in shape. The advantages of the elongated shapes of the conductive metals (e.g., fine cables / fibers, flakes, and polymeric fibers coated with the conductive metals) include a lower bulk density and therefore better floatability / suspension in the composition. topical; a greater probability of being connected to each other when low concentrations of the conductive metals are used; and a broader and deeper reach of the membrane tissue (eg, the skin) that the galvanic current passes through and to which it provides benefits.

In one embodiment, the first and second particulate conductive metals are formulated in different compositions and stored in separate compartments of a dual chamber dispenser package. For example, zinc particles or their alloys, less chemically stable (for example, more oxidizable), can be formulated in an anhydrous composition, fundamentally non-conductive, with organic solvents, such as polyethylene glycols, propylene glycol, glycerin, liquid silicone and / or alcohol, or other pharmaceutically acceptable organic solvents. The more chemically stable (eg less oxidizable) silver and silver chloride particles can be formulated in an aqueous composition. Active agents can be formulated in any composition depending on their chemical stability and solubility. During use, the compositions are dispensed from the dual chamber container (eg, a pump, tube, bag, bottle, etc. chamber) and are mixed prior to or during application to the skin to form galvanic pairs in situ to generate a galvanic electrical current and to treat skin disorders.

In another embodiment, the aforementioned galvanic couples are manufactured as particles to be incorporated into topical compositions. The particles may have any shape including, but not limited to, spherical or non-spherical particles, or elongated or flattened shapes (eg, metal or metal-coated spheres, hollow or metal-coated metal spheres, coated fibers or fabrics with short metals, and flakes), regular shapes (for example, metallic crystals), and irregular shapes (for example, aggregated spheres). In one embodiment, the particles have a mean particle size of from about 1 micron to about 2 centimeters. Particle size means the maximum dimension in at least one direction. In one embodiment, the particles have a mean particle size of from about 1 micron to about 2 millimeters for non-elongated shapes. In another embodiment, the elongated shaped particles have an average particle size of from about 10 microns to about 2 centimeters, such as from about 100 microns to about 50 millimeters. For example, a polymeric fiber with a length of about 100 microns to about 10 millimeters can be partially coated with silver or silver-silver chloride at one end (or only certain portions of the fiber), and with zinc at the other end ( or in the rest of the servings). In another example, the polymeric fiber is fully coated with the first conductive metal (for example, silver-silver oxide, or silver-silver chloride), and one end (or certain portions of the fiber) is coated with the second metal. conductor (eg zinc or magnesium).

In practice, silver-coated polymeric fibers manufactured by Noble Fiber Technologies, Inc. (Clarks Summit, PA) can be zinc coated using procedures such as conductive zinc ink printing, electrolytic plating, electroless deposition, vacuum deposition. , and spray coating. Alternatively, metallic zinc or magnesium particles (eg, spheres or fine wires) can be coated at one end or in certain portions with silver-silver oxide or silver-silver chloride. Spherical or non-spherical particles with an average particle size ranging from about one micron to about 5 millimeters can be partially covered with coatings of the first and second conductive metal in a similar manner.

The coating processes for said first and second conductive metals to prepare the galvanic pairs can be electroless deposition, electrolytic plating, vacuum vapor deposition, arc spray, conductive metal ink, and other metal coating processes. Known metals commonly used in medical and electronic device manufacturing processes. The particles of the galvanic couple are preferably stored in the anhydrous forms mentioned above, for example, as a dry powder or immobilized on a fabric with binding agents, or as a fundamentally anhydrous non-conductive organic solvent composition (for example, dissolved in polyethylene glycols, propylene glycol, glycerin, liquid silicone and / or alcohol). Galvanic particles have great versatility in their

ES 2 372 050 T3 applications, and can be used in many consumer and medical products, such as patches, bandages, masks, garments, fabrics, socks, bed sheets (for example, immobilized on the vehicle or fabric), compositions of facial mask to spread (such as a paste, cream or gel), creams, lotions, gels, shampoos, cleansers, powders, or incorporated in personal hygiene and medical products, such as 5 toothbrushes, dental floss, wound dressings, diapers, compresses, dry wipes, pre-moistened wipes (with the anhydrous solvents mentioned above), tampons, and rectal and vaginal suppositories. Galvanic particles can also be incorporated into transdermal drug delivery patches to enhance penetration of the drug into the skin by iontophoresis and to reduce skin irritation through electrical stimulation and electrically generated beneficial ions, such as zinc ions. .

Example 1: Vehicles

Examples of various carriers are listed in Table 1, including the weight percent range of ingredients in such carriers.

Table 1

<td>Component</td><td colspan="6">Vehicle weight percentage</td>

<td></td><td>n ° 1</td><td>n ° 2</td><td>n ° 3</td><td>n ° 4</td><td>n ° 5</td><td>n ° 6</td>

<td>Salicylic acid</td><td> 0,1-10</td><td> 2</td><td> 2</td><td> 0</td><td> 0</td><td> 0,1-10</td>

<td>Benzyl peroxide</td><td> 0</td><td> 0</td><td> 0</td><td> 0,5-10</td><td> 0</td><td> 0</td>

<td>Sulfur</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 3</td><td> 3</td>

<td>Resorcinol</td><td> 0</td><td> 0</td><td> 0</td><td> 1</td><td> 1</td><td> 1</td>

<td>Benzalkonium chloride</td><td> 0-2</td><td> 0,1</td><td> 0,1</td><td> 0-2</td><td> 0-2</td><td> 0-2</td>

<td>Benzetonium or methylbenzetonium chloride</td><td> 0-2</td><td> 0</td><td> 0</td><td> 0-2</td><td> 0-2</td><td> 0-2</td>

<td>Cetylpyridium chloride</td><td> 0-2</td><td> 0,1</td><td> 0,1</td><td> 0-2</td><td> 0-2</td><td> 0-2</td>

<td>CDM phospholipid</td><td> 0-40</td><td> 5</td><td> 5</td><td> 0-40</td><td> 0-40</td><td> 0-40</td>

<td>Hydrogen peroxide</td><td> 0-30</td><td> 0</td><td> 3</td><td> 0-30</td><td> 0-30</td><td> 0-30</td>

<td>Buffer (citrate, lactate or phosphate salts of sodium, potassium or lithium)</td><td> 0-10</td><td> 2</td><td> 2</td><td> 0-10</td><td> 0-10</td><td> 0-10</td>

<td>Gelling agent (for example, polyacrylates, cellulose, natural or synthetic gums, or polyacrylamide)</td><td> 0-20</td><td> 5</td><td> 5</td><td> 0-20</td><td> 0-20</td><td> 0-20</td>

<td>Chelating agent (for example, EDTA)</td><td> 0-2</td><td> 0,1</td><td> 0,1</td><td> 0-2</td><td> 0-2</td><td> 0-2</td>

<td>Propylene glycol</td><td> 0-30</td><td> 20</td><td> 15</td><td> 0-30</td><td> 0-30</td><td> 0-30</td>

<td>Polyethylene glycol</td><td> 0-50</td><td> 0</td><td> 0</td><td> 0-50</td><td> 0-50</td><td> 0-50</td>

<td>Polypropylene glycol</td><td> 0-40</td><td> 0</td><td> 0</td><td> 0-40</td><td> 0-40</td><td> 0-40</td>

<td>Ethyl alcohol</td><td> 0-50</td><td> 0</td><td> 15</td><td> 0-50</td><td> 0-50</td><td> 0-50</td>

<td>Isopropyl alcohol</td><td> 0-50</td><td> 0</td><td> 0</td><td> 0-50</td><td> 0-50</td><td> 0-50</td>

<td>Dimethylisosorbide</td><td> 0-20</td><td> 2</td><td> 0</td><td> 0-20</td><td> 0-20</td><td> 0-20</td>

<td>Isopropyl myristate</td><td> 0-30</td><td> 1</td><td> 1</td><td> 0-30</td><td> 0-30</td><td> 0-30</td>

<td>Purified water</td><td>Cs up 100</td><td>Cs up 100</td><td>Cs up to 100</td><td>Cs up to 100</td><td>Cs up to 100</td><td>Cs up to 100</td>

ES 2 372 050 T3

To evaluate the proposed mechanism of action for the electrochemically generated beneficial agents, an in vitro microbiological study was conducted to investigate the effect of electrolysis on the inhibition of P. acnes in certain electrochemical systems; and an in vivo study was performed with human volunteers using a commercial iontophoresis device.

Example 2: In vitro inhibition of P. acnes by electrolysis

A BacT / ALERT system (BioMerieux, Inc., Durham, NC) was used in the P. acnes inhibition experiment. Briefly, 40 ml of an anaerobic soybean and casein-based culture broth medium in a bottle (BacT / ALERT SN, Organon Tekniks Corp., Durham, NC) was inoculated with P. acnes. The fully automatic BacT / ALERT system was used to detect the growth of P. acnes over a 14-day study at 35 ° C by continuously monitoring CO production.₂ using an optical colorimetric detector system. A selected pair of electrodes (Table 2, columns 2 and 3) were disinfected with 70% isopropyl alcohol, and inserted through the rubber stopper into the culture medium in a nitrogen glove box. Some electrodes were connected to the poles of a battery (1.5 or 3 V, as indicated in Table 2, column 3) for 30 minutes. The electrodes were then immediately removed from the BacT / ALERT bottle, which was then placed in the automatic control and incubation system for two weeks. Other electrodes (ie # 3 and 5 in Table 2) were not connected to an external battery, but were connected directly to each other at their ends outside of the BacT / ALERT bottle to form a galvanic pair. The electrodes of these galvanic pairs (ie # 3 and # 5) remained in contact with the culture medium in the bottle during the 14-day study.

Zinc as the positive electrode (anode), with various materials as the negative electrode (cathode), were evaluated with test conditions 1 to 7 (# 1-7 in column 1). Column 4 shows the voltage applied to the conductive electrode by the external cell. However, simply connecting two conductive electrode materials also generated a voltage just from the galvanic pair. For example, the zinc silver / silver chloride galvanic pair has a voltage of 0.9849 V or about 1 V (Zn²⁺ + 2e^- = Zn, standard potential: 0.7626 V, and AgCl + e^- = Ag + Cl^-, standard potential: 0.2223 V), and the zinc-copper galvanic pair has a voltage of approximately 1.1-1.3 V (Cu²⁺ + 2e^- = Cu, standard potential: 0.340 V, and Cu⁺ + e^- = Cu, standard potential: 0.520 V). Reference: Electrochemistry Handbook, 1995, table 14.1, McGraw-Hill, Inc., New York, NY).

In test condition # 7, the electrodes (i.e. zinc-silver / silver chloride galvanic pair) were obtained from a commercial iontophoresis device (IontoPatch, SP, Birch Point Medical, Inc., Oakdale, MN ). The IontoPatch is an iontophoresis device powered by a galvanic pair of "battery strip" fabricated from zinc and silver / silver chloride in a bandage type device. In this experiment, the IontoPatch "battery strip" was removed from the bandage device and placed in the BacT / ALERT bottle. Electrodes of the commercial zinc-silver / silver chloride galvanic pair (# 7) remained in the BacT / ALERT bottle throughout the two week experiment. Assay conditions # 15-17 were positive controls (ie, no electrodes). Test condition # 15 employed a concentrated culture of P. acnes that was used to inoculate the rest of the culture medium in each bottle of BacT / ALERT until a P. acnes count of 10⁶ per ml, and test conditions # 16 and # 17 used the culture medium inoculated with P. acnes counts of 10⁶ per ml (the # 16 rubber stoppers are also perforated in a manner similar to the rest of the electrode test conditions, to eliminate any false P. acnes inhibition results due to potential environmental oxygen ingress into the bottle test affecting the growth of anaerobic P. acnes).

Table 2

<td>n °</td><td>Positive electrode</td><td>Negative electrode</td><td>Applied voltage by connecting to a battery or batteries</td><td>Mean time to growth of positive P. acnes (days)</td><td>no. of positives / n ° tested</td>

<td> 1</td><td>zinc</td><td>silver / silver chloride</td><td>3 V</td><td></td><td> 0/3</td>

<td> 2</td><td>zinc</td><td>zinc</td><td>3 V</td><td> -</td><td> 0/1</td>

<td> 3</td><td>zinc</td><td>copper</td><td>neither³</td><td> -</td><td> 0/2</td>

<td> 4</td><td>zinc</td><td>copper</td><td>1.5 V</td><td> -</td><td> 0/1</td>

<td> 5</td><td>zinc</td><td>silver / silver chloride</td><td>neither^to</td><td></td><td> 0/2</td>

ES 2 372 050 T3

<td> 6</td><td>zinc</td><td>silver / silver chloride</td><td>1.5 V</td><td> -</td><td> 0/2</td>

<td> 7</td><td>zinc</td><td>silver / silver chloride</td><td>neither^to</td><td>b</td><td> 2/6</td>

<td> 8</td><td>copper</td><td>silver / silver chloride</td><td>3 V</td><td></td><td> 0/3</td>

<td> 9</td><td>copper</td><td>copper</td><td>3 V</td><td> -</td><td> 0/2</td>

<td> 10</td><td>platinum</td><td>silver / silver chloride</td><td>3 V</td><td> 1,6</td><td> 2/2</td>

<td> 11</td><td>platinum</td><td>platinum</td><td>3 V</td><td> 1,1</td><td> 1/1</td>

<td> 12</td><td>silver</td><td>silver / silver chloride</td><td>3 V</td><td> 5,7^c</td><td> 2/3</td>

<td> 13</td><td>silver</td><td>silver</td><td>3 V</td><td>2,8d</td><td> 2/2</td>

<td> 14</td><td>silver / silver chloride</td><td>silver / silver chloride</td><td>3 V</td><td> 3,0</td><td> 2/2</td>

<td> 15</td><td>neither</td><td>neither</td><td>neither</td><td> 0,8</td><td> 2/2</td>

<td> 16</td><td>neither</td><td>neither</td><td>neither</td><td> 1,4</td><td> 2/2</td>

<td> 17</td><td>neither</td><td>neither</td><td>neither</td><td> 1,3</td><td> 2/2</td>

<td colspan="6">to. The conductive metal electrodes were not connected to any cell but to each other. Therefore, there is a voltage across the two electrodes dictated by the galvanic couple. b. A total of 6 samples were tested; 4 were negative and 2 were positive (0.6d and 0.8d). The positives were most likely due to bacterial contamination, since they were detected more quickly than the positive control samples (# 16 and 17) and were therefore omitted. c. Two positive samples were averaged out of 3 samples (4.1d and 7.3d).</td>

Surprisingly, the zinc anode was found to almost completely inhibit the growth of P. acnes during the 14-day incubation study under all voltage conditions tested (# 1-7; at # 7, two out of six Commercial galvanic pairs showed positive P. acnes growth probably due to bacterial contamination, see note c of table 2). The copper anode was also found to significantly inhibit the growth of P. acnes (# 8-9). Under these experimental conditions, the platinum anode showed little inhibition of P. acnes, and the silver or silver / silver chloride anodes provided only weak inhibition of P. acnes. Since all positive control conditions (# 15-17) showed positive P. acnes growth in less than two days after the start of the study, the growth of P. Negative acnes can be attributed to the inhibiting effect of the electrochemically generated species or the passage of electrical current through the culture medium. Since the passage of electric current in # 10-14 did not show an inhibition of P. acnes as strong as in # 1-9, the bacterial inhibition observed in # 1-9 is probably due to certain electrochemical reactions produced at the anode, specifically when zinc and copper are used as the anode. It was also unexpected that the silver ions released from the silver anode or silver / silver chloride under these experimental conditions did not show the same inhibition of P. acnes (# 12-14), since silver ions are an agent well known antimicrobial. See, for example, Spacciapoli et al. (Antimicrobial activity of silver nitrate against periodontal pathogens, J. Periodontal Res., 36: 2, 108-113, April 2001). It was surprising that, in the absence of an external battery (# 3, 5 and 7), a pair of electrodes of the galvanic pair with zinc as anode were sufficient to inhibit the growth of P. acnes for the entire two week study.

Example 3: Compatibility of electrodes-salicylic acid in vitro

The following experiment was performed to determine the compatibility of the electrodes with salicylic acid. A pair of test electrodes were immersed in 5 ml of a 1.5% salicylic acid solution (26

ES 2 372 050 T3 50% ethanol / 50% water). A predetermined voltage was applied to the electrodes (connecting the electrodes to a cell or cells) for a certain length of time, as indicated in Table 3. Observations were made on the color change of the test solution.

The solution with the zinc anode showed no discoloration, which indicates good compatibility with salicylic acid during the passage of electric current. The use of the platinum anode produced discoloration unexpectedly, indicating incompatibility with salicylic acid under this experimental condition.

Table 3

<td colspan="2">Electrode material</td><td rowspan="2">Voltage (V)</td><td rowspan="2">Test duration (min)</td><td>Observation</td>

<td>Anode (+)</td><td>Cathode (-)</td><td>Solution color change</td>

<td>platinum</td><td>platinum</td><td> 3</td><td> 10</td><td>colorless ® yellow</td>

<td>platinum</td><td>platinum</td><td> 9</td><td> 10</td><td>colorless ® brown</td>

<td>zinc</td><td>platinum</td><td> 1,5</td><td> 10</td><td>no color change</td>

<td>zinc</td><td>platinum</td><td> 3</td><td> 10</td><td>no color change</td>

<td>zinc</td><td>platinum</td><td> 9</td><td> 30</td><td>no color change</td>

Example 4: Iontophoresis study in humans in vivo

An in vivo study was performed with human volunteers using a commercial iontophoresis device (IontoPatch®, model: SP, Birch Point Medical Inc., North Oakdale, MN). The study recruited healthy female volunteers with oily skin, aged 20-45 years. The forehead sebometer reading of each subject was at least greater than 150 mg / cm²/ hr. The study was blind and controlled. Briefly, an IontoPatch® with a voltage of 1 volt, an operating current of 0.06 mA, and an active treatment area of ​​3.17 cm², was applied to the human subject's treatment site (eg, forehead). The positive and negative electrode consisted of a zinc and silver / silver chloride (Ag / AgCl) material, respectively. Both electrodes were filled with saline solution (0.9% NaCl). As soon as the saline solution was added to the different electrodes, the electric patch started working. The patch was left on the treatment area overnight (eg, approximately 8 hours).

The following evaluations were performed: (i) the effects of electrolysis on the skin disorder were monitored using a normal photograph, and (ii) the change in P. acnes counts was determined by analyzing the wash solution cup for the treatment site before and after wearing the patch overnight. The micro-sampling procedure of the wash cup was performed as follows: a cylindrical cup (2.1 cm diameter and 2.5 cm height) having two open ends was fixed over the treatment area. The treatment area within the cylinder was then washed with 2 ml of cleaning buffer (0.075M sterile phosphate buffer containing 0.1% Triton X-100) while the same area with a sterile polished glass. Then the wash solution was collected. This washing procedure was then repeated. The two collected samples were pooled and used in the analysis of P. acnes.

The P. acnes counts were determined by spiral deposition of the scrub samples anaerobically on Actinomyces agar for 5 days, and the major contaminants on the spiral plates were Gram stained and identified using the VITEK system. Using an automated colony counter, the P. acnes count per ml of each sample buffer was determined.

After only one night of applying the patch, the measurement of the quantification of P. acnes on the treatment area shows a reduction of P. acnes of 45% in relation to the baseline under the zinc anode and of 30% under the Ag / AgCl cathode. After four consecutive overnight applications of the patch, the photographic images showed clear evidence of a significant reduction in the color and size of the post-acne hyperpigmentation spot under the zinc electrode. This test subject had a post-acne hyperpigmentation spot at the test site of the skin. The appearance of the hyperpigmented spot improved from a very dark color to a lighter color.

In addition, after four consecutive overnight applications of the patch, the photographic images also showed evidence of a significant reduction in the color and size of an acne pimple under the Ag / AgCl electrode. This test subject had an acne pimple on the skin test site. The redness of

ES 2 372 050 T3 the pimple was rapidly reduced from a very red color to almost invisible, while the pimples in the untreated area of ​​the skin remained largely unchanged.

Example 5: In vivo human iontophoresis study using histamine hydrochloride as a marker

An in vivo study was performed in three human volunteers using a zinc-silver / silver oxide galvanic device to deliver histamine hydrochloride as a marker into the skin. Histamine-induced skin itching and erythema were recorded during and after the study. The study recruited two healthy male and one female volunteers ranging in age from 41 to 40 years. Galvanic devices were prepared by cutting a thin zinc foil (0.25mm thickness, Alfa Aesar, Word Hill, MA) into rectangular pieces (2.5cm width and 3cm length). A silver ink (Silver Print, MG Chemicals, Toronto, Ontario, Canada) was painted on one side of the zinc sheet as a 0.5 cm wide strip along the long axis in the center. The ink was air dried to produce a silver electrode strip on the zinc foil. Two strips of rectangular Scotch® adhesive tape with a width of 0.5 cm and a length of 3 cm were placed on both sides of the silver electrode tape creating an electrical insulating gap on the surface (electrode gap = 0.5 cm). A rectangular piece of non-flat fabric (50% rayon / 50% PET, 75 gsm, PGI Polymer Group Inc., Landisville, NJ) with a width of 3 cm and a length of 3.5 cm was placed on the side of the zinc-silver electrode of the zinc foil. A rectangular adhesive backing film with a width of 4 cm and a length of 5 cm was attached to the opposite side of the zinc foil to complete the zinc-silver galvanic device.

A second type of zinc-silver galvanic device without an electrical insulating gap on the surface (electrode gap = 0 cm) was prepared simply by omitting the addition of the adhesive Scotch® tape . A third type of patch (control) was prepared using only the zinc foil, the non-woven pad, and the adhesive backing film to construct the device.

To begin histamine iontophoresis, 0.8 ml of a 0.1% aqueous histamine hydrochloride solution (Sigma-Aldrich, St. Louis, MO) was added to each device, which was then attached to the skin of the forearm. of each volunteer for 30 minutes.

At the end of the study, red spots (histamine-induced erythema) appeared under both zinc-silver galvanic patch devices, which disappeared in approximately half an hour. A careful examination revealed red spots around the hair follicles. Itching was also indicated at the galvanic patch sites during patch application. In contrast, there was no change in skin color under the control patch devices nor was itching indicated by them.

Example 6: In vivo human iontophoresis study using histamine hydrochloride with a galvanic nose patch comprising a zinc mesh

As a continuation of the in vivo human studies of the previous example, a galvanic patch device (referred to herein as "test device D") comprising a zinc mesh (diamond-shaped openings with a length of 1 cm) was prepared and a width of 0.4 cm, Exmet Corporation, Naugatuck, CT) instead of a zinc foil, with the same dimensions and procedures as the galvanic device (electrode gap = 0) of Example 5. The device prepared in this way resembles the design of FIGURE 11, with three parallel electrodes: the silver electrode in the center and the zinc electrodes on both sides. Two male volunteers participated in this study using test conditions similar to those of Example 5. A test device containing 0.8 ml of 0.1% histamine hydrochloride was applied to the nose of each volunteer for 30 minutes. Itching was indicated within 5 minutes of application of the nose patch, indicating rapid delivery of histamine into the relatively large pores of the skin on the nose. For both test subjects a pronounced erythema was observed at the skin site under the nose patch after patch removal at the end of the study, compared to the study performed on the skin of the forearm.

It is understood that although the invention has been described in conjunction with its detailed description, the foregoing description is intended to be illustrative and not to limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the claims.