WO2020227367A1 - Compositions d'oxyde nitrique et leurs utilisations topiques - Google Patents

Compositions d'oxyde nitrique et leurs utilisations topiques Download PDF

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Publication number
WO2020227367A1
WO2020227367A1 PCT/US2020/031611 US2020031611W WO2020227367A1 WO 2020227367 A1 WO2020227367 A1 WO 2020227367A1 US 2020031611 W US2020031611 W US 2020031611W WO 2020227367 A1 WO2020227367 A1 WO 2020227367A1
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composition
subject
skin
nitric oxide
vitamin
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PCT/US2020/031611
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English (en)
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Nathan S. Bryan
Gregory CHERNOFF
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Pneuma Nitric Oxide, Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/008—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/008—Preparations for oily skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/88—Two- or multipart kits
    • A61K2800/882—Mixing prior to application
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/114—Nitric oxide, i.e. NO

Definitions

  • the present invention relates generally to nitric oxide (NO) compositions and topical uses thereof, and specifically to the use of NO compositions to increase blood flow and circulation.
  • NO nitric oxide
  • Nitric oxide is a free radical gas produced endogenously by a variety of mammalian cells and is synthesized from arginine by nitric oxide synthase. Physiologically, NO mediates vasodilation, inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Specifically, NO dilates blood vessels and increases blood flow through capillary recruitment.
  • NO nitrogen dioxide
  • NO2 is one of a group of highly reactive gases known as oxides of nitrogen or nitrogen oxides and is a poisonous, noxious gas.
  • Other nitrogen oxides include nitrous acid and nitric acid.
  • NO2 primarily gets in the air from the burning of fuel. NO2 forms from emissions from cars, trucks and buses, power plants, and off road equipment.
  • NO2 is irritating to the eyes, skin, mucous membranes, and respiratory tract. Breathing air with a high concentration of NO2 can irritate airways in the human respiratory system. Such exposures over short periods can aggravate respiratory diseases, particularly asthma, leading to respiratory symptoms (such as coughing, wheezing or difficulty breathing), hospital admissions and visits to emergency rooms. Longer exposures to elevated concentrations of NO2 may contribute to the development of asthma and potentially increase susceptibility to respiratory infections. On contact with moisture, NO2 forms a mixture of nitric and nitrous acids, which can cause irritation and inflammation.
  • the present invention is based on the seminal discovery that nitric oxide (NO) can be generated and incorporated into compositions, without the generation of nitric dioxide (NO2), and that NO compositions can be topically applied for the treatment of a variety of diseases, disorders and conditions, as well as for cosmetic, anti-inflammatory and antimicrobial uses.
  • NO nitric oxide
  • NO2 nitric dioxide
  • the present invention provides a composition including a mixture of equivalent volumes of a first formulation including sodium nitrite in a viscous hydrogel medium and a second formulation including an electron donor and/or an oxygen independent nitrite reductase in a viscous hydrogel medium.
  • the sodium nitrite concentration is about 0.5-5%.
  • the pH of the first formulation is about 6.5-8.
  • the electron donor and/or the oxygen independent nitrite reductase concentration is about 5-25%.
  • the electron donor is ascorbic acid.
  • the pH of the second formulation is about 2.5-3.5.
  • the viscous hydrogel medium is hyaluronic acid (HA), glutaraldehyde, polysorbate 20, hydroxyethylcellulose, d-tocopheryl acetate, dehydroacetic acid, benzyl alcohol, sodium sulfite, sodium metabi sulfite, tetrasodium EDTA, glycol or glycerol.
  • mixing equivalent volumes of the first and second formulations generates nitric oxide (NO) and does not generate nitrogen dioxide (NO2).
  • NO2 nitrogen dioxide
  • the mixture generates about 5-30 ppm of NO.
  • the pH of the mixture is about 5-6.
  • the composition further includes one or more agents which may be HA, retinol, kojic acid, acrylates, oxylacrilamide coplymer, silica, cannabidiol (CBD) oil, witch hazel, aloe, glycolic acid, silver ions, silver sulfadiazine, diclofenac diethylamine, triamcinolone acetonide, hydrocortisone, NAD + , NADH , niacin, glutathione, N-acetyl cysteine, vitamin A, vitamin D or vitamin E.
  • agents which may be HA, retinol, kojic acid, acrylates, oxylacrilamide coplymer, silica, cannabidiol (CBD) oil, witch hazel, aloe, glycolic acid, silver ions, silver sulfadiazine, diclofenac diethylamine, triamcinolone acetonide, hydrocortisone, NAD
  • the invention provides a system for the delivery of a nitric oxide (NO) composition for topical administration including a first container comprising sodium nitrite in a viscous hydrogel medium, a second container comprising an electron donor and/or an oxygen independent nitrite reductase in a viscous hydrogel medium, and a means to deliver the composition comprising equivalent volumes of the content of the first and second containers.
  • the first and the second containers are airless.
  • delivering the composition generates NO and does not generate nitrogen dioxide (NO2).
  • the invention provides a method of treating a disease, a disorder or a condition in a subject by topically administering to the subject in need thereof a nitric oxide (NO) composition that improves blood flow and circulation to the administration site.
  • a nitric oxide (NO) composition that improves blood flow and circulation to the administration site.
  • administering the NO composition induces an local erythema, and one or more agents that may be hyaluronic acid (HA), retinol, kojic acid, acrylates, oxylacrilamide coplymer, silica, hemp oil, cannabidiol (CBD) oil, witch hazel, aloe, glycolic acid, silver ions, silver sulfadiazine, diclofenac diethylamine, triamcinolone acetonide, hydrocortisone, NAD + , NADH, niacin, glutathione, N-acetyl cysteine, vitamin A, vitamin D or vitamin E is applied while the erythema induced by the NO composition is visible.
  • HA hyaluronic acid
  • retinol retinol
  • kojic acid acrylates
  • oxylacrilamide coplymer silica
  • hemp oil cannabidiol (CBD) oil
  • CBD canna
  • the NO composition also contains one or more agents which may be HA, retinol, kojic acid, acrylates, oxylacrilamide coplymer, silica, hemp oil, CBD oil, witch hazel, aloe, glycolic acid, silver ions, silver sulfadiazine, diclofenac diethylamine, triamcinolone acetonide, hydrocortisone, NAD + , NADH, niacin, glutathione, N-acetyl cysteine, vitamin A, vitamin D or vitamin E.
  • the erythema is visible for about 2-5 minutes.
  • the method also includes administering a nitric oxide oral dissolvable tablet to the subject.
  • the disease, disorder or condition is acne or symptoms thereof, saucerized acne scarring, viral shedding, skin condition, hair loss, wound healing, microvascular disease, incision healing, diabetic ulcer, laser resurfaced tissue, improvement in stretch marks, vaginal dryness, painful intercourse, urinary incontinence, fecal incontinence, skin fungal infection, skin bacterial infection, genital fungal infection, genital bacterial infection, penile dysfunction, bums, pain, swelling, skin inflammation, arthritis, sinusitis, skin irritation, hemorrhoidal irritation, vaginal irritation, Raynauds’ syndrome, multi resistant staphylococcus aureus infection (MRSA) or skin itching.
  • MRSA multi resistant staphylococcus aureus infection
  • the disease or disorder is aging skin, acne, a scar, or wound care.
  • aging skin is characterized by wrinkles;, enlarged pore size; poor skin tone; poor skin texture; pigment variation (i.e. red or brown spots); increased oiliness; and/or vasculature such as telangiectasia or rosacea related erythema.
  • treating aging skin is determined by improvement in fine lines; wrinkles; pore size; skin tone and texture; coloration and oiliness.
  • acne was characterized as mild, moderate or severe based on the number of nodules and pustules.
  • treating acne is determined by pustule and/or nodule reduction.
  • scars are atrophic scars, striae, acne scars, hypertrophic scars and excised keloid scar beds.
  • treating a scar is determining by a reduction on the visibility of striae; softening of hypertrophic scars; reduction in scar volume; and improved vascularity.
  • wounds are surgical incision scars, surgical local and regional flaps.
  • wounds are non-healing wounds such as diabetic ulcers, burn wounds, and smoking-induced vascular-compromised wounds.
  • treating wound care is determined by reduction in bruising; reduction in edema; re-epithlialisation, healing of wounds and increased or improved vascularity.
  • the invention provides a method of treating a disease, a disorder or a condition in a subject by providing a system for topical administration of a nitric oxide (NO) composition and topically administering the NO composition to the subject in need thereof.
  • NO nitric oxide
  • the disease or disorder is aging skin, acne, a scar, or wound care.
  • aging skin is characterized by wrinkles;, enlarged pore size; poor skin tone; poor skin texture; pigment variation (i.e. red or brown spots); increased oiliness; and/or vasculature such as telangiectasia or rosacea related erythema.
  • treating aging skin is determined by improvement in fine lines; wrinkles; pore size; skin tone and texture; coloration and oiliness.
  • acne was characterized as mild, moderate or severe based on the number of nodules and pustules.
  • treating acne is determined by pustule and/or nodule reduction.
  • scars are atrophic scars, striae, acne scars, hypertrophic scars and excised keloid scar beds.
  • treating a scar is determining by a reduction on the visibility of striae; softening of hypertrophic scars; reduction in scar volume; and improved vascularity.
  • wounds are surgical incision scars, surgical local and regional flaps.
  • wounds are non-healing wounds such as diabetic ulcers, burn wounds, and smoking-induced vascular-compromised wounds.
  • treating wound care is determined by reduction in bruising; reduction in edema; re-epithlialisation, healing of wounds and increased or improved vascularity.
  • the invention provides a non-toxic method of producing a nitric oxide (NO) composition for topical administration including mixing equivalent volumes of sodium nitrite in a viscous hydrogel medium and electron donor and/or an oxygen independent nitrite reductase in a viscous hydrogel medium, wherein mixing the equivalent volumes generates NO and does not generate nitrogen dioxide (NO2).
  • NO nitric oxide
  • the invention provides a method of increasing vascularity for improved ancillary absorption in a subject including providing a system for topical administration of a nitric oxide (NO) composition and topically administering the NO composition to the subject in need thereof.
  • NO nitric oxide
  • the invention provides a use of a nitric oxide (NO) composition for cosmetic application by providing a system for topical administration of a nitric oxide (NO) composition and topically administering the NO composition to a subject in need thereof.
  • NO nitric oxide
  • the cosmetic application is neocollagenesis, neoellastogenesis; improvement in skin tone, skin quality re-epithelialization, skin healing time, skin moisturization, skin exfoliation, saucerized acne scarring, skin vascularization; lip plumping, time of lipstick application and/or skin cleansing improvement; improvement for acne symptoms, stretch mark appearance, skin pigmentation issues, skin irritation, skin itching, and/or skin inflammation reduction; or hair loss management.
  • the cosmetic application is aging skin, acne, or a scar.
  • aging skin is characterized by wrinkles;, enlarged pore size; poor skin tone; poor skin texture; pigment variation (i.e.
  • treating aging skin is determined by improvement in fine lines; wrinkles; pore size; skin tone and texture; coloration and oiliness.
  • acne was characterized as mild, moderate or severe based on the number of nodules and pustules.
  • treating acne is determined by pustule and/or nodule reduction.
  • scars are atrophic scars, striae, acne scars, hypertrophic scars and excised keloid scar beds.
  • treating a scar is determining by a reduction on the visibility of striae; softening of hypertrophic scars; reduction in scar volume; and improved vascularity.
  • the NO composition is topically administered to the face, neck, declotette, abdomen, back, arm, leg, chest, abdomen, hand and/or lip of the subject.
  • the invention provides a method for improving stromal vascular fraction homing, delivery and/or efficacy in a subject in need thereof by administering to said subject a nitric oxide (NO) composition in combination with a stromal vascular fraction, wherein the stromal vascular fraction comprises mesenchymal stem cells.
  • a nitric oxide (NO) composition in combination with a stromal vascular fraction, wherein the stromal vascular fraction comprises mesenchymal stem cells.
  • the administration of the stromal vascular fraction is topical or by injection.
  • the invention provides a method for improving exosome homing, delivery and/or efficacy in a subject in need thereof by administering to said subject a nitric oxide (NO) composition in combination with an exosome composition.
  • a nitric oxide (NO) composition in combination with an exosome composition.
  • the invention provides a method of enhancing the efficacy of a delivery particle in a subject in need thereof by administering to said subject a nitric oxide (NO) composition in combination with or in conjunction with a delivery particle composition.
  • a nitric oxide (NO) composition in combination with or in conjunction with a delivery particle composition.
  • the delivery particle is a nanoparticle of gold.
  • the invention provides a method of dilating a vein in a subject in need of a venipuncture by topically administering to said subject a nitric oxide (NO) composition.
  • NO nitric oxide
  • the NO composition induces an erythema visible for about 2-5 minutes.
  • the NO composition also contains one or more agents which might be lidocaine, bupivacaine, tetracaine or a combination thereof.
  • the invention provides a method of dilating a vein in a subject including providing a system for topical administration of a nitric oxide (NO) composition and topically administering the NO composition to the subject in need thereof.
  • NO nitric oxide
  • Figure l is a linear analog scale used to determine patient improvement.
  • Figures 2A-2B are photographs showing an antecubital vein before (A) and after (B) the application of a NO composition. Dotted line: visible erythema; arrow: dilated antecubital vein.
  • Figure 3 is a picture of the NO composition killing pseudomonas using increasing amounts of the serum.
  • the present invention is based on the seminal discovery that nitric oxide (NO) can be generated and incorporated into compositions, without the generation of nitric dioxide (NO2), and that NO compositions can be topically applied for the treatment of a variety of diseases, disorders and conditions, as well as for cosmetic, anti-inflammatory and antimicrobial uses.
  • NO nitric oxide
  • NO2 nitric dioxide
  • references to“the method” includes one or more methods, and/or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
  • the present invention provides a composition including a mixture of equivalent volumes of a first formulation including sodium nitrite in a viscous hydrogel medium and a second formulation including an electron donor and/or an oxygen independent nitrite reductase in a viscous hydrogel medium.
  • viscous hydrogel medium refers to a semisolid emulsion using a solvent to carry an active ingredient.
  • the solvent might be water or alcohol.
  • the hydrogel of the present invention carries sodium nitrite, an electron donor and/or an oxygen independent nitrite reductase as the active ingredients. Additionally, the hydrogel limits the reaction of NO with oxygen, thereby limiting the formation of NO2. Hydrogels can encapsulate various compounds or elements, and thus can be used as drug delivery systems.
  • the viscous hydrogel medium is hyaluronic acid (HA), glutaraldehyde, polysorbate 20, hydroxyethylcellulose, d-tocopheryl acetate, dehydroacetic acid, benzyl alcohol, sodium sulfite, sodium metabi sulfite, tetrasodium EDTA, glycol or glycerol.
  • HA hyaluronic acid
  • glutaraldehyde polysorbate 20
  • hydroxyethylcellulose d-tocopheryl acetate
  • dehydroacetic acid benzyl alcohol
  • sodium sulfite sodium metabi sulfite
  • tetrasodium EDTA glycol or glycerol.
  • the term‘electron donor’ refers to a chemical entity that donates electrons to another compound. As used herein, it refers to any reducing agent that donates electron and oxidizes itself in the process. Reducing agents undergo permanent chemical alteration through
  • reducing agent refers both to elements and compounds that lose (or donate) electron to another chemical species in a redox chemical reaction.
  • reducing agents include the earth metals, formic acid, and sulfite compounds.
  • Commons reducing agents include: lithium aluminum hydride (LiAlEE), nascent (atomic) hydrogen, hydrogen, sodium amalgam (Na(Hg)), sodium-lead alloy (Na + Pb), diborane, sodium borohydride (NaBEE), compounds containing the Fe 2+ ion, compounds containing the Sn 2+ ion, sulfur dioxide (sometimes also used as an oxidizing agent), sulfite compounds, dithionates, thiosulfates, iodides, hydrogen peroxide, hydrazine, diisobutylaluminum hydride, oxalic acid (C2H2O4), formic acid (HCOOH), ascorbic acid (O ⁇ EEO ⁇ ), reducing sugars, phosphi
  • oxygen independent nitrite reductase refers to any enzyme capable of catalyzing the reduction of nitrite, in an oxygen independent chemical reaction.
  • oxygen independent nitrite reductases include, but are not limited to, hawthome berry, beet root extract, green tea extract, pine bark, and schizandra.
  • the sodium nitrite concentration is about 0.5-1%, 0.5-2%, 0.5-3%, 0.5- 4%, 0.5-5%, 0.5-6% or 0.5-7%.
  • the electron donor and/or the oxygen independent nitrite reductase concentration is about 5-15%, 5-20%, 5-25%, 5-30% or 5-35%.
  • the pH of the first formulation is about 6.5-8. In many aspects, the pH of the second formulation is about 2.5-3.5. In other aspects, the pH of the mixture is about 5- 6
  • the electron donor is ascorbic acid.
  • Ascorbic acid or vitamin C, is a weak sugar acid structurally related to glucose. In solutions above pH 5, ascorbic acid is predominantly found in its ionized form, ascorbate. Both ascorbate and ascorbic acid have vitamin C activity and anti-oxidant properties. As a reducing agent, ascorbic acid donates electrons and prevents oxidation.
  • mixing equivalent volumes of the first and second formulations generates nitric oxide (NO) and does not generate nitrogen dioxide (NO2).
  • Nitric oxide, nitrogen oxide or nitrogen monoxide is a colorless gas with the formula NO. It is one of the principal oxides of nitrogen. In mammals, including humans, nitric oxide is a signaling molecule in many physiological and pathological pathways. NO is a gaseous signaling molecule also known as an endothelium-derived relaxing factor (EDRF).
  • EDRF endothelium-derived relaxing factor
  • Nitric oxide synthase It is biosynthesized endogenously from L-arginine, oxygen, and NADPH by various nitric oxide synthase (NOS) enzymes, and is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells. Nitric oxide binds to the haem region of target enzymes which leads to its activation, in the presence of iron.
  • NOS nitric oxide synthase
  • Nitric oxide is a highly reactive molecule with a short lifetime (a few seconds), which diffuses freely across membranes. Thus, NO can act as a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule. NO is a potent vasodilator, which induces the endothelium of blood vessels to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow.
  • Nitric oxide should not be confused with nitrogen dioxide (NO2), a brown toxic gas and a major air pollutant. However, nitric oxide can be converted into nitrogen dioxide when exposed to oxygen:
  • NO2 is a trace gas in the atmosphere of Earth, where it plays a role in absorbing sunlight and regulating the chemistry of the troposphere, especially in determining ozone concentrations. While Mhhas numerous uses, it is a toxic gas, which diffuses into the epithelial lining fluid (ELF) of the respiratory epithelium, dissolves, and chemically reacts with antioxidant and lipid molecules in the ELF. Mh's health effects are caused by the reaction products or their metabolites, which are reactive nitrogen species and reactive oxygen species that can drive bronchoconstriction, inflammation, reduced immune response, and may have effects on the heart.
  • ELF epithelial lining fluid
  • composition of the present invention generates NO, but is prevented from any exposure to O2 and thus from generating toxic NO2.
  • the reaction leading to the production of NO from sodium nitrite is as follow:
  • the mixture generates about 5-10 ppm, 5-15 ppm, 5-20 ppm, 5-25 ppm, 5-30 ppm, 5-35 ppm or 5-40 ppm of NO.
  • the composition further includes one or more agents which may be HA, retinol, kojic acid, acrylates, oxylacrilamide coplymer, silica, cannabidiol (CBD) oil, witch hazel, aloe, glycolic acid, silver ions, silver sulfadiazine, diclofenac diethylamine, triamcinolone acetonide, hydrocortisone, NAD + , NADH, glutathione, niacin, N-acetyl cysteine, vitamin A, vitamin D or vitamin E.
  • agents which may be HA, retinol, kojic acid, acrylates, oxylacrilamide coplymer, silica, cannabidiol (CBD) oil, witch hazel, al
  • agent refers to any active ingredient that might be included in the NO composition.
  • agent can include, but is not limited to, anti inflammatory agents, topical bleaching agents, anti-aging agents, and antimicrobial agents.
  • Anti-inflammatory agents refers to active ingredients capable of blocking, halting or preventing an inflammatory reaction.
  • COX2 inhibitors include Celebrex and Vioxx; nonsteroidal anti-inflammatory drugs (NSAIDS), such as acetylsalicylic acid (ASA), Ibuprofen and Naproxen inhibiting both COX1 and COX2 enzymes, which can lead to colon, kidney and liver damage.
  • NSAIDS nonsteroidal anti-inflammatory drugs
  • ASA acetylsalicylic acid
  • Ibuprofen Ibuprofen
  • Naproxen inhibiting both COX1 and COX2 enzymes
  • topical anti-inflammatory agents include, but are not limited to, turmeric, ginger, kelp, kombu, wakeme, arame, brown algae extract, moui, salmon oil, green tea, papaya, pineapple, blueberry, sweet potato, spinach, rosemary, willow bark, tea tree oil, and cayenne pepper.
  • Topical bleaching agents refers without any distinction to agent that can be used to lighten, brighten, depigment, and bleach the skin.
  • Skin-lightening (or‘skin-bleaching’) agents are essential tools in the management of disorders of hyperpigmentation, such as melasma and post- inflammatory hyperpigmentation.
  • topical bleaching agents include, but are not limited to, hydroquinone, kojic acid, alpha-arbutin- from bearberry leaf, Canadian rum ex plant, licorice extract, glycolic acid, retinA, ascorbyl palmitate, indian gooseberry, ginga white, azaelic acid, beta-arbutin, paper mulberry, nicotinamide, aloe, tea tree oil, and grape seed extract.
  • Anti-aging agents refers to active ingredients capable of blocking, halting or preventing skin aging.
  • anti-aging agents include, but are not limited to, NAD + , NADH, glutathione, and N-acetyl cysteine.
  • Nicotinamide adenine dinucleotide exist in two forms, an oxidized form NAD + and a reduced form, NADH; both can be included in the NO composition of the present invention.
  • Anti-microbial agents is meant to include antibacterial, anti-fungal and anti-viral agents, that are capable of blocking, halting or preventing bacterial, fungal and/or viral infection.
  • topical anti -bacterial agents include, but are not limited to, apple stem cells, salicylic acid powder, pumpkin oil, silver nitrate, mandelic acid, sodium nitrate, cucumber astringent and peach extract.
  • silver ions is meant to include structured, nanoparticles, and colloidal silver ions.
  • the invention provides a system for the delivery of a nitric oxide (NO) composition for topical administration including a first container comprising sodium nitrite in a viscous hydrogel medium, a second container comprising an electron donor and/or an oxygen independent nitrite reductase in a viscous hydrogel medium, and a means to deliver the composition comprising equivalent volumes of the content of the first and second containers.
  • NO nitric oxide
  • the first and the second containers are airless.
  • delivering the composition generates NO and does not generate nitrogen dioxide (NO2).
  • the invention provides a method of treating a disease, a disorder or a condition in a subject by topically administering to the subject in need thereof a nitric oxide (NO) composition that improves blood flow and circulation to the administration site.
  • a nitric oxide (NO) composition that improves blood flow and circulation to the administration site.
  • treating is used herein to refer to a therapeutic method and refers to both 1) the application of therapeutic treatments or measures to cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic conditions or disorder, and 2) the application of prophylactic/ preventative measures.
  • Those in need of treatment may include individuals already having a particular medical disorder as well as those who may ultimately acquire the disorder (z.e., those needing preventive measures).
  • subj ect refers to any individual or patient to which the subj ect methods are performed.
  • the subject is human, although as will be appreciated by those in the art, the subject may be an animal.
  • other animals including vertebrate such as rodents (including mice, rats, hamsters and guinea pigs), cats, dogs, rabbits, farm animals including cows, horses, goats, sheep, pigs, chickens, etc., and primates (including monkeys, chimpanzees, orangutans and gorillas) are included within the definition of subject.
  • Administration routes can be enteral, topical or parenteral.
  • administration routes include but are not limited to intracutaneous, subcutaneous, intravenous, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal, oral, sublingual buccal, rectal, vaginal, nasal ocular administrations, as well infusion, inhalation, and nebulization.
  • administering the NO composition induces an local erythema, and one or more agents which may be hyaluronic acid (HA), retinol, kojic acid, acrylates, oxylacrilamide coplymer, silica, cannabidiol (CBD) oil, witch hazel, aloe, glycolic acid, silver ions, silver sulfadiazine, diclofenac diethylamine, triamcinolone acetonide, hydrocortisone, NAD + , NADH, niacin, glutathione, N-acetyl cysteine, vitamin A, vitamin D or vitamin E is applied while the erythema induced by the NO composition is visible.
  • HA hyaluronic acid
  • retinol retinol
  • kojic acid acrylates
  • oxylacrilamide coplymer silica
  • cannabidiol (CBD) oil witch hazel, aloe, glycolic acid
  • the administration of the NO composition can be in combination with one or more additional therapeutic agents.
  • the phrases‘combination therapy’,‘combined with’ and the like refer to the use of more than one medication or treatment simultaneously to increase the response.
  • the composition of the present invention might for example be used in combination with other drugs or treatment in use to treat a disease of interest.
  • Such therapies can be administered prior to, simultaneously with, or following administration of the composition of the present invention.
  • erythema refers to the redness of the skin caused by the application of the NO composition and visually indicates the transient increased blood flow during which any other active compounds should be applied to the skin.
  • the erythema is visible for about 2-5 minutes.
  • the erythema generally appears within about 2 seconds following the application of the NO composition, and lasts for up to 5 minutes. In some aspects, the erythema appears within 2 seconds, 5 seconds, 10 seconds, 30 seconds, 45 seconds, or 60 seconds following the application of the NO composition and lasts for up to 5 minutes. In other aspects, the erythema is visible for about 2-3 minutes, 2-4 minutes, or 2-5 minutes.
  • the NO composition also contains one or more agents which may be HA, retinol, kojic acid, acrylates, oxylacrilamide coplymer, silica, CBD oil, witch hazel, aloe, glycolic acid, silver ions, silver sulfadiazine, diclofenac diethylamine, triamcinolone acetonide, hydrocortisone, NAD + , NADH, niacin, glutathione, N-acetyl cysteine, vitamin A, vitamin D or vitamin E.
  • the present invention also includes the complementary systemic administration of NO.
  • the mode of delivery chosen for administration of NO according to the present invention to a subject, such as a human patient or mammalian animal, depends on the formulation of said NO. The actual final dosage for a given route of administration can be easily determined by routine experimentation.
  • the NO can be administered in a variety of unit dosage forms depending upon the method of administration.
  • Suitable unit dosage forms include, but are not limited to powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, lipid complexes, etc.
  • the method further includes administering a nitric oxide oral dissolvable tablet to the subject.
  • the disease, disorder or condition is acne or symptoms thereof, saucerized acne scarring, viral shedding, skin condition, hair loss, wound healing, microvascular disease, incision healing, diabetic ulcer, laser resurfaced tissue, improvement in stretch marks, vaginal dryness, painful intercourse, urinary incontinence, fecal incontinence, skin fungal infection, skin bacterial infection, genital fungal infection, genital bacterial infection, penile dysfunction, burns, pain, swelling, skin inflammation, arthritis, sinusitis, skin irritation, hemorrhoidal irritation, vaginal irritation, Raynauds’ syndrome, multi resistant staphylococcus aureus infection (MRSA) or skin itching.
  • MRSA multi resistant staphylococcus aureus infection
  • the disease or disorder is aging skin, acne, a scar, or wound care.
  • aging skin is characterized by wrinkles;, enlarged pore size; poor skin tone; poor skin texture; pigment variation (i.e. red or brown spots); increased oiliness; and/or vasculature such as telangiectasia or rosacea related erythema.
  • treating aging skin is determined by improvement in fine lines; wrinkles; pore size; skin tone and texture; coloration and oiliness.
  • acne was characterized as mild, moderate or severe based on the number of nodules and pustules.
  • treating acne is determined by pustule and/or nodule reduction.
  • scars are atrophic scars, striae, acne scars, hypertrophic scars and excised keloid scar beds.
  • treating a scar is determining by a reduction on the visibility of striae; softening of hypertrophic scars; reduction in scar volume; and improved vascularity.
  • wounds are surgical incision scars, surgical local and regional flaps.
  • wounds are non-healing wounds such as diabetic ulcers, burn wounds, and smoking-induced vascular-compromised wounds.
  • treating wound care is determined by reduction in bruising; reduction in edema; re-epithlialisation, healing of wounds and increased or improved vascularity.
  • skin conditions includes, but is not limited to, rosacea, acne, dermatitis, and fungal infections.
  • microvascular disease is meant to refer to diseases such as scleroderma.
  • the invention provides a method of treating a disease, a disorder or a condition in a subject by providing a system for topical administration of a nitric oxide (NO) composition and topically administering the NO composition to the subject in need thereof.
  • NO nitric oxide
  • the present invention provides a non-toxic method of producing a nitric oxide (NO) composition for topical administration including mixing equivalent volumes of sodium nitrite in a viscous hydrogel medium and electron donor and/or an oxygen independent nitrite reductase in a viscous hydrogel medium, wherein mixing the equivalent volumes generates NO and does not generate nitrogen dioxide (NO2).
  • NO nitric oxide
  • non-toxic it is meant that the method used to generate NO doesn’t generate NO2.
  • the invention provides a method of increasing vascularity for improved ancillary absorption in a subject by providing a system for topical administration of a nitric oxide (NO) composition and topically administering the NO composition to the subject in need thereof.
  • NO nitric oxide
  • vascularity generally refers to the number, the ramification, and/or the prominence of superficial veins or capillaries.
  • ‘increasing vascularity’ means enhancing or improving superficial vein or capillary number, ramification and/or prominence in order to increase ancillary absorption of a compound applied to the skin. It also includes reducing or limiting the distance between said superficial vein or capillary and the skin surface.
  • the invention provides a use of a nitric oxide (NO) composition for cosmetic application including providing a system for topical administration of a nitric oxide (NO) composition and topically administering the NO composition to a subject in need thereof.
  • the cosmetic application is neocollagenesis, neoellastogenesis, skin tone, skin quality re-epithelialization, skin healing time, skin moisturization, skin exfoliation, saucerized acne scarring, skin vascularization lip plumping, time of lipstick application and/or skin cleansing improvement; acne symptoms, stretch mark appearance, skin pigmentation issues, skin irritation, skin itching, and/or skin inflammation reduction; or hair loss management.
  • the NO composition of the present invention generally improves fibroblast function, which subsequently increases neocollagenesis, neoellastogenesis. Improving fibroblast function has numerous applications associated with skin tone, skin quality and skin healing.
  • hair loss management refers to both the increase of hair follicle diameter, and the reduction of hair shedding.
  • the invention provides a method for improving stromal vascular fraction homing, delivery and/or efficacy in a subject in need thereof by administering to said subject a nitric oxide (NO) composition in combination with a stromal vascular fraction, wherein the stromal vascular fraction comprises mesenchymal stem cells.
  • NO nitric oxide
  • stromal vascular fraction refers to a fraction of an adipose tissue which contains cells including pre-adipocytes, fibroblasts, vascular endothelial cells, mesenchymal stem cells and a variety of immune cells such as adipose tissue macrophages.
  • MSCs Mesenchymal stem cells
  • MSCs are spindle-shaped plastic adherent cells that can be isolated from many tissues including bone marrow and adipose tissue. MSCs have multipotent differentiation capacity in vitro and can be treated to generate differentiated cells such as osteoblasts, adipocytes and chondrocytes in vitro, but do not have the capacity to reconstitute an entire organ.
  • the administration of the stromal vascular fraction is topical or by injection.
  • the invention provides a method for improving exosome homing, delivery and/or efficacy in a subject in need thereof by administering to said subject a nitric oxide (NO) composition in combination with an exosome composition.
  • a nitric oxide (NO) composition in combination with an exosome composition.
  • exosome refers to extracellular vesicles that are produced in the endosomal compartment of eukaryotic cells. Exosomes are a family of small nanoparticles having a diameter comprised between 30 and 100 nm. Exosomes are generated inside multivesicular endosomes or multivesicular bodies (MVBs) and are secreted when these compartments fuse with plasma membrane. Exosome secretion is a general cellular function that plays an important role in the intercellular transfer of information, as such exosomes exert their function through paracrine effects.
  • Exosomes can be found in tissues and can also be found in biological fluids including blood, urine, and cerebrospinal fluid; and are released in vitro by cultured cells into the culture- conditioned medium. These secreted vesicles serve as cell-to-cell messengers that modify cellular function in normal state as well as in disease state. The most interesting feature of is that they can be isolated from cultured cells and be subcutaneously administered, making exosomes an exciting therapeutic delivery system.
  • the invention provides a method of enhancing the efficacy of a delivery particle in a subject in need thereof by administering to said subject a nitric oxide (NO) composition in combination with or in conjunction with a delivery particle composition.
  • a nitric oxide (NO) composition in combination with or in conjunction with a delivery particle composition.
  • the delivery particle is a nanoparticle of gold.
  • the invention provides a method of dilating a vein in a subject in need of a venipuncture by topically administering to said subject a nitric oxide (NO) composition.
  • NO nitric oxide
  • venipuncture refers to the process of obtaining intravenous access for the purpose of intravenous therapy or for blood sampling of venous blood.
  • the process of venipuncture can be complicated; the use of the NO composition of the present invention helps dilating the veins, which allows easier access to the veins either for injection or blood withdraw. This also apply to subject that are sensitive or afraid of needles, such as kids.
  • the NO composition induces an erythema visible for about 2-5 minutes.
  • the NO composition also contains one or more agents which might be lidocaine, bupivacaine, tetracaine or a combination thereof.
  • the NO composition might include one or more additional agents. Combined with numbing or local anesthetic agents, NO dilates veins, which make them more visible and more accessible, and reduces the pain associated with the needle.
  • local anesthetic agent include, but are not limited to, lidocaine, bupivacaine, tetracaine, and a combination thereof.
  • the invention provides a method of dilating a vein in a subject including providing a system for topical administration of a nitric oxide (NO) composition and topically administering the NO composition to the subject in need thereof.
  • NO nitric oxide
  • Presented below are examples discussing the non-toxic generation of a NO composition contemplated for the discussed applications. The following examples are provided to further illustrate the embodiments of the present invention, but are not intended to limit the scope of the invention. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.
  • a viscous hydrogel medium such as water, polysorbate 20, hydroxyethylcellulose, d-tocopheryl acetate, dehydroacetic acid, benzyl alcohol, sodium sulfite, sodium metabisulfite, tetrasodium EDTA, glycol, glycerol, and the like, generating a first composition having a pH of about 6.5-8.0.
  • a 5-25% solution of ascorbic acid (or any other electron donor and/or oxygen independent nitrite reductase derived from natural products) is added to a viscous hydrogel medium (as described above), generating a second composition having a pH of about 2.5-3.5.
  • a specific volume of about 100-500uL of each composition is dispensed.
  • the mixture When mixed together and applied onto the skin, the mixture generates about 5-30ppm of nitric oxide gas on the surface of the skin without the generation of nitrogen dioxide.
  • the resulting pH of the combined mixture is about 5-6.
  • the NO gas diffuses in three dimensions with some being diffused into the space above the skin where it can be detected and quantified. Part of the NO gas diffuses into the dermal layers of the skin to dilate blood vessels and recruits capillaries thereby increasing local blood flow only to the area upon which it is applied to.
  • NO compositions such as a NO serum is applied topically to the skin and has the ability to increase vascularity for increased absorption of ancillary ingredients.
  • the NO serum by itself, via improving vascularity, improves fibroblast function, and subsequently increases neocollagenesis and neoellastogenesis thereby improving skin tone and quality.
  • the serum is applied on the face, neck, declotette, abdomen, back, arms and/or legs as separate area indications.
  • an increased vascularity improves the absorption and activity of active compounds, such as CBD oil, witch hazel and aloe (for hemorrhoidal and vaginal irritation relieve for instance), HA (to reduce Raynauds syndrome symptoms), triamcinolone acetonide (at a 0.147 mg/gm dosage in nasal spray to improve symptoms of sinusitis).
  • active compounds such as CBD oil, witch hazel and aloe (for hemorrhoidal and vaginal irritation relieve for instance), HA (to reduce Raynauds syndrome symptoms), triamcinolone acetonide (at a 0.147 mg/gm dosage in nasal spray to improve symptoms of sinusitis).
  • NO is useful in vaginal health, reduce vaginal dryness, painful intercourse, as well as for the treatment of urinary and fecal incontinence.
  • NO composition or serum in conjunction with topical or injectable stromal vascular fraction containing mesenchymal stem cells can improve homing, delivery, and facilitate efficacy; in conjunction with exosomes, NO serum can improve homing, delivery and facilitate delivery; and when combined with or in conjunction with the application of nanoparticles of gold or other delivery substances, NO serum can enhance the efficacy of said particles.
  • nitric oxide When applied at relatively high concentration, nitric oxide has anti-microbial properties; topical application of a NO composition is thus used to treat microbial infection, alone or in combination with other active compounds.
  • NO has proven anti -bacterial capability though the effective killing of bacteria without the need for nitrogen dioxide which is also antimicrobial.
  • the NO composition is for example applied with 0.147 mg/gm triamcinolone acetonide in a nasal spray to improve the symptoms of sinusitis.
  • NO can also be combined with other topical antibacterial agents such as apple stem cells, salicylic acid powder, pumpkin oil, silver nitrate, mandelic acid, sodium nitrate, cucumber astringent and peach extract.
  • topical antibacterial agents such as apple stem cells, salicylic acid powder, pumpkin oil, silver nitrate, mandelic acid, sodium nitrate, cucumber astringent and peach extract.
  • NO has proven anti-fungal capability, though the effective killing of fungi, mold spores without the need for nitrogen dioxide which is also antimicrobial.
  • the NO composition can also be complemented by any additional known anti-fungal agent, and thus be useful to treat fungal infection.
  • NO has proven anti -viral capability, though the effective killing of viruses without the need for nitrogen dioxide which is also antimicrobial. Specifically, NO has proven reduced viral shedding capability.
  • NO When topically applied, NO increases blood flow and circulation and is thus used for multiple cosmetic applications, when applied to the face, neck, chest abdomen, hands, back or legs.
  • NO is used to improve skin health. For instance, NO reduces the appearance of stretch marks (striae); improves vascularization, skin tone and skin quality, especially smoker’s skin tone and quality.
  • glycolic acid NO improves skin exfoliation and can be used in skin cleansers.
  • NO is also used in combination with bleaching agents for topical application.
  • the NO composition is combined with hydroquinone 2%, 4%, or 8 %; kojic acid 1-4% (malted rice by-product); alpha-arbutin 1%, isolated from bearberry leaf; Canadian rumex plant, which is lOx more stable and decreases erythema; licorice extract, which contains glabridinin known for its anti-inflammatory properties when applied at 0.5%; glycolic acid; retinA; ascorbyl palmitate, extracted from lemon/orange peel; indian gooseberry from the emblica plant, ginga white, from peppermint, mallow, cowslip; azaelic acid, from pityrosporum ovale, which has cytotoxic properties and thus has great applications for acne; beta-arbutin 1%, from uva ursi; paper mulberry 1%; nicotinamide, which has anti-inflammatory properties; aloe, which contains aleosin; tea tree oil
  • the NO composition (or serum) by itself via improving vascularity improves fibroblast function, and subsequently increases neocollagenesis and neoellastogenesis thereby improving skin tone and quality. This can be applied on the face, neck, declotette, abdomen, back, arms and legs as separate area indications.
  • NO serum By having both anti-bacterial and anti-inflammatory properties, NO serum also has proven benefit in improving active acne symptoms and reducing mild to moderate saucerized acne scarring.
  • NO When topically applied, NO has proven anti-inflammatory capabilities, which allows its use for multiple applications.
  • COX2 inhibitors such as Celebrex and Viox
  • nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (ASA), Ibuprofen and Naproxen
  • Naturally derived anti-inflammatory agents include turmeric, which has curcumin, a COX2 inhibitor at 400-600-mg; ginger, which has zingabain, a COX2 inhibitor that blocks arachidonic acid release; kelp, i.e.
  • kombu, wakeme, or arame which contain fucidin a promoter of collagen synthesis; brown algae extract, which promotes collagen synthesis; moui, a tongan fucidin powerhouse; salmon oil, which contains powerful omega-3, alpha linoleic acid; green tea, containing flavonoids; papaya, which contains papain useful for protein digesting, vitamin C and E; pineapple, whose bromelain has strong NSAID activity; blueberry, which is an anti-oxidant powerhouse; sweet potato, containing beta-carotene, vitamin B6 and C; spinach, containing flavonoids, carotenoids, vitamin A, B2, B6, C, E, K, Ca, folate, and iron; rosemary, which contains tryptophan, Mg, and K; willow bark and tea tree oil, which contain potent natural salicylic acid; and cayenne pepper, which is a strong COX2 inhibitor.
  • NO decreases time to re-epithelialization, thereby shortens healing time.
  • a NO composition, prepared as disclosed in Example 1 was applied onto the skin, at the antecubital fossa location, to dilate the superficial antecubital vein of a patient, in preparation for venipuncture.
  • the Active acne patients were divided into mild, moderate and severe states based on nodule and pustule counts.
  • NO serum was applied am and pm after cleansing. Photographs were taken weekly for 4-12 weeks. Pustule and nodule counts were recorded weekly. NO serum was applied bid in the treatment of atrophic scars, striae, acne scars, hypertrophic scars post Needle Radiofrequency, and around the C02 laser excised keloid scar beds. Photographs were taken weekly for 4-12 weeks. Several wound types were examined: Surgical incisions, healing surgical flaps, diabetic ulcers, and smoking induced, vascular compromised skin. NO serum was applied qid daily. Photographs were taken at 4, 8, and 12 weeks.
  • Nitric oxide is an important biological messenger in human physiology. This multifunctional signaling molecule takes part in the control of vasodilation, and is involved in the inhibition of platelet aggregation and platelet adhesion to vascular endothelium.
  • NO is involved in the proliferation and differentiation of epidermal cells, regulation of innate immune reactions and inflammatory responses, the control of allergic skin manifestations, microbicidal activity, and antigen presentation.
  • NO is also a key molecule in wound healing regulation and tissue regeneration due to its gene regulatory properties, as well as its influence on the proliferation and differentiation of fibroblasts, keratinocytes, monocytes and macrophages.
  • NO is a short-lived free radical produced enzymatically by nitric oxide synthase (NOS) endogenously.
  • NOS converts the amino acid precursor L-arginine to NO and L-citrulline with the help of several co-factors such as tetrahydrobiopterin, flavine mononucleotide (FMN), flavine adenine dinucleotide (FAD), nicotinamide-adenine-dinucleotide phosphate (NADHP) and an oxygen molecule.
  • FMN flavine mononucleotide
  • FAD flavine adenine dinucleotide
  • NADHP nicotinamide-adenine-dinucleotide phosphate
  • Nitric oxide is synthesized and released by many skin cells including fibroblasts, keratinocytes, melanocytes, endothelial cells, macrophages, neutrophils, and adipocytes.
  • NO is a hydrophobic molecule with a stoke radius of 3-4A that can diffuse across most biological membranes.
  • Neo40 humanN, Austin TX
  • Study Population The effect of a Nitric Oxide generating topical serum was studied on 100 patients in two Centers between December 2018 and December 2019. There were 82 females and 18 males. The population consisted of 42 Caucasian, 18 Asian, 8 African American, 12 Hispanic, 14 Mediterranean, and 6 Indian patients.
  • Exclusion criteria in this study included an unwillingness to avoid excessive sunlight or wear protective clothing and sunscreen, unwillingness to forgo any other topical dermatological or drug therapy, the use of topical corticosteroid, alpha and beta-hydroxyacids, retinoids, or vitamin C containing topicals within 30 days before, as well as throughout the course of the study. Washout periods adhered to by subjects in this study included 6 months free from dermabrasion, deep chemical peels, ablative laser treatments, neurotoxin or filler injections: 3 months free from non-ablative laser, light, radiofrequency or ultrasound treatments; and 1 month free from microdermabrasion, light and medium depth peels.
  • the Aging Skin population used the NO serum morning and evening after cleaning their skin with a gentle cleanser. Photographs were taken at 4- week intervals for 12 weeks. Patient linear analog scales were administered. Tissue attributes examined included wrinkles, pores, skin clarity, quality, and pigmentation.
  • the Active Acne population was divided into mild, moderate and severe based upon nodule and pustule counts.
  • the NO serum was applied morning and evening after cleaning their skin with a gentle cleanser. Photographs were taken weekly for 30 days. Pustule and nodule counts were recorded weekly. Linear analog scales were administered.
  • the Scar Therapy population consisted of atrophic scars, striae, acne scars, hypertrophic scars and excised keloid scar beds. The NO serum was applied twice daily for 12 weeks. Photos were taken at 4 week intervals. Linear analog scales were administered to both patients and physicians to examine scar quality improvement.
  • the Aging Skin population results were consistently favorable and increasingly positive with greater duration of use. Sixty percent of subjects noticed a decrease in visible wrinkles at 4 weeks, 68% by 8 weeks, and 84% by 12 weeks. Decreased pore size was reported by 45% of patients at 4 weeks, 55% of patients at 8 weeks, and 68% of patients at 12 weeks. An increase in skin tone was perceived by 72% of patients at 4 weeks, 80% by 8 weeks, and 83 % by 12 weeks. Textural improvement was reported by 68% of patients at 4 weeks, 83% at 8 weeks, and 88% at 12 weeks. Unwanted pigment variation was improved in 55% of patients at 4 weeks, 65% by 8 weeks, and by 78% of patients at 12 weeks.
  • a decrease in skin oiliness was perceived by 72% of subjects at 4 weeks, 80% by 8 weeks, and 85% by 12 weeks.
  • Unwanted vasculature such as telangiectasia or rosacea-related erythema was improved in 20% of patients at 4 weeks, 38% by 8 weeks, and 53% by 12 weeks.
  • the Active Acne population showed very promising results for utilizing nitric oxide topically.
  • Rhytidectomy, blepharoplasty, and rhinoplasty patients displayed less bruising, edema, and faster re-epithelialization on the treated side when compared to the contralateral untreated control side.
  • Previously non-healing diabetic ulcers and pressure ulcers healed within 30-45 days.
  • Compromised local and regional flaps showed improved vascularization and viability within 30 days.
  • the Scar Therapy population showed positive trends, worthy of further investigation.
  • Atrophic scars and striae, particularly abdominal and breast showed the most improvement with 37% describing less visibility of striae at 4 weeks, 49% at 8 weeks, and 72% by 12 weeks.
  • Softening of hypertrophic scars was noted at 4 weeks, with some scar volume reduction noted by 12 weeks. Improved vascularity in these latter scars is postulated.
  • Nitric oxide generating serum showed a positive effect in the acne population.
  • the anti-inflammatory and ant-bacterial benefits of NO have been described. As it relates to inflammatory conditions, acne vulgaris and subsequent sequalae, lead in conditions having a negative impact on a patients’ self- esteem.
  • Acne vulgaris is a chronic inflammatory disease that affects 40-50 million Americans per year, and hundreds of millions of patients worldwide per year. Acne patients present an excellent model for studying scar pathophysiology. The complex interactions of infection, inflammation, tissue injury, wound healing and the propensity for scar formation allow scientists a unique opportunity to investigate alternate forms of therapy.
  • Acne is characterized by comedones, pustules, and papules. Left untreated, saucerized and pitted scars can form.
  • the pathogenesis of acne is multifactorial.

Abstract

La présente invention concerne un procédé non toxique pour la génération de compositions d'oxyde nitrique (NO), et des procédés d'utilisation de telles compositions de NO. Les utilisations des compositions de NO comprennent le traitement de maladies, de troubles et d'états, ainsi que des utilisations cosmétiques, antimicrobiennes et anti-inflammatoires.
PCT/US2020/031611 2019-05-06 2020-05-06 Compositions d'oxyde nitrique et leurs utilisations topiques WO2020227367A1 (fr)

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