HK1149478A - Electricity-generating particulates and the use thereof - Google Patents

Description

Particles for generating an electric current and use thereof

Background

The use of galvanic couples as a power source in iontophoresis patch devices is well known in the art. See, e.g., U.S. 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, and U.S. patent applications 2004/0267237 and 2004/0138712. The galvanic couple is made of different metals, such as a zinc donor electrode and a silver chloride counter electrode. When body tissue and/or fluids complete an electrical circuit with the electrical current system, the ion introduction patch device powered by one of these couples automatically activates to generate an electrical current. These devices are commonly applied to the human body to provide desired benefits, such as electrical stimulation, accelerated healing, or antimicrobial therapy.

While the foregoing electrical patches as drug delivery devices are useful therapeutic products, they can be cumbersome to use and expensive to manufacture. The present invention aims to overcome these disadvantages by providing galvanic particulates (galvanic particulates).

Disclosure of Invention

In one aspect, the invention features a galvanic particulate including a first conductive material and a second conductive material, wherein both the first conductive material and the second conductive material are exposed at a surface of the particulate, wherein the particulate has a particle size of about 10 nanometers to about 100 micrometers, wherein the second conductive material comprises about 0.01 wt% to about 10 wt% of a total weight of the particulate, and wherein a difference in standard potential of the first conductive material and the second conductive material is at least about 0.2V.

In another aspect, the present invention features a method of making the galvanic particulates of the invention by contacting particles of the first conductive material with a salt solution comprising the second conductive material.

In another aspect, the invention features an ingestible composition including the particles of the invention and a bioabsorbable polymer.

In another aspect, the invention features an oral dosage form including the particles of the invention and a pharmaceutically acceptable carrier.

In another aspect, the invention features a method of treating gastrointestinal disorders by orally administering the particles of the invention.

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

Detailed Description

It is believed that one skilled in the art can, using the description herein, utilize the present invention to its fullest extent. The following specific examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. Percentages refer to weight percent (i.e., (W/W)) unless otherwise indicated.

Definition of

By "product" is meant a product comprising the galvanic particulates (or a composition comprising the galvanic particulates) in a finished packaged form. In one embodiment, the product comprises instructions directing the user to ingest, topically apply, or otherwise administer the galvanic particulates or compositions (e.g., for treating a skin disorder). Such instructions may be printed on the exterior of the product, on a label insert, or on any other packaging.

In one aspect, the invention features facilitating the intended use of a galvanic particulate or a composition comprising a galvanic particulate of the invention. By "promotion" is meant promotion, promotion and promotion. Examples of promotions include, but are not limited to, text, visual or verbal statements about a product or made in a mall, magazine, newspaper, radio, television, internet, etc.

As used herein, "pharmaceutically acceptable" means that the ingredients described by the term are suitable for their intended use (e.g., suitable ingestion or contact with the skin or mucous membranes) without undue toxicity, incompatibility, instability, allergic response, and the like.

As used herein, "safe and effective amount" means an amount of an ingredient or composition that is large enough to achieve the desired degree of desired effect, but low enough to avoid serious side effects. The safe and effective amount of the ingredient or composition will vary depending upon the site being treated, the age of the end user, the duration and nature of the treatment, the particular ingredient or composition used, the particular pharmaceutical carrier used, and like factors.

As used herein, the term "treatment" or "treatment" means the treatment (e.g., alleviation or elimination of symptoms and/or cure) and/or prevention or inhibition of a condition (e.g., a skin, mucosal or nail condition). In one embodiment, the galvanic particulates are administered locally or systemically to a subject (e.g., a human) in need of such treatment. In one embodiment, galvanic particulates are used in living organisms including vertebrates (mammals, including humans), insects, plants, microorganisms (e.g., bacteria, fungi, and viruses) to produce effects (i.e., for treating, promoting health, healing, eliminating, and/or reducing the number of) thereof.

Galvanic particulates

The galvanic particulates of the present invention comprise a first conductive material and a second conductive material, wherein both the first conductive material and the second conductive material are exposed on the surface of the particulate. In one embodiment, the galvanic particulates comprise a first conductive material and the surface of the particulates is partially coated with a second conductive material.

In one embodiment, the galvanic particulates are made by a coating process wherein the weight percentage of the second conductive material is from about 0.001 wt% to about 20 wt% of the total weight of the particulate, such as from about 0.01 wt% to about 10 wt% of the total weight of the particulate. In one embodiment, the coating thickness of the second conductive material may vary from a single atom to several hundred microns. In yet another embodiment, the galvanic particulate surface comprises from about 0.001% to about 99.99%, for example from about 0.1% to about 99.9% of the second conductive material.

In one embodiment, the galvanic particulates are made by a non-coating process (e.g., by sintering, printing, or machining first and second conductive materials together to form the galvanic particulates), wherein the second conductive material comprises from about 0.1% to about 99.9% of the total weight of the particulate, e.g., from about 10% to about 90% of the total weight of the particulate.

In one embodiment, the galvanic particulates are sufficiently fine that they can be suspended in the semi-solid composition during storage. In yet another embodiment, it is flat and/or elongated in shape. Advantages of the flat and elongated shape of the galvanic particulates include lower apparent density, and thus better floating/suspending ability in topical compositions, and better coverage on biological tissues, resulting in wider and/or deeper galvanic currents through biological tissues (e.g., skin or mucosal membranes). In one embodiment, the longest dimension of the galvanic particulates is at least twice (e.g., at least five times) the shortest dimension of such particulates.

The galvanic particulates may be any shape including, but not limited to, spherical or non-spherical particles or elongated or flat shapes (e.g., cylindrical, fibrous, or flake-like). In one embodiment, the galvanic particulates have an average particle size of about 10 nanometers to about 500 microns, such as about 100 nanometers to about 100 microns. By particle size is meant the largest dimension in at least one direction.

In one embodiment, when the galvanic particulates are made using a coating process, the galvanic particulates comprise at least 90 wt.%, such as at least 95 wt.%, or at least 99 wt.% of the conductive materials (e.g., the first conductive material and the second conductive material).

Examples of first conductive material/second conductive material combinations include (oxidized but substantially insoluble form of the metal is represented by the "/" symbol) but are not limited to zinc-copper, zinc-copper/copper halide, zinc-copper/copper oxide, magnesium-copper/copper halide, 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, zinc-carbon, magnesium-gold, magnesium-silver/silver oxide, magnesium-silver/silver halide, magnesium-silver/silver chloride, magnesium-silver/silver bromide, magnesium-silver/silver iodide, magnesium-silver/silver halide, magnesium-copper/copper halide, zinc-silver/silver halide, zinc-silver halide, magnesium-silver/, Magnesium-silver/silver fluoride, magnesium-carbon, aluminum-copper, aluminum-gold, aluminum-silver/silver oxide, aluminum-silver/silver halide, aluminum-silver/silver chloride, aluminum-silver/silver bromide, aluminum-silver/silver iodide, aluminum-silver/silver fluoride, aluminum-carbon, copper-silver/silver halide, copper-silver/silver chloride, copper-silver/silver bromide, copper-silver/silver iodide, copper-silver/silver fluoride, iron-copper/copper oxide, copper-carbon, iron-copper/copper 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 first or second conductive material may also be an alloy, in particular the first conductive material. Non-limiting examples of alloys include alloys of zinc, iron, aluminum, magnesium, copper, and manganese as the first conductive material and alloys of silver, copper, stainless steel, and gold as the second conductive material.

In one embodiment, particles made of a first conductive material are partially coated with a plurality of conductive materials, for example, partially coated with second and third conductive materials. In yet another embodiment, the particles comprise at least 95% by weight of the first, second, and third conductive materials. In one embodiment, the first conductive material is zinc, the second conductive material is copper, and the third conductive material is silver.

In one embodiment, the difference in the standard electrode potentials (or simply the standard potential) of the first conductive material and the second conductive material is at least about 0.1 volts, such as at least 0.2 volts. In one embodiment, the materials comprising the galvanic couple have a standard potential difference of equal to or less than about 3 volts. For example, for a galvanic couple made of metallic zinc and copper, zinc (Zn/Zn 2)⁺) Has a standard potential of-0.763V, copper (Cu/Cu 2)⁺) Has a standard potential of +0.337, so that the zinc-copper couple has a standard potential difference of 1.100V. Similarly, for a magnesium-copper couple, magnesium (Mg/Mg 2)⁺) is-2.363V, so that the standard potential difference is 2.700V. Other examples of standard potential values for some materials suitable for a galvanic couple are: Ag/Ag⁺：+0.799V，Ag/AgCl/Cl^-：0.222V，Pt/H₂/H⁺: 0.000V. Platinum may also be replaced by carbon or another conductive material. See, for example, physicochemical, author Gordon M.Barrow, fourth edition, published by McGraw-Hill Book Company, 1979, page 626.

Manufacture of galvanic particulates

In one embodiment, the conductive electrode is combined by chemical, electrochemical, physical, or mechanical processing (e.g., electroless deposition, electroplating, vacuum vapor deposition, arc spraying, sintering, pressing, stamping, extrusion, printing, and pelletizing) and other known metal coating and powder processing methods commonly used in powder metallurgy, electronic, and medical device manufacturing processes, such as those described in U.S. handbook of metals, volume 7: powder metal technology and applications (published by AsmInternational Handbook Committee, edited by Peter W.Lee, 1998, pages 31-109, pages 311-320) are described. In another embodiment, all of the conductive electrodes are fabricated sequentially or simultaneously by a chemical reduction process (e.g., electroless deposition) in the presence of a reducing agent. Examples of reducing agents include those comprising phosphorus-containing reducing agents (such as the hypophosphite salts described in U.S. patent nos. 4,167,416 and 5,304,403), boron-containing reducing agents, and aldehyde-or ketone-containing reducing agents, such as sodium tetrahydroborate (NaBH4) (such as described in US 20050175649).

In one embodiment, the second conductive electrode is deposited or coated on the first conductive electrode by physical deposition, such as spray coating, plasma coating, conductive ink coating, screen printing, dip coating, metal bonding, particle bombardment at high temperature and high pressure, fluidized bed process, or vacuum deposition.

In one embodiment, the coating method is based on a displacement chemistry reaction, i.e., contacting particles of a first conductive material (e.g., metallic zinc particles) with a solution containing a dissolved salt of a second conductive material (e.g., copper acetate, copper lactate, copper gluconate, or silver nitrate). In yet another embodiment, the method includes flowing the solution over the first conductive material (e.g., zinc powder), or through a packed powder of the first conductive material. In one embodiment, the salt solution is an aqueous solution. In another embodiment, the solution comprises an organic solvent, such as a monohydric alcohol, a dihydric alcohol, glycerol, or other solvents commonly used in pharmaceutical manufacturing, to adjust the deposition rate of the second conductive material onto the surface of the first particles, thereby controlling the activity of the fabricated galvanic particulates.

In another embodiment, galvanic particulates of the present invention may also be coated with other materials to prevent degradation of the galvanic material during storage (e.g., oxidative degradation due to oxygen and moisture), or to regulate the electrochemical reaction and control the generation of current in use. Exemplary coating materials on one or more galvanic materials are inorganic or organic polymers, natural or synthetic polymers, biodegradable or bioabsorbable polymers, silica, glass, various metal oxides (e.g., zinc, aluminum, magnesium, or titanium oxides), and other inorganic salts of low solubility (e.g., zinc phosphate). Coating methods are known in the art of metal powder processing and metal pigment production, such as those described in U.S. patent publication nos. US5,964,936, US5,993,526, US 7,172812, US 20060042509a1, and US 20070172438.

In one embodiment, the galvanic particulates are stored in anhydrous form, for example as a dry powder or immobilized in a fabric using a binder, or as a substantially anhydrous non-conductive organic solvent composition (e.g., dissolved in polyethylene glycol, propylene glycol, glycerin, liquid silicone, and/or monohydric alcohols). In another embodiment, the galvanic particulates are embedded in an anhydrous carrier (e.g., within a polymer) or coated on a substrate (e.g., as or in a coating of a health care product such as a wound dressing or dental floss). In yet another embodiment, the galvanic particulates are encapsulated in microcapsules, liposomes, micellar compositions, or embedded in an oil-in-water (O/W) or water-in-oil (W/O) type emulsion system (e.g., W/O emulsion, W/O ointment, or O/W cream) and the lipophilic phase of a self-emulsifying composition to achieve self-life stability, delay activation of the galvanic particulates, or prolong the effect of the galvanic particulates.

Galvanic particulates may also be compressed into tablets, incorporated into polymer compositions in tablet coating films, incorporated into hard or soft gelatin capsules or incorporated into wax materials (e.g., for suppositories) or polymers (e.g., within bioabsorbable polymers in biocompatible polymers used in implant products or in braces and toothbrushes). The coating (shell) material used in the microcapsules may be enteric (e.g., insoluble under acidic conditions and soluble only when exposed to media having a pH near or equal to neutral pH), or pH sensitive permeable or biodegradable or bioabsorbable with respect to water and solute molecules and ions.

Compositions and products

Galvanic particulates have many uses in applications and are useful in many applications in human and animal consumer and medical products such as ingestible compositions (e.g., tablets and solutions), topical compositions (e.g., creams, lotions, gels, shampoos, cleansers, powder patches, bandages, and masks applied to skin or mucosal membranes), clothing (e.g., intimate apparel, underwear, bras, shirts, pants, pantyhose, socks, hats, face masks, mitts and mitts), linens (e.g., towels, pillowcases, or pillowcases, and sheets), and personal and medical products (e.g., disinfecting products for household and clinical devices, antiseptics for plants), and devices (e.g., toothbrushes, dental floss, periodontal implants or inserts, braces, joint wraps/supports, buccal patches, ocular inserts/implants such as contact lenses, eye inserts/implants, and medical devices, Nasal implants or inserts and contact lens cleaning products, wound dressings, diapers, sanitary napkins and wipes, hemostatic cotton, rectal and vaginal suppositories, and galvanic particulate coated or embedded surfaces on medical devices and other surfaces where antimicrobial or other benefits are desired). A variety of such compositions and products are discussed further below.

In one embodiment, the galvanic particulates elicit some desirable biological response that facilitates treatment of septal disorders (e.g., elicitation and/or enhanced delivery of an active agent by passage of an electrical current through the skin, intestine, or mucosa). In one embodiment, the galvanic particulates provide multiple mechanisms of action to treat a condition, such as enhancing delivery of an active agent by iontophoresis and/or electrodialysis, and provide electrical stimulation to treat contacted tissue (e.g., to promote blood circulation or other beneficial effects).

By "active agent" is meant a compound (e.g., a synthetic compound or a compound isolated from a natural source) that has a cosmetic or therapeutic effect on the septum and surrounding tissues (e.g., a substance capable of exerting a biological effect on the human body), such as a therapeutic drug or cosmetic agent. Examples of such therapeutic drugs include small molecules, peptides, nucleic acid materials and nutrients, such as minerals and extracts. The amount of active agent in the carrier will depend on the active agent and/or the intended use of the composition or product. In one embodiment, the composition comprising galvanic particulates further comprises a safe and effective amount of an active agent, for example, from about 0.001 to about 20 weight percent, such as from about 0.01 to about 10 weight percent of the composition.

The galvanic particulates may be combined with active agents (e.g., antimicrobial agents, anti-inflammatory agents, and analgesics) to enhance or enhance the biological or therapeutic effect of the active agents. In another embodiment, the galvanic particulates may also be combined with other substances to enhance or enhance the activity of the galvanic particulates. Substances that may increase or enhance the activity of galvanic particulates include, but are not limited to, organic solvents (e.g., alcohols, glycols, glycerin, polyethylene glycol, and polypropylene glycol), surfactants (e.g., nonionic, zwitterionic, anionic, cationic, and polymeric surfactants), and water-soluble polymers. For example, the galvanic particulates of the present invention can form conjugates or compositions using synthetic or natural polymers including, but not limited to, proteins, polysaccharides, hyaluronic acid of various molecular weights, hyaluronic acid analogs, polypeptides, and polyvinyl alcohol.

In one embodiment, the composition comprises a chelating or chelating agent. Examples of chelating agents include, but are not limited to, amino acids such as glycine, lactoferrin, edetate, citrate, pentetate, tromethamine, sorbate, deferoxamide, derivatives thereof, and mixtures thereof. Other examples of useful chelating agents are disclosed in U.S. Pat. No.5,487,884 and PCT publication Nos.91/16035 and 91/16034.

Use method of galvanic particulates

In one embodiment, galvanic particulates are used to provide the desired therapeutic electrical stimulation (e.g., local or internal to the body) by directly applying the galvanic particulates to a target site of the body in need of such treatment, including, for example, soft tissue (e.g., skin, mucosa, epithelial tissue, wounds, eyes and surrounding tissue, cartilage and other musculoskeletal tissue such as ligaments, tendons, or menisci), hard tissue (e.g., bone, teeth, nail beds, or hair follicles), and soft tissue-hard tissue junctions (e.g., conductive tissue surrounding soft tissue of teeth, bones, or joints involving periodontal areas).

Such therapeutic effects include, but are not limited to, antimicrobial effects (e.g., antibacterial, antifungal, antiviral, and antiparasitic effects); anti-inflammatory effects, including but not limited to superficial or deep tissue (e.g., reduction or elimination of edema or redness of soft tissue); eliminating or reducing pain, scabies or other discomfort (e.g., headaches, stinging or numbness); promoting soft and hard tissue regeneration or healing; modulating stem cell differentiation and tissue growth development, for example modulating tissue growth (e.g., increasing the growth rate of nails or promoting the regeneration of hair loss due to hair loss) or increasing soft tissue volume (e.g., increasing collagen or elastin in the skin or lips); promoting cellular metabolism or improving body appearance (e.g., affecting body shape or form); and promoting blood or lymph circulation.

One skilled in the art will appreciate that in vivo and in vitro assays using suitable known and generally accepted cell and/or animal models have the ability to predict the composition, composition or product to be used to treat or prevent a given condition. It will also be appreciated by those skilled in the art that human clinical trials, including human first-in-human (first-in-human), dose range and efficacy trials in healthy patients and/or patients with a given condition or disease may be performed according to methods well known in the clinical medicine art.

Ingestible compositions

Ingestible compositions useful in the present invention relate to compositions suitable for use by a mammal, such as a human, in need of such treatment. In one embodiment, the composition comprises a safe and effective amount of (i) galvanic particulates and (ii) a pharmaceutically acceptable carrier.

In one embodiment, the ingestible compositions herein comprise per dosage unit (e.g., tablet, capsule, powder, injection, teaspoonful amount) the amount of galvanic particulates and/or active agent required to deliver an effective dose as described above. In one embodiment, the ingestible compositions herein comprise from about 1mg to about 5mg of galvanic particulates and/or active agent per unit dosage unit, for example from about 50mg to about 500mg, and may be administered at a dosage of from 1 mg/kg/day to about 1 g/kg/day, for example from about 50 to 500 mg/kg/day. The dosage may vary depending on the patient's need, the severity of the condition being treated and the galvanic particulates being used. Daily administration or post-periodic (post-periodic) administration may be employed. In one embodiment, the compositions are in unit form, such as tablets, pills, capsules, powders, granules, solutions or suspensions, and drops.

In one embodiment, the composition is provided in a tablet, e.g., comprising 1,5, 10, 25, 50, 100, 150, 200, 250, 500, and/or 1000 milligrams of galvanic particulates and/or active agent, to adjust the dosage to the patient to be treated according to the symptoms. The composition can be administered by taking 1 to 4 times per day. Advantageously, the composition may be administered in a single daily dose, or the total daily dose may be divided into two, three or four administrations per day.

The optimal dosage to be administered is readily determined by one skilled in the art and will vary depending on the particular galvanic particulate and/or active agent used, the mode of administration, the strength of manufacture, and the progression of the disease/disorder being treated. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust the dosage.

Ingestible compositions comprising one or more of the galvanic particulate types of the invention described herein may be prepared by intimately mixing the galvanic particulates with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the type of formulation. Thus for liquid formulations such as suspensions, special effect liquids and solutions, suitable carriers and additives include, but are not limited to, water, glycols, alcohols, silicones, waxes, fragrances, buffers (e.g., citrate buffer, phosphate buffer, lactate buffer, gluconate buffer), preservatives, stabilizers, colorants, and the like; for solid formulations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, separating agents and the like. Solid oral formulations may also be coated with, for example, sugars, soluble polymer films, insoluble but solute-permeable polymer films. Oral formulations may also be coated with an enteric coating that is insoluble in the acidic gastric fluid environment, but soluble in the intestine, which adjusts the primary site of galvanic particulate action as the pH becomes neutral. For product storage and stability, the galvanic particulates are preferably maintained in an anhydrous or relatively non-conductive state or compartment.

For the preparation of solid compositions such as tablets, the galvanic particulates are mixed with a pharmaceutically acceptable carrier, such as corn starch, lactose, sucrose, sorbic acid, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutically acceptable diluents to form a solid preformulation composition comprising a homogeneous mixture of galvanic particulates. The pre-formulation compositions are said to be homogeneous, that is, the galvanic particulates are uniformly dispersed throughout the composition so that the composition can be readily subdivided into equivalent dosage forms such as tablets, pills and capsules. The solid preformulation composition may then be subdivided into unit dosage forms of the type described above. Tablets or pills of the new composition may be coated or compounded to provide a dosage form that provides long-lasting benefits. For example, a tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating on the outside of the former. The two components may be separated by an enteric layer which serves to prevent disintegration in the stomach, thereby allowing the inner component to pass intact into the duodenum or to delay drug release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acid materials such as shellac, cetyl alcohol and cellulose acetate.

(a) Ingestible compositions for the treatment of gastrointestinal disorders

In one embodiment, the ingestible composition comprising the galvanic particulates is used to treat gastrointestinal diseases, such as ulcers, dysentery, and gastrointestinal pain.

In one embodiment, the galvanic particulates may be combined with active agents known to treat diarrhea, including but not limited to: bismuth (e.g., bismuth subsalicylate), loperamide, simethicone, nitazoxanide, ciprofloxacin, and rifaximin, and salts and prodrugs (e.g., esters) thereof.

In one embodiment, the galvanic particulates may be combined with active ingredients known for the treatment of peptic gastric ulcers, including, but not limited to: lansoprazole, naproxen, esomeprazole, famotidine, nizatidine, ranitidine and omeprazole, and salts and prodrugs thereof.

In one embodiment, the galvanic particulates may be combined with active agents known for the treatment of intra-abdominal infections, including but not limited to: moxifloxacin, ciprofloxacin, ceftazidime, gentamicin, ertapenem; cefepime, cefoxitin, cilastatin, imipenem; ceftriaxone, clavulanic acid and ticarcillin, and salts and prodrugs thereof.

(b) Ingestible compositions for pain treatment

In one embodiment, the ingestible composition comprises galvanic particulates for the treatment of pain (e.g., sore throat). Oral dosage forms may be, but are not limited to, lozenges or liquids. The galvanic particulates may be combined with active agents known for the treatment of laryngitis, including but not limited to: acetaminophen, dextromethorphan, pseudoephedrine, chlorpheniramine, pseudoephedrine, guaifenesin, doxylamine, zinc, and ibuprofen, and salts and prodrugs thereof.

(c) Oral supplement ingestible compositions

In one embodiment, the ingestible composition comprises galvanic particulates used as an oral supplement or an additive to an oral supplement. Oral dosage forms can be, but are not limited to, lozenges, tablets, film-coated tablets, powders or liquids. The galvanic particulates may be combined with vitamin and mineral supplements including, but not limited to: calcium hydrogen phosphate, magnesium oxide, potassium chloride, microcrystalline cellulose, ascorbic acid (vitamin C), ferrous fumarate, calcium carbonate, DL-alpha-tocopherol acetate (vitamin E), gum arabic, ascorbyl palmitate, beta carotene, BHT, calcium pantothenate, calcium stearate, chromium trichloride, citric acid, polyvinylpyrrolidone, copper oxide, cyanocobalamin (vitamin B)₁₂) Calciferol (vitamin D), folic acid, gelatin, hypromellose, lutein, lycopene, magnesium borate, magnesium stearate, magnesium sulfate, nicotinamide, nickel sulfate, plant methylnaproxen (vitamin K), potassium iodide, pyridoxine hydrochloride (vitamin BB)₆) Riboflavin (vitamin B)₂) Silicon dioxide, sodium aluminosilicate, sodium ascorbate, sodium benzoate, sodium borate, sodium citrate, sodium vanadate, sodium molybdate, sodium selenate, sorbic acid, stannous chloride, sucrose, thiamine nitrate (vitamin B)₁) Titanium dioxide, calcium phosphate, vitamin a acetate (vitamin a) and zinc oxide and salts and prodrugs thereof.

Additionally, in one embodiment, the metal component of the galvanic particulates can be used as an in situ generated mineral supplement, such as metallic zinc that is converted to zinc ions in situ.

Topical composition for skin

In one embodiment, the topical composition useful in the present invention relates to a composition comprising galvanic particulates suitable for administration to mammalian skin, such as human skin. In one embodiment, the composition comprises a safe and effective amount of (i) galvanic particulates and (ii) a pharmaceutically acceptable carrier.

The compositions can be formulated into a variety of products including, but not limited to, leave-on products (e.g., lotions, creams, gels, sticks, sprays, and ointments), skin cleansing products (e.g., liquid lotions, solid bars, and ointments), hair care products (e.g., shampoos, conditioners, sprays, and mousses), shaving creams, film forming products (e.g., masks), make-up products (e.g., foundations, eye liners, and eye shadows), deodorants, and antiperspirants, and the like. These products may comprise various types of pharmaceutically acceptable carrier forms including, but not limited to, solutions, suspensions, emulsions, gels, and solid carrier forms, emulsions being, for example, microemulsions and nanoemulsions. Other product forms may be formulated by one of ordinary skill in the art.

In one embodiment, the composition or product is for treating a skin condition. Examples of such treatment methods include, but are not limited to: acne treatments (e.g., blackheads and whiteheads), rosacea, cysts, and other microbial infections of the skin; reducing visible signs of skin aging (e.g., wrinkles, sagging, sallowness, and age spots); tightening the skin; increase skin elasticity; folliculitis and pseudofolliculitis barbae; balanced oil care (e.g., oily or oily/shiny skin appearance suppression or control); pigmentation modulation (e.g., reducing hyperpigmentation such as freckles, chloasma, actinic age spots, post-inflammatory hypermelanosis, Becker nevi and facial melanosis or increasing pale skin pigmentation); hair growth inhibition (e.g., leg skin) or promotion of hair growth (e.g., with respect to the scalp); and dermatitis treatment (e.g., atopic, contact, or seborrheic dermatitis), dark circles under the eyes, stretch marks, cellulite, excessive sweating (e.g., hyperhidrosis), and/or psoriasis.

(a) Topical anti-acne/anti-rosacea composition

In one embodiment, the composition or product comprises an anti-acne and/or anti-rosacea active agent. Examples of anti-acne and anti-rosacea 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 (e.g., hydrocortisone), ibuprofen, naproxen, and ketoprofen; and imidazoles such as ketoconazole and dichlorophenyl imidazole dioxolan; and salts and prodrugs thereof. Other examples of anti-acne agents include essential oils, alpha-bisabolol, dipotassium glycyrrhizinate, camphor, beta-glucan, allantoin, agrimony, flavones such as soy isoflavones, sabal, chelators such as ethylenediaminetetraacetic acid, lipase inhibitors such as silver and copper ions, hydrolyzed vegetable proteins, chlorine, iodine, inorganic fluoride ions and chlorine, iodine, nonionic fluoride derivatives, and synthetic and natural phospholipids such as aralisilk^TMPhospholipids (CDM, SV, EFA, PLN) and GLA (Uniqema, ICI Group of Companies, Wilton, UK).

(b) Topical anti-aging compositions

In one embodiment, the composition or product comprises 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 methoxycinnamate; retinoids; dimethylaminoethanol (DMAE), copper-containing peptides, vitamins such as vitamin E, vitamin a, vitamin C and vitamin B, and vitamins such as ascorbyl diglucoside and vitamin E acetate or palmitate; α salicylic acid and its precursors, such as glycolic acid, citric acid, lactic acid, malic acid, mandelic acid, ascorbic acid, α -hydroxybutyric acid, α -hydroxyisobutyric acid, α -hydroxyisocaproic acid, altrolactic acid, α -hydroxyisovaleric acid, ethyl pyruvate, galacturonic acid, glucoheptonic acid, D-glucono-1, 4-lactone, gluconic acid, gluconolactone, isopropyl pyruvate, methyl pyruvate, mucic acid, pyruvic acid, glucaric acid-1, 4-lactone, tartaric acid, and tartronic acid; beta-salicylic acids such as beta-hydroxybutyric acid, beta-phenyllactic acid and beta-phenylpyruvic acid; tetrahydroxypropyl ethylenediamine, N' -tetrakis (2-hydroxyethyl) ethylenediamine (THPED); and plant extracts such as green tea, soybean, milk thistle, seaweed, aloe, round angelica, bitter orange, coffee, coptis, grapefruit, poria, honeysuckle, coix, alkanna tinctoria root, mulberry, peony, pueraria, rice and safflower; and salts and prodrugs thereof.

(c) Topical depigmenting compositions

In one embodiment, the composition or product comprises a depigmenting agent. Examples of suitable depigmenting agents include, but are not limited to: soy isoflavones; retinoids, such as retinol; kojic acid; kojic acid dipalmitate; hydroquinone; arbutin; tranexamic acid; vitamins such as niacin and vitamin C; azelaic acid; linolenic acid and linoleic acid; placertia; licorice, licorice; and extracts, such as chamomile and green tea; and salts and prodrugs thereof.

(d) Topical antipsoriatic compositions

In one embodiment, the composition or product comprises an anti-psoriatic active agent. Examples of anti-psoriatic active agents (e.g., for the treatment of seborrheic dermatitis) include, but are not limited to, corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, triamcinolone acetonide, dexamethasone, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone valerate, hydrocortisone butyrate, alclometasone dipropionate, fludroxypropionone, mometasone furoate, methylprednisolone), methotrexate, cyclosporine, calcipotriol, anthralin, shale oil and derivatives thereof, dichlorophenyl imidazole dioxolane, ketoconazole, cypress oil, salicylic acid, 1-oxo-2-zinc pyrithione, selenium sulfide, hydrocortisone, sulfur, menthol and pramoxine hydrochloride, and salts and prodrugs thereof.

(e) Other ingredients

In one embodiment, the composition or product comprises a plant extract as an active agent. Examples of plant extracts include, but are not limited to, agrimony, soybean, wild soybean, oatmeal, aloe vera, blueberry, witch hazel, alder, arnica tincture, artemisia capillaries, asiasari radix, birch, calendula, chamomile, ligusticum wallichii, comfrey, fennel, gallnut, hawthorn, houttuynia cordata, hypericum, date, kiwi, licorice, magnolia, olive, peppermint, amur cork tree, sage, japanese bamboo, natural isoflavones, soy isoflavones, and natural essential oils.

In one embodiment, the composition or product comprises a buffer, such as a citrate buffer, a phosphate buffer, a lactate buffer, a gluconate buffer or a gelling agent, a thickener or a polymer.

In one embodiment, the composition or product comprises a fragrance effective for reducing stress, calming, and/or affecting sleep, such as lavender and chamomile.

Mucosal topical pharmaceutical composition

In one embodiment, the topical composition useful in the present invention relates to compositions comprising galvanic particulates suitable for administration to mucosal membranes, such as oral, rectal and vaginal mucosa. In one embodiment, the composition comprises a safe and effective amount of (i) galvanic particulates and (ii) a pharmaceutically acceptable carrier.

The composition can be made into a variety of products for application to mucous membranes including, but not limited to, vaginal creams, tampons, suppositories, dental floss, mouthwashes, toothpastes. Other product forms may be formulated by one of ordinary skill in the art.

In one embodiment, the composition or product is for use in treating a mucosal disorder. Examples of such treatments include, but are not limited to, vaginal candidiasis and vaginosis, genital and oral herpes, cold sores, oral ulcers, oral hygiene, periodontal disease, tooth whitening, halitosis, prevention of biofilm attachment, and other microbial infections of the mucous membranes.

The galvanic particulates may be added to a composition for treating candidiasis, the active agents of which include, for example, but are not limited to: tioconazole; clotrimazole; and nystatin.

The galvanic particulates may be added to a composition for the treatment of bacterial vaginosis, the active agents of which include, for example, but are not limited to, clindamycin hydrochloride and metronidazole.

The galvanic particulates can be added to compositions for the treatment of periodontal disease whose active agents include, for example, but are not limited to, minocycline.

Composition for treating wounds and scars

In one embodiment, galvanic particulates are added to wound dressings and bandages to provide electrical therapy, promote healing, and prevent scarring. In one embodiment, wound exudate and/or wound cleansing solutions are used in wound dressings/bandages comprising galvanic particulates to (i) deliver active agents pre-incorporated into the wound dressing/bandage and/or (ii) generate beneficial electrochemical metal ions which are subsequently delivered into the wound and/or (iii) treat the wound with a therapeutic current which can promote blood circulation, promote tissue immune response and/or inhibit tissue inflammation, which can result in accelerated healing and reduced scarring.

In one embodiment, the composition or product comprises active agents commonly used in the treatment of topical wounds and scars, such as topical antibiotics, antiseptics, wound healing promoting agents, topical antifungals, and anti-inflammatory agents.

Examples of antifungal agents include, but are not limited to, miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voriconazole, clioquinol, bifonazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, dichlorophenyl imidazole dioxolane, griseofulvin, and pharmaceutically acceptable salts and prodrugs thereof. In one embodiment, the antibacterial agent is aloe, allylamine, or a mixture thereof.

Examples of antibiotics (or disinfectants) include, but are not limited to, mupirocin, neomycin sulfate, bacitracin, polymyxin B, 1 ofloxacin, tetracycline (chlortetracycline hydrochloride, oxytetracycline hydrochloride, and tetracycline hydrochloride), clindamycin phosphate, gentamicin sulfate, metronidazole, hexylresorcinol, benzethonium chloride, phenol, quaternary ammonium compounds, tea tree oil, and pharmaceutically acceptable salts and prodrugs thereof.

Preservatives include, but are not limited to chlorhexidine salts such as iodopropynyl butyl carbamate, diazolidinyl urea, chlorhexidine gluconate, chlorhexidine acetate, chlorhexidine isethionate and chlorhexidine hydrochloride. Other cationic preservatives may also be used, for example alkylbenzyldimethylammonium chloride, benzethonium chloride, trichlorocarbanilide, polyhexamethylenebiguanide, cetylpyridinium chloride, benzethonium chloride. Other preservatives include, but are not limited to: halogenated phenolic resin compounds, such as 2, 4, 4' -trichloro-2-hydroxydiphenyl ester (triclosan); p-chloro-m-xylenol (PCMX); and short chain alcohols such as ethanol, propanol, and the like. In one embodiment, the monohydric alcohol is at a low concentration (e.g., less than 10% by weight of the carrier, such as less than 5% by weight of the carrier) so that it does not cause excessive drying of the separator.

Examples of antiviral agents for viral infections such as herpes and hepatitis include, but are not limited to, imiquimod and its derivatives, pradafilo, pelargonium, interferon alpha, acyclovir, famciclovir, reticos (anti-HIV virus drug) and cidofovir and salts and prodrugs thereof.

Examples of anti-inflammatory agents include, but are not limited to, suitable steroidal anti-inflammatory agents, such as corticosteroids, e.g., hydrocortisone, triamcinolone alpha methyl dexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoximetasone, deoxycorticosterone acetate, dichloropine, diflorasone diacetate, diflucortolone valerate, fluadronolone, flurandrenolide, fluhydrocortisone, flumethasone pivalate, fluocinolone, fluocinonide, fluocortexine acetate, fluocortolone, fluprednide (fluprednisone acetate), fludrox, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortolone, flucetonide, fludrocortisone acetate, fluocinolone acetonide, fludaradarenalone acetonide, medroxcinolone, amfect, amcinonide, betamethasone, prednisone, prednisolone acetate, clobetamethasone, clincinolone, dichloropine, difluprednate, fluorodichloropine, flunisolide, fluoromethoxyprednisolone, fluoroperidole, hydrocortisone valerate, hydrocortisone cypionate, hydrocortisone urethane, methylprednisolone, paramethasone, hydroprednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone, and salts and prodrugs thereof. In one embodiment, the steroidal anti-inflammatory agent used in the present invention is hydrocortisone. A second class of anti-inflammatory agents useful in the compositions of the present invention include non-steroidal anti-inflammatory agents.

Examples of wound healing promoters include recombinant human platelet growth factor (PDGF) and other growth factors, ketosertraline, iloprost, prostaglandin E₁And hyaluronic acid, scar-removing agents such as mannose-6-phosphate, analgesics, anesthetics, hair growth promoting agents such as minoxidil, hair growth inhibitors such as eflornithine hydrochloride, hypotensive agents, agents for treating coronary heart disease, anticancer agents, endocrine and metabolic drugs, neurological drugs, chemical additive excision drugs, motion sickness, protein and polypeptide drugs.

Treatment of microbial infections of the body

In one embodiment, galvanic particulates used with or without other antifungal active agents for treating and preventing fungal infections (e.g., dermatophytes, such as trichophyton mentagrophytes) include, but are not limited to, onychomycosis, sporotrichosis, onychomycosis, tinea pedis (tinea pedis), tinea cruris (groin tinea), tinea corporis (ringworm), tinea capitis, tinea versicolor, and candida infection-related diseases (e.g., candida albicans) such as diaper rash, oral thrush, cutaneous and vaginal candidiasis, genital rash, malassel's mildew infection-related diseases such as pityriasis versicolor, pityrosporum folliculitis, seborrheic dermatitis, and dandruff.

In another embodiment, galvanic particulates and other antimicrobial active agents are used together or separately for treatment including but not limited to acne, cellulitis, erysipelas, impetigo, folliculitis, and furuncle carbuncle, as well as acute and chronic wounds (venous ulcers, diabetic ulcers, and pressure sores).

In another embodiment, galvanic particulates are used with or without an antiviral active agent for the treatment and prevention of skin and mucosal infections, including but not limited to molluscum contagiosum, warts, herpes simplex virus infections such as cold sores, oral ulcers, and genital herpes.

In another embodiment, galvanic particulates are used with or without antiparasitic active agents for the treatment and prevention of parasitic infections including, but not limited to, hookworm infections, lice, scabies, sea water eruptions, and schistosomiasis dermatitis.

In one embodiment, the particles are administered to aid in the treatment of ear infections (e.g., infections caused by streptococcus pneumoniae), rhinitis and/or sinusitis (e.g., caused by haemophilus influenzae, moraxella catarrhalis, staphylococcus aureus, and streptococcus pneumoniae), and septic pharyngolaryngitis (e.g., caused by streptococcus pyogenes).

In one embodiment, the particles are ingested by an animal (e.g., as animal feed) or a human (e.g., as a dietary supplement) to help prevent a food-borne disease outbreak (e.g., caused by a food-borne pathogen such as campylobacter jejuni, listeria monocytogenes, salmonella).

Drug-resistant microorganisms

In one embodiment, the invention features a method of killing a pathogen-resistant microorganism by contacting the microorganism with a composition comprising galvanic particulates comprising a first conductive material and a second conductive material, wherein the first conductive material and the second conductive material are exposed at the surface of the particulates, and wherein the difference in the standard potentials of the first conductive material and the second conductive material is at least about 0.2 volts. In one embodiment, the particles have a particle size of from about 10 nanometers to about 1000 microns, such as from about 1 micron to about 100 microns. In one embodiment, the second conductive material is about 0.01 wt% to about 10 wt% of the total weight of the particle. In one embodiment, the drug-resistant microorganism is a bacterium, such as methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). In one embodiment, the particles are applied by nasal spray, rinse solution, or salve.

Nail treatment composition

Galvanic particulates can also be used to promote nail growth and reduce nail infection or discoloration. The galvanic particulates may be added to compositions for the treatment of onychomycosis, the active ingredients of which are exemplified by, but not limited to, miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voriconazole, clioquinol, bifonazole (bifoconazole), terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, dichlorophenyl imidazole dioxolane, griseofulvin, and pharmaceutically acceptable salts and prodrugs thereof. The galvanic particulates may be incorporated into compositions for improving the look and feel of nails, the ingredients of which are such as, but not limited to: biotin, calcium pantothenate, tocopheryl acetate, panthenol, phytantriol, nicotinamide, calcium chloride, aloe vera (leaf juice), silk protein, soy protein, hydrogen peroxide, carbamide, green tea extract, acetylcysteine, and cysteine.

Tissue culture compositions

In one embodiment, galvanic particulates can be used to reduce the visible extent of facial skin wrinkles, reduce atrophy, or increase collagen stimulation. Galvanic particulates may also be used alone or in combination with other components well known in the art, such as subcutaneous fillers, implants, periodontal implants, intramuscular injections, and subcutaneous injections, such as bioabsorbable polymers. For example, galvanic particulates can be used in conjunction with collagen and/or hyaluronic acid injections.

In another embodiment, galvanic particulates can be bonded to biodegradable scaffolds for tissue engineering and organ printing by techniques known in the art.

Transdermal drug delivery patch

In one embodiment, galvanic particulates are incorporated into transdermal drug delivery patches to facilitate penetration of the active agent into the skin by iontophoresis and to mitigate skin irritation by electrical stimulation and electrical generation of beneficial ions such as zinc ions.

Examples of such active agents include peptides, polypeptides, proteins, and nucleic acid materials comprising DNA; and a nutrient substance. Examples of polypeptide and protein active agents include thyroid stimulating hormone releasing hormone (TRH), vasopressin, gonadotropin releasing hormone (GnRH or LHRH), Melanocyte Stimulating Hormone (MSH), calcitonin, growth hormone releasing hormone (GRF), insulin, Erythropoietin (EPO), alpha interferon, beta interferon, oxytocin, captopril, bradykinin, atrial natriuretic factor, cholecystokinin, endorphin, nerve growth factor, melanocyte inhibitor-I, gastrin antagonists, somatostatin, cephalin, melatonin, vaccines, botulinum toxin (botulinum neurotoxin), cyclosporins and derivatives (e.g., biologically active fragments or analogs) thereof. Other active agents include anesthetics; analgesics (e.g., fentanyl and salts thereof, e.g., fentanyl citrate); medicaments for the treatment of psychotic disorders, epilepsy and migraine; drugs for inhibiting drug addiction and abuse; an anti-inflammatory agent; drugs for the treatment of hypertension, cardiovascular diseases, gastric acid and ulcers; drugs for hormone replacement therapy and contraception, such as estrogen and androgen; antibiotics, antifungal agents, antiviral agents, and other antimicrobial agents; antineoplastic agents, immunosuppressive agents and immune enhancing agents; and blood-acting drugs and blood-forming nut oils, including hematopoietics and anticoagulants, thrombolytic agents, and antiplatelet drugs. Other active agents that may be delivered into the body using such patches include vaccines for a variety of diseases, such as influenza, aids, hepatitis, measles, mumps, rubella, rabies, avercella, tetanus, hypogammaglobulinemia, Rh disease, diphtheria, botulism, snake bites, black widow spider bites and other insect bites/bites, Idiopathic Thrombocytopenic Purpura (ITP), chronic lymphocytic leukemia, Cytomegalovirus (CMV) infection, acute kidney transplant rejection, oral polio vaccines, tuberculosis vaccines, pertussis vaccines, hepatitis b virus vaccines, pneumococcal vaccines and staphylococcus aureus.

Bonded to a substrate

Galvanic particulates can be bonded to fibers, nonwoven fabrics, hydrocolloids, adhesives, films, polymers, and other substrates. Products include, but are not limited to, dental floss, toothbrushes, sanitary napkins, tampons, bandages, wound dressings, immobilization dressings, brushes, and clothing. In one embodiment, the galvanic particulates are in contact with a tissue interface. Methods of applying galvanic particulates to a substrate include electrostatic spraying, mechanical sieving, coextrusion, and adhesive spraying.

The particles may also be coated on medical implants or surgical tools (e.g., to help prevent infection).

Examples of the invention

The invention will be further illustrated by the following examples, but is not limited thereto.

EXAMPLE 1 fabrication of galvanic particulates according to the chemical displacement method

(a)In pure aqueous medium: 0.1% copper plated galvanic zinc particles were made by electroless plating of copper onto zinc powder. 10g of zinc dust equal to or less than 45 microns were uniformly distributed on a vacuum filtered buchner funnel with a 0.22 micron filter. 5g of copper acetate solution were then poured evenly over the zinc powder and allowed to react for about 30 seconds. Suction was then applied to the filter until the filtrate was completely withdrawn. The resulting cake was then broken up, 10g of deionized water was added, and then aspirated. 10g of ethanol was then added to the powder under suction. The powder was then carefully removed from the filter system and allowed to dry in a desiccator.

(b)In a medium containing ethanol: 0.1% copper-zinc plated galvanic particulate was made by electroless plating of copper onto zinc powder. 10g of zinc powder of 45 μm or less was weighed into a glass jar. 0.61% w/w copper acetate was dissolved in 200% ethanol. The resulting copper solution was dark blue. Then 5g of copper acetate solution were poured evenly over the zinc powder and the reaction was carried out until the copper solution became clear. When the solution became clear, the reaction lasted for about 48 hours at room temperature. The composition was uniformly distributed on a vacuum filtered buchner funnel with a 0.22 micron filter. The filter was then subjected to vacuum to draw it until the filtrate was completely withdrawn. The resulting cake was then spread out, 10g of deionized water was added, and then aspirated. 10g of ethanol was then added to the powder under suction. The powder was then carefully removed from the filter system and allowed to dry in a desiccator.

(c)In pure aqueous medium: the same process as described in example 1(a) was used, except that magnesium powder was used instead of zinc powder, and copper-plated magnesium galvanic particulates of about 0.1% were produced by electroless plating of copper onto the magnesium powder.

(d)In pure aqueous medium: the same process as described in example 1(a) was used, except that magnesium powder was used instead of zinc powder and ferric chloride solution was used instead of copper lactate, to make about 0.1% copper plated magnesium galvanic particulate by electroless plating iron onto magnesium powder.

Example 2-coating of galvanic particulates onto hydrocolloid substrates

(a)Coating process for deposition onto a substrate by powder sieving: first, the surface area of the self-adhesive hydrocolloid was measured and was determined according to 1.2mg/cm²The surface coating calculates the amount of galvanic particulates needed. The galvanic particulates of example 1(a) were placed into a #325(45 micron) sieve with a hydrocolloid plate placed below the sieve. The sieve was gently shaken to form a uniform powder coating on the hydrocolloid surface. A PET release liner was placed on the surface of the galvanic particulate coated hydrocolloid. The release liner is removed prior to use.

(b)Coating process for electrostatically depositing a powder onto a substrate: the feasibility of coating galvanic particulates onto a substrate by electrostatic powder deposition techniques was demonstrated using a commercially available high voltage powder electrostatic coating system (HV powder coating system, available from casswell, inc. The galvanic particulates and hydrocolloid material and sample preparation procedure were the same as for example 2 a. The voltage of the HV powder coating system was set at 45kV and the compressed air was controlled at 15psi (pounds per inch). This simple and high-speed coating process forms a uniform coating of galvanic particulates on the hydrocolloid plates.

Example 3-in vitro efficacy of galvanic particulates to prevent methicillin-resistant staphylococcus aureus, yeast and bacteria.

Agar plates containing galvanic particulates were made by suspending galvanic particulates from example 1(a) in 2ml of sterile distilled water at 47 ℃ mixed with 8ml of melted agar. The mixture was then poured into a 100X 15mm petri dish. The mixture was solidified in a petri dish, and the galvanic particulates were fixed and uniformly dispersed in the agar. A sterile cork perforator (inner diameter D ═ 12.2mm) was used to cut out smaller agar plates from the agar containing galvanic particulates for further testing of the galvanic particulates.

Agar plates (D12.2 mm, thickness 1.2mm) containing a concentration of 0.5% or 1% galvanic particulates were placed on the surface of the agar plate inoculated with about 6log CFU of the indicated microorganism. The plate was incubated at 37 ℃ for 24 hours. The inhibition zone (distance between disc edge and edge of apparently no growth area) was measured using a digital caliper. The test was performed with multiple replicate samples. The results are shown in Table 1.

TABLE 1

Bacterial strains	Categories	Inhibition zone (mm) 0.5%	Inhibition zone (mm) 1%
				MRSA (methicillin-resistant staphylococcus aureus 33593)	Gram + bacteria	1.3	2.9
MRSE (methicillin-resistant Staphylococcus epidermidis 51625)	Gram + bacteria	1.8	3.6
				Candida albicansPearl oyster 10231	Yeast	0.9	2.0
Pseudomonas aeruginosa 9027	Gram-bacteria	0.4	1.2
				Aquatic corynebacterium 14665	Gram + bacteria	1.0	1.4
Corynebacterium jeikeium 43734	Gram + bacteria	1.9	3.3
				Lysostaphin 29970	Gram + bacteria	1.0	1.3
Micrococcus Lailalis 27566	Gram + bacteria	1.0	2.3

Results are the average of multiple replicates

These results indicate that galvanic particulates inhibit a large number of microorganisms, including antibiotic-resistant bacteria (MRSAand MRSE), yeast (candida albicans) and odor-producing species (corynebacterium aquaticum, corynebacterium jeikeium, staphylococcus haemolyticus, micrococcus lira, staphylococcus epidermidis). This in vitro efficacy shows the promise of galvanic particulates for use in wound infection products, vaginal health products, and odor reduction products.

Example 4 work of galvanic particulates to prevent MRSA and Candida albicans compared to Metal salt controls Effect of (1)

Containing copper-zinc galvanic particles from example 1(a) or agar plates at concentrations of 0.1%, 0.5% or 1% were exposed to approximately 6log CFU of MRSA or candida albicans in saline in a microplate and incubated at 37 ℃ and 200rpm for 24 hours. Plate counts were performed after incubation to count visible microorganisms. Log reduction is defined as the log difference of the test item inoculum before and after incubation (e.g., 6log reduction for 6log inoculum means all inoculum is killed, 3 log reduction for 6log inoculum means 50% inoculum is killed). The results are shown in table 2 below.

TABLE 2

The results show that the antimicrobial potential of the galvanic particulates is significantly better than the metal salt control zinc acetate.

Example 5 resistance of galvanic particulates to MRSA and VRE with copper and zinc metal powders Comparison of physical Activity

Agar plates with copper metal powder, zinc metal powder of example 1(a) or control, i.e. TSA only agar plates, were inoculated with 10e 3VRE or 10e5 MRSA. The inhibition zone was evaluated. The results reported in table 3 show that 1% copper-zinc galvanic particulates completely inhibited the growth of the inoculum, whereas agar plates of control, copper metal powder and zinc metal powder showed no inhibition.

TABLE 3

Test material	MRSA (10e3 inoculum)	MRSA (10e5 inoculum)
			Control substance: TSA agar plates only	Does not inhibit	Does not inhibit
1% w/w copper Metal	Does not inhibit	Does not inhibit
			1% w/w zinc metal	Does not inhibit	Does not inhibit
1% w/w copper-zinc galvanic particulate	Suppression of	Suppression of

Example 6-antimicrobial action of galvanic particulate with copper and Zinc acetate against Candida albicans and MRSA Comparison of biological Activity

Zone of inhibition testing was performed on agar plates containing 0.5% copper-zinc galvanic particulate, 0.5% zinc acetate, and 0.1% copper acetate of example 1 (a). These agar plates were placed on TSA agar surfaces, inoculated with 6log CFU of MRSA or candida albicans, and incubated at 37 ℃ for 24 hours. It was found that 0.5% of the galvanic particulates showed a clearly visible zone of inhibition for both MRSA and candida albicans. The 0.5% zinc acetate showed a smaller zone of inhibition, approximately half the radius of the zone formed by the 0.5% galvanic particles. Copper acetate at 0.1% did not show any visible zone of inhibition for MRSA and candida albicans.

EXAMPLE 7 comparison of galvanic particulates with Zinc and copper acetate by agar plate microwell assay

Agar plates containing 0.1% copper plated zinc galvanic particles or 1% zinc acetate or 0.1% copper acetate of example 1(a) were exposed to approximately 6log CFU of MRSA or Candida albicans in saline in a microplate and incubated at 37 ℃ for 24 hours at 200 rpm. Plates were counted after incubation to count visible microorganisms. Log reduction was defined as the log difference of inoculum before and after incubation for the test article. The results are shown in table 4 below.

TABLE 4

EXAMPLE 8 galvanic particulates compared to Zinc acetate to assess long-term persistence

Agar plates containing the galvanic particulates described in example 1(a) or 1% zinc acetate were placed on a TSA agar surface, inoculated with about 6log CFU of MRSA or candida albicans, and incubated at 37 ℃ for 24 hours (day 1). After incubation, the inhibition zone of the agar plate was observed, then removed from the plate and placed on a freshly inoculated TSA plate and incubated for 24 hours (day 2) using the same inoculum. It was found on day 1 that the galvanic particulate disks and the zinc acetate disks formed zones of inhibition against candida albicans and MRSA, and that the zones formed by the galvanic particulates were larger than the zones formed by the zinc acetate disks. But on day 2, only the plates containing the galvanic particulates showed visible zones of inhibition; the disks containing zinc acetate did not show any inhibitory effect. This indicates that the galvanic particulates have an antimicrobial or inhibitory effect for a sustained period of time.

EXAMPLE 9 immunomodulation by PHA stimulation of human T-cell cytokine Release

The ability of the galvanic particulates of example 1(a) to modulate immune responses is demonstrated by the ability of human T cell activation stimulated by the T Cell Receptor (TCR) active agent Phytohemagglutinin (PHA) to reduce cytokine formation in the following assay.

Human T cells were collected from healthy adult males by leukapheresis. T cells were isolated from peripheral blood by Ficol gradient and cells were adjusted to a density of 1X 10 in serum-free lymphocyte growth medium (ExVivo-15, Biowhittaker, Walkersville, Md.)⁶cells/mL. Human T cells were stimulated with 10. mu.g/mL PHA in the presence or absence of test compounds according to published methods (Hamamoto Y et al, Experimental dermatology, Vol.2, pp.231-235, 1993). 5% CO at 37 deg.C₂After 48 hours of incubation, the supernatant was removed and cytokine concentration was assessed using a commercially available multiplex cytokine detection kit. The results are shown in table 7.

TABLE 7

(wherein IL-2 ═ interleukin-2 (cytokine))

Galvanic particulates were found to be able to modulate the release of inflammatory mediators caused by T cell stimulation. Moreover, the anti-inflammatory activity is greater than copper metal powder, zinc metal powder, copper ions (copper (II) acetate) or zinc ions (zinc chloride) alone.

EXAMPLE 10 inhibition of NF-kB Activity

The nuclear factor k β (NF-kB) is a transcription factor that binds to the NF-kB binding site in the promoter region of proinflammatory genes, such as COX-2 and nitric oxide synthase (iNOS) (Bell S et al (2003) cell signaling; 15 (1): 1-7). NF-kB is involved in modulating multiple aspects of cellular activity in stress, injury, and particularly in the immune response pathway, by stimulating pro-inflammatory proteins such as cyclooxygenase-2 (COX-2), thereby causing inflammation (Chun KS et al (2004) carcinogenesis 25: 445-454; Fenton MJ (1992) immunopharmacology 14: 401-411). NF-kB itself is induced by, for example, pro-inflammatory cytokines (e.g., TNF- α and IL-1 β), bacterial toxins (e.g., LPS and exotoxin B), various viral/viral products (e.g., HIV-1, HTLV-I, HBV, EBV, and herpes simplex), and pro-apoptotic and necrotic stimuli (e.g., oxygen radicals, UV light, and gamma irradiation). Inhibition of NF-kB activity may reduce inflammation by blocking subsequent signals leading to transcription of new pro-inflammatory genes.

Solar ultraviolet radiation activates the transcription factor NF-kB, inducing the formation of matrix metalloproteinases that may lead to the degradation of matrix proteins such as elastin and collagen. NF-kB inhibitors may inhibit subsequent signals that lead to the presence of matrix metalloproteinases in the epidermal matrix, and the more pathways inhibited, the more likely there is no induction of matrix metalloproteinases. Recently, inhibition of the NF-kB pathway has been shown to lead to subsequent induction in collagen synthesis (Schreiber J et al (2005) surgery, Vol. 138: p. 940-. Thus, inhibition of NF-kB activity may also provide anti-aging benefits to the skin by increasing collagen synthesis.

To evaluate the activity of the galvanic particulates from example 1(a) in inhibiting NF-kB activation, a test sample containing a strain obtained from Panomics (Fremont, CA) was usedA stably transferred human epithelial cell line, FB293 cell, for a reporter gene of NF-kB. FB293 cells at 5X 10⁴cells/mL density was overlaid in Dartbox Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (Invitrogen, San Diego, CA). FB293 cells were stimulated with 50ng/mL 12-O-tetradecanoyl phorbol-13-acetate (TPA) (Sigma St Louis, Mo.) in the presence or absence of galvanic particulates. 5% CO at 37 deg.C₂After 24 hours of incubation, cells were lysed using 40 μ l of reporter lysis buffer (Promega, Madison, WI). A20- μ l aliquot of the lysate was assayed using the luciferase assay kit (Promega) and counted in a chemiluminescent microplate reader (molecular devices, Sunnyvale, Calif.) for 10 seconds, with data expressed in relative light units/second. Galvanic particulates were found to inhibit NF-kB activation as shown in table 8.

TABLE 8

	NF-kB reporter gene activation (luminescence)	Percent inhibition
			Untreated	4.06±0.6	-
Stimulation with TPA (10ng/ml)	28.46±2.21	-
			TPA + galvanic particulates (100ug/ml)	3.20±1.98	88.7％
UV (10kJ) stimulation	11.45±1.89	-
			UV (10kJ) + galvanic particulates (100ug/ml)	5.51±1.74	51.6％

Galvanic particulates were thus found to greatly reduce NF-kB activation. This example demonstrates that galvanic particulates can modulate the production of inflammatory mediators, which are responsible for skin inflammation. This example also shows that galvanic particulates can also protect elastin and collagen fibers from damage and deterioration which can lead to skin aging.

Example 11-anti-inflammatory Activity on the Release of UV-induced proinflammatory mediators on reconstructed epidermis

The effect of galvanic particulates on local anti-inflammatory activity on human epidermal equivalents was evaluated. Epidermal equivalent (EPI 200HCF), a multilayered differentiated epidermis comprising normal human epidermal keratinocytes was purchased from MatTek (Ashland, MA). These epidermal equivalents were incubated at 37 ℃ for 24 hours in maintenance medium without hydrocortisone. The equivalent is usually 70kJ/m measured at 360nm in an exposure to sunlight UV light (1000W-sunlight simulation system equipped with a 1-mmSchott WG320 filter; applied UV dose: 70kJ/m²) Previously, galvanic particulates from example 1(a) (1mg/ml) were used for topical treatment (2 mg/cm) in 70% ethanol/30% propanol vehicle²) For 2 hours. The equivalents were incubated at 37 ℃ for 24 hours using maintenance medium, then incubated using a commercially available kit (Upstate Biotechnology, Charlottesville,VA) supernatants were analyzed for IL-8 cytokine release. The results are shown in table 9.

TABLE 9

Treatment (dose,% w/v)	Mean of IL-1A release +/-Standard deviation (ng/ml)	Percent inhibition of skin inflammation
			Untreated, no UV	223.5±168.0	-
UV (60KJ), vehicle treated	944.9±205.3	-
			UV (60KJ) + galvanic particulate (1mg/ml)	477.7±177.9	50.4％

Student t-test with significance level set as P < 0.05 showed significant difference from "UV, vehicle treated".

According to this example, topical application of galvanic particulates can significantly reduce UV-stimulated release of inflammatory mediators. Therefore, the galvanic particulates are expected to have a good anti-inflammatory effect when applied to the skin.

EXAMPLE 12 reduction of skin erythema caused by Niacin methyl ester

Methyl nicotinate (methyl 3-pyridinecarboxylic acid) is a known vasodilator that increases skin blood flow when applied to the skin. See Guy r.h., dermato logical research archive (1982) 273: pages 91-95. In this experiment, a 10mM methyl nicotinate solution (Aldrich Chemical, St. Louis, Mo.) was topically applied for 30 seconds on the inner forearm of the volunteers in the presence of a mask (2.5cm disk, Hill Top Research Inc, Cincinnati, Ohio) according to Jumbelic et al (dermopharmacology and physiology (2006) 19: 147-152). After erythema caused by the methyl nicotinate test, galvanic particulates from example 1(a) (10mg/ml) were topically coated in a 70% ethanol/30% propanol vehicle. Redness was assessed by diffuse reflectance spectroscopy. See Kollias N et al in Photonic chemistry and Photonic biosciences (PhotochemPhotobiol. (1992) (56): 223-. A marine optical diode array spectrophotometer (Dunedin, Fla.) connected to a laptop computer through a USB port was used to control the experiment and collect and analyze spectral data.

The fiber optic bundle is used to conduct light from the lamp to the skin and transmit reflectance measurements back from the skin to the spectrophotometer. The results are shown in table 10.

Watch 10

Treatment (dose,% w/v)	Mean value of apparent hemoglobin +/-standard deviation	Percent inhibition of skin erythema
			Contrast agent	0.72±0.22	-
Galvanic particulates (10mg/ml)	0.43±0.19*	40.2％

Treatment with student t-test with significance level set as P < 0.05 indicated significant differences from "control".

These results indicate that topical application of galvanic particulates reduces erythema on human hair red patterns caused by methyl nicotinate.

Example 13 hydrogen peroxide stimulation by galvanic particulates

Hydrogen peroxide (H)₂O₂) Has strong oxidizing property, and is a high-efficiency bleaching agent. Hydrogen peroxide is also an effective antibacterial, antifungal and antiviral compound that is even effective in preventing methicillin-resistant Staphylococcus aureus (MRSA) separations (Flournoy DJ, Robinson MC. (1990) methods find Exp Clin Pharmacol.12: 541-. In addition, rinsing the oral cavity with a hydrogen peroxide solution resulted in a significant reduction of aerobic and anaerobic bacteria in saliva (Matula C, Hildebrandt M, Nahler G. (1988) J Int Med Res.; 16: 98-106). The reduction of bacteria in the oral cavity can help reduce the incidence of gingivitis.

Peroxide has been used for tooth whitening for over 100 years, and hydrogen peroxide is one of the most commonly used active agents for tooth whitening (Li Y. (1996) Food Chem toxicol. (Food and chemical toxicology.). 34: 887-. Hydrogen peroxide is also a potent vasoconstrictor that reduces the appearance of dark circles and acts as a skin whitening agent (Stamatas GN, Kollias N. (2004) J Biomed Opt.9: 315-.

The ability of the galvanic particulates from example 1(a) to cause hydrogen peroxide formation is shown in the detection analysis below. Human keratinocytes were seeded at similar densities in the assay plates and 5% CO was used at 37 deg.C₂. The culture was carried out for 48 hours. To detect hydrogen peroxide production, 5 μ M hydrogen peroxide sensitive fluorescent probe 5- (and 6) -chloromethyl-2 ', 7' -dichlorofluorescent yellow diacetate, acetyl ester (CM-H2DCFDA, Invitrogen Carlsbad, Calif.) was added to keratinocytes and incubated for 30 minutes. Cells were treated with galvanic particulates or zinc or copper metal powder alone at increasing times. Control wells were treated with 0.03% hydrogen peroxide as a positive control. The production of hydrogen peroxide was quantitatively analyzed using a fluorescence analyzer set to excitation 485/emission 530 wavelengths. The results are shown in tables 11 and 12.

TABLE 11

Compound (I)	Base line	30 minutes	60 minutes	200 minutes	240 minutes
						Untreated	42.3±9.3	61.4±13.9	88.1±29.5	215.4±125.8	243.9±138.9
Galvanic particulates (1%)	77.3±16.2	385.5±98.6**	726.6±158.6**	877.6±186.3**	842.2±176.2**
						H2O2(0.03％)	98.1±4.4	416.6±61.3**	591.4±82.7**	1117.5±153.8**	1214.8±149.7**

Student t-test with significance level set as P < 0.05, showed significant differences from baseline hydrogen peroxide levels at this time point.

TABLE 12

Compound (I)	60 minutes
		Copper metal (0.1%)	62.7±4.27
Zinc metal (0.1%)	76.4±10.31
		Galvanic particulates (0.1%)	190.5±0.84

According to this example, the galvanic particulates are capable of significantly inducing the production of hydrogen peroxide. Moreover, the production of hydrogen peroxide generated from galvanic particulates is significantly greater than the effect of using copper metal powder or zinc metal powder alone. Thus, galvanic particulates are expected to provide skin lightening, tooth whitening and antibacterial activity when applied to the skin.

EXAMPLE 14 examples of topical formulations

(a)Topical gel: the topical gel formulation of table 13 comprising the galvanic particulates of example 1 can be made as follows:

watch 13

INCI name	Formulation Medium% (w/w)
		Propylene glycol	0-60
Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer	0-5
		99.7 percent of glycerol	0-50
PEG-12 polydimethylsiloxane	0-50
		Cyclopentasiloxane	0-50
Galvanic particulates	0.01-5

Propylene glycol and glycerin were added to the main vessel. The hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer was then added and mixed well and subsequently heated to 40C until the composition was clear and transparent and no particles were present. The batch was then cooled to 40 ℃, the remaining ingredients were then added, and mixing was homogenized and further cooled.

(b)Topical stick: the topical gel formulation of table 14(a) comprising the galvanic particulates of example 1 can be made as follows:

watch 14(a)

INCI name	Formulation Medium% (w/w)
		Cyclic methicone (Cyclomethicone)	0-75
Propylene glycol	0-50
		Sodium stearate	0-50
PEG 400	0-100
		Earth wax	0-30
Paraffin wax	0-50
		Agar wax	0-50

INCI name	Formulation Medium% (w/w)
		Galvanic particulates	0.01-5

In the main vessel, all ingredients except propylene glycol and galvanic particulates were mixed and heated to 85-90 ℃ until completely melted. In a separate vessel, the propylene glycol and galvanic particulates were mixed until the particulates were uniformly dispersed. When the composition in the main vessel was homogeneous, the propylene glycol and galvanic particulate mixture was added to the main batch at 85 ℃. The whole batch was mixed well and then cooled to 65-70 ℃.

(c)Dual chamber or dual phase topical medicament: dual compartment packaged topical compositions can be made with the aim of dispensing two separate formulations that might otherwise not be suitable for long term storage in a single compartment. Dual compartment topical compositions having an aqueous composition in one compartment separate from the aqueous or conductive composition in the second compartment can be made according to the following method. Chamber 1 contains the composition described in example 14 (a). Chamber 2 contained the formulation in Table 14(b) below.

Watch 14(b)

INCI name	Formulation Medium% (w/w)
		Water (W)	0-99
acrylate/C10-30 alkyl acrylate crosspolymer	0.05-2
		Alkyl benzyl dimethyl ammonium chloride	0-0.1
Tetrahydroxypropyl ethylenediamine	0-5

The formulations are packaged in dual chamber packages, each in a separate chamber. In use, the formulations are applied to the application site and mixed. An alternative to applying the formulation is a two-step process, wherein the first formulation is applied to the skin first, followed by the second formulation. The two formulations are mixed together and applied to the desired application site.

EXAMPLE 15 antifungal Effect

The galvanic particulates of example 1(a) were found to have a particle size similar to Yang et al fungal pathology 148: 79-82, 1999 in vitro models of onychomycosis. Bovine hooves were used to stimulate onychomycosis. Bovine hooves were punched into 1.3cm diameter pieces and then sterilized in an autoclave. The pieces of bovine hoof were placed in a sterilized petri dish, the outer surface of which was on sterilized filter paper soaked with an antifungal formulation or sterile water as a control. Agar blocks from the dermatophyte culture medium were transplanted onto the inner surface. The entire device was placed in a larger petri dish containing sterile water to prevent dehydration. After inoculation, the dermatophytes were moistened daily with 5 microliters of saprola's glucose broth. The broth was deposited on the inner surface of a beef hoof plate at the bottom of the agar block using a micropipette. Will be provided withThe experimental materials were placed on the cow's hoof device on day 0 and the growth of the fungus was monitored daily to determine the first day the fungus grew through the toenail. The date of appearance and the amount of growth were recorded. Will be coated with 3.6mg/cm²The galvanic particulates were compared to untreated controls. All samples were replicated three times.

The results show that the first penetration of fungal growth was 2 days for the untreated control and 5 days for the galvanic particulate hydrocolloid. This indicates that the galvanic particulates inhibit fungal growth or have antifungal activity.

EXAMPLE 16 anti-aging Effect of galvanic particulates

Aging of the skin is a complex phenomenon caused by the interaction of a variety of intrinsic and extrinsic factors. Intrinsic aging is inevitable and is usually a programmed process. Of these extrinsic effects (e.g., wind, heat, cigarette smoke, chemicals, etc.), ultraviolet radiation appears to be the single most important factor associated with skin aging. As skin ages, the skin typically loses elasticity as it ages. This is due to the thinning of the skin and the loss of elastin and collagen in the epidermal matrix and the loss of the subcutaneous tissue (e.g. fat layer and muscle mass), which is expressed as sagging of the skin. This mechanical property of the skin is particularly affected by the microstructural organisation pattern of collagen and elastin in the epidermal matrix. Elastin is an important component of the extracellular matrix and is particularly abundant in tissues subject to body deformation, such as the skin. The galvanic particulates are found to be effective in inhibiting enzymes in the skin that degrade elastin, and thus are expected to improve the elasticity of the skin.

Human Leukocyte Elastase (HLE) was purchased from Sigma (st. louis, Mo.) and replicated in 1 unit/ml phosphate buffered saline (PBS, Invitrogen life Technologies, Carlsbad, Calif.). Soluble bovine cervical ligament elastin labeled with BODIPY FL dye was purchased from Molecular Probes, Inc (Eugene, Oreg.) such that the fluorescent dye was quenched in the conjugate and can be activated upon elastase uptake. Human leukocyte elastase (0.0625U/ml), elastin substrate (25. mu.g/ml) and increasing concentrations of test material were incubated at 37C for two hours. Fluorescence was measured at 490nm excitation and 520nm emission using a fluorescence analyzer Gemini from Molecular Devices (Sunnyvale, Calif.).

The galvanic particulates of example 1(a) inhibited HLE activity in a dose-dependent manner, as shown in table 15. Galvanic particulates as low as 10ug/ml resulted in about a 50% reduction in HLE activity. This example demonstrates that galvanic particulates can prevent damage and degradation of elastin fibers.

Watch 15

Electric coupling particle (ug/ml)	Elastase inhibitory effect (%)
		0	0
1.0	46.5
		10	48.7
100	53.8
		1000	60.8

Example 17: galvanic particulates reduce pigmentation in epidermal equivalents with darkened skin color

Regulation of pigmentation is an important aspect of improving skin uniformity, skin appearance and skin tone. The galvanic particulates of example 1(a) were also tested for their ability to reduce pigmentation in darkened epidermal equivalents. The darkened epidermal equivalent comprises normal human melanocytes and normal human derived epidermal keratinocytes, which have been cultured to form a multilayered, well-differentiated model of the human epidermis. The epidermal equivalent used was reconstituted human epidermis, EpiDerm, purchased from MatTek Corp. (Ashland, MA)^TM. The darkened epidermal equivalents (MEL-a, containing normal human keratinocytes collected from various exposed (phototype) skin types and normal human melanocytes from asian donors) were treated with 1% galvanic particulates suspended in water for six days and samples were collected at day seven of the study. The collected equivalents were used in Fontana-Mason (F)&M) (Sheenan DC, Hrapckak BB: tissue engineering techniques Theory and practice (Theory and practice of tissue engineering of Histo-Thchology (St Louis: CV Mosby, 1980) pp 223-. F&M staining can confirm that silver nitrate reduces activity, which can spot melanin in the skin.

The galvanic particulates were suspended in water at 1% (w/v) and topically applied daily for 6 days. On the seventh day of the study, equivalents were fixed, segmented and given F&And M staining. To F&The tissue sections stained by M were evaluated for changes in pigmentation. The images used were obtained and analyzed by Image Pro Plus 4.0 software (MediaCybernetics, Silver Spring, MD). The measured parameters were the surface area of the staining material in the melanocytes nuclei keratinocytes and the total surface area of the cells in the medium, and the relative skin tone deepening area was calculated. Untreated controls were set to a value of 100% and the values of the treated groups were normalized to their relevant controls. Data with standard deviation of (5.0，SPSS Science, Chicago, IL). At least three equivalents were processed per experiment, three segments per equivalent. Each experiment was repeated three times.

Table 16 gives the relative control (H) to that₂O) normalized representative data, indicating that galvanic particulate treatment can reduce pigmentation. This indicates the properties of the compositions of the present invention in reducing pigmentation (e.g., reducing pigmentation by up to 51%).

TABLE 16

Test material	Concentration of	Melanin%
			Control (H)2O)	-	100％
Galvanic particulates	1％(W/V)	51+/-5％

EXAMPLE 18 in vitro depigmentation

Regulation of pigmentation is an important aspect of improving skin uniformity, skin appearance and skin tone. Galvanic particulates described in example 1(a) using skin-darkened epidermal equivalentsThe test was performed in an in vitro pigmentation model. The darkened epidermal equivalent comprises normal human melanocytes and normal human derived epidermal keratinocytes, which have been cultured to form a multilayered, well-differentiated human epidermis. 0.01% galvanic particulates were suspended in water and set to the epidermal equivalent (4.2 cm)²) The above. The study included a placebo control of water only. Epidermal equivalents were tested for 7 days. Histological results on day 7 show that galvanic particulate treatment reduced melanin deposition in skin equivalents compared to controls. This indicates that galvanic particulates may have the benefit of skin depigmentation.

It should be understood that while the invention has been described in conjunction with specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the following claims. Other aspects, advantages, and modifications are within the claims.

EXAMPLE 19 galvanic particulate encourages Hydrogen peroxide production

Hydrogen peroxide (H)₂O₂) Has strong oxidizing property, and is a high-efficiency bleaching agent. Hydrogen peroxide is also an effective antibacterial, antifungal and antiviral compound that is even effective in preventing methicillin-resistant Staphylococcus aureus (MRSA) separations (Flournoy DJ, Robinson MC. (1990) Methods and findings in Experimental and clinical pharmacology; "Methods Find Exp Clin Pharmacol.12: 541-). In addition, rinsing the oral cavity with a hydrogen peroxide solution resulted in a significant reduction of aerobic and anaerobic bacteria in saliva (Matula C, Hildebrandt M, Nahler G. (1988) J Int Med Res.; 16: 98-106). The reduction of bacteria in the oral cavity can help reduce the incidence of gingivitis.

Peroxide has been used for tooth whitening for over 100 years, and hydrogen peroxide is one of the most commonly used active agents for tooth whitening (Li Y. (1996) food and chemical toxicology 34: 887-. Hydrogen peroxide is also a potent vasoconstrictor that reduces the appearance of dark circles and acts as a skin whitening agent (Stamatas GN, Kollias N. (2004). J Biomed Opt.9: 315-.

The ability of the galvanic particulates from example 1(b) to cause hydrogen peroxide formation is shown in the following analysis. Human keratinocytes were seeded at similar densities in the assay plates and 5% CO was used at 37 deg.C₂. The culture was carried out for 48 hours. To detect the formation of hydrogen peroxide, 5 μ M hydrogen peroxide sensitive fluorescent probe 5- (and 6) -chloromethyl-2 ', 7' -dichlorofluorescent yellow diacetate, acetyl ester (CM-H2DCFDA, Invitrogen Carlsbad, Calif.) was added to keratinocytes and incubated for 30 minutes. Cells were treated with galvanic particulates or zinc or copper metal powder alone at more times. Control wells treated with 0.03% hydrogen peroxide were used as positive controls. The generation of hydrogen peroxide was quantified using a fluorescence analyzer at 485 excitation/530 absorption wavelengths. The results are described in tables 17 and 18.

TABLE 17

Student t-test with significance level set as P < 0.05, showed significant differences from baseline hydrogen peroxide levels at this time point.

Student t-tests with significance levels set at P < 0.05 showed significant differences in the level of hydrogen peroxide in the galvanic particulates made by the water process at this time point.

Watch 18

Compound (I)	60 minutes
		Metal copper (0.1%)	62.7±4.27
Metal zinc (0.1%)	76.4±10.31
		Galvanic particulates (0.1%)	190.5±0.84

According to this example, the galvanic particulates are capable of inducing the production of hydrogen peroxide in large quantities. The hydrogen peroxide generated by the galvanic particulates is significantly greater than the metallic copper or zinc powder alone. Also, the hydrogen peroxide generated by galvanic particulates formed using the ethanol process is significantly greater than the hydrogen peroxide generated by galvanic particulates formed using the water process. Thus, galvanic particulates formed using the ethanol process are expected to provide skin lightening, tooth whitening and antibacterial activity when applied to the skin.

EXAMPLE 20 reaction Rate, Mass and Activity control of galvanic particles

The effect of varying the metal plating conditions from one metal to another on the activity of the galvanic particulates has been shown in example 19. The reaction medium can thus be adjusted for polarity and the presence of other agents, such as complexing and chelating agents, to form galvanic particulates with altered properties, including but not limited to coating thickness, coating density, coating mode, and/or reaction rate. The plating rate control capability of copper to zinc powder is shown by the following example. The process described in example 1(b) was carried out using various types of 0.61% w/w copper acetate solutions listed in table 19. In Table 19, the reaction time refers to the time it took for the copper to completely deposit on the zinc powder, expressed as the time the copper salt solution changed from blue to clear.

Watch 19

% water	% ethanol	Reaction time (hours)
			0	100	48.00
10	90	5.67
			15	85	0.50
17	83	0.52
			18	82	0.50
20	80	0.00

According to this example, the coating reaction rate can be adjusted by the polarity of the metal salt solution. Example 19 shows that the activity of the resulting galvanic particulates is affected by the manufacturing conditions.

Claims (25)

1. A galvanic particulate comprising a first conductive material and a second conductive material, wherein both the first conductive material and the second conductive material are exposed on a surface of the particulate, wherein the particle size of the particulate is from about 10 nanometers to about 100 micrometers, wherein the second conductive material comprises from about 0.01 weight percent to about 10 weight percent of the total weight of the particulate, and wherein the difference in the standard potentials of the first conductive material and the second conductive material is at least about 0.2V.

2. The galvanic particulate of claim 1, wherein said particulate comprises said first conductive material, and wherein a surface of said particulate is partially coated by said second conductive material.

3. The galvanic particulate of claim 1, wherein said particulate comprises at least 95% by weight of said first and second conductive materials.

4. The galvanic particulate of claim 1, wherein said first conductive material is zinc.

5. The galvanic particulate of claim 1, wherein said second conductive material is copper or silver.

6. The galvanic particulate of claim 4, wherein said second conductive material is copper or silver.

7. The galvanic particulate of claim 2, wherein said particulate is partially coated with a third conductive material.

8. The galvanic particulate of claim 6, wherein said particulate comprises at least 95% by weight of said first, second and third conductive materials.

9. The galvanic particulate of claim 6, wherein said first conductive material is zinc, said second conductive material is copper, and said third conductive material is silver.

10. The galvanic particulate of claim 8, wherein said second conductive material is copper and said third conductive material is silver.

11. A method of making a galvanic particulate according to claim 2, wherein said method comprises contacting a particle of said first conductive material with a solution comprising a salt of said second conductive material.

12. The method of claim 11, wherein the method comprises flowing the solution over the particles.

13. The method of claim 11, wherein the solution comprises an organic solvent.

14. The method of claim 13, wherein the organic solvent is selected from the group consisting of monohydric alcohols, dihydric alcohols, or glycerin.

15. A composition comprising the galvanic particulates of claim 1 and a bioabsorbable polymer.

16. The composition of claim 21, wherein the bioabsorbable polymer is selected from the group consisting of collagen, hyaluronic acid, or mixtures thereof.

17. An oral dosage comprising galvanic particulates according to claim 1 and a pharmaceutically acceptable carrier.

18. A method of treating gastrointestinal disorders, comprising orally administering the oral formulation of claim 17.

19. The method of claim 18, wherein the gastrointestinal disorder is selected from the group consisting of ulcers, diarrhea, and gastrointestinal pain.

20. A method of killing a drug-resistant microorganism, the method comprising contacting the microorganism with a composition comprising galvanic particulates comprising a first conductive material and a second conductive material, wherein both the first conductive material and the second conductive material are exposed at the surface of the particulates, and wherein the difference in the standard potentials of the first conductive material and the second conductive material is at least about 0.2 volts.

21. The method of claim 1, wherein the particles have a particle size of from about 10 nanometers to about 1000 micrometers.

22. The method of claim 1, wherein the particles have a particle size of from about 1 micron to about 100 microns.

23. The method of claim 1, wherein the second conductive material comprises from about 0.01 wt% to about 10 wt% of the total weight of the particle.

24. The method of claim 20, wherein the microorganism is a bacterium.

25. The method of claim 1, wherein the bacteria are selected from MRAA and VRE.