Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
• • 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
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/18—Antioxidants, e.g. antiradicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • 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
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/52—Stabilizers
  • A61K2800/522—Antioxidants; Radical scavengers

Definitions

• Aging is an inevitable biological process generally characterized by decline in physiological function that leads to morbidity and mortality.
• the aging process occurres gradually over a person's lifetime.
• the decline in physiological function is exemplified as a general decrease in physical and mental ability.
• Aging involves death of cells or cell dysfunction due to production of free radicals, oxidative damage and energy depletion due to mitochondrial dysfunction. Harman (1988) linked senescence or death to the injurious effects of free radicals arising from the one-electron reduction of oxygen during metabolism. There has been an inverse relationship between auto-oxidation rate in different animal species and life expectancy in the same species (Cutler 1985; Sohal 1995). Mitochondria are the major source of oxygen radicals through the respiratory chain and are also deeply affected by reactive oxygen species (ROS), resulting in serious risks to their function. Mitochondrial dysfunction could result in defects in electron transport, oxidative phosphorylation and energy production resulting in cell damage and ultimately cell death.
• ROS reactive oxygen species
• Oxidative damage to the brain mitochondrial DNA has been linked to increased incidence of neurodegenerative diseases with aging. Oxidative damage to muscular mitochondria has been linked to increased lethargy. Toxicity by oxygen radicals has also been suggested as a major cause of cancer, heart disease and aging in general.
• an anti-oxidant or a free-radical quenching agent is the ability to chemically react with the oxidant or free-radical, in a biologically nondestructive manner.
• oxidant or free-radicals include superoxide (O 2 ), H 2 O 2 , hydroxyl radicals (OH) and singlet oxygen i ( O 2 ).
• superoxide O 2
• H 2 O 2 H 2 O 2
• OH hydroxyl radicals
• O 2 singlet oxygen i
• One aspect of this invention is directed to a method and composition for quenching free-radicals and oxidants in intracellular fluids.
• a still further aspect of the present invention is directed to a method and composition for the delivery of cosmeceuticals.
• a further aspect of the present invention is a micro-cluster liquid having anti- oxidant and free-radical quenching properties.
• micro-cluster liquid such as micro-cluster water
• the micro-cluster liquid, such as micro-cluster water, of the present invention further provides at least one property selected from the group comprising, increased potential energy, enhanced bioavailability, transdermal migration and transdermal facilitator.
• transdermal migration shall mean having the ability to migrate through or across the dermis.
• transdermal facilitator shall mean the property of facilitating the transdermal passage of another substance across the dermal membrane often coincident with its own migration.
• cosmaceutical shall mean a cosmetic formulation which includes at least one nutritional and/or pharmaceutical agent.
• a cosmaceutical may, for example, incorporate titanium dioxide (as the physical sunblock) and creatine pyruvate (as the cellular repair pharmaceutical) in a micro-cluster water vehicle.
• This composition may further include permeation enhancers to further facilitate delivery of the pharmaceutical deep into the dermis.
• the anti-oxidant and anti-free radical properties of the present micro-cluster water further provide the un-expected result of increased cell-longevity, decreased DNA mutation rates, increased mitochondria cell membrane longevity and increased cellular membrane longevity, in general.
• Figure 1 is a bar graph comparing the uptake of creatine into cells and mitochondria.
• Figure 2 is a graph depicting thegel and bar graphs of creatine and normal cells response to UVA-induced mtDNA mutagenesis.
• Figure 3 is a graphic of the chronic oxidative stress cycle.
• Figure 4 is a graphic of the defective powerhouse model of cutaneous aging.
• Figure 5 is a graph comparing the number of mutations between cells grown in media made with micro-cluster water (Penta) or lab water (a.d.).
• Figure 6 is a set of bar graphs comparing the number of common deletion mutations between cells grown media made with micro-cluster water (Penta) or lab water (a.d.).
• Figure 7 is a set of bar graphs comparing the number of common deletion mutations between cells grown media made with micro-cluster water (Penta) or lab water (a.d.).
• Figures 8a and 8b are graphs showing the differences between double distilled water (“DDW”) and micro-cluster water (Micro-cluster) regarding changes to intracellular pH under standard incubation conditions.
• Figure 9 is a bar graph representation of the intracellular pH change in macrophages under standard incubation conditions.
• Figure 10 is a bar graph of the differences in propensity for damage to cellular membranes under standard incubation conditions, where the incubation medium was made from DDW or Micro-cluster water.
• Figure 11 is a bar graph comparing the occurrence of common deletion mutations in mtDNA between UV exposed skin and un-exposed skin.
• the methods of the present invention generally comprise administering to a subject an amount of a micro-cluster fluid, topically, orally, transdermally or other routes of administration known in the art. It is thought that the micro-cluster liquids modulate one or more of the ROS and/or free radicals responsible for oxidative tissue damage associated with pre-mature aging.
• the present invention further generally comprises incorporating neutriceutical and pharmaceutical agents in the micro-cluster fluid, together with a transdermal enhancer.
• the micro-cluster liquids in association with creatine compounds modulate one or more of the structural or functional components of mtDNA mutagenesis and/or the creatine kinase/phosphocreatine system sufficient to prevent, reduce or ameliorate symptoms of aging and damage to the skin.
• Components of the systems which can be modulated include the rate of mtDNA mutation, intracellular pH, intercellular pH, ROS concentration, cell longevity, the enzyme creatine kinase, the substrates creatine and creatine phosphate, and the transporter of creatine.
• modulate includes any increase or decrease in the activity of any component of the creatine kinase/phosphocreatine system.
• a mammal e.g., a mammal, preferably, a human
• a cosmaceutical comprising a creatine compound in a micro-cluster liquid such that the skin damage is treated.
• Creatine compounds are predicted to preserve tissue by boosting up energy reserves in the skin and also by arresting mechanisms involved in oxidative damage and cell death.
• the micro-cluster liquids are predicted to independently preserve tissue by arresting deleterious oxidative mechanisms involved in oxidative damage and cell death.
• the combination of creatine compounds and micro-cluster liquids provides a synergistic composition predicted to preserve tissue by boosting up energy reserves in the skin, by arresting deleterious oxidative mechanisms involved in oxidative damage and cell death and by enhanced transdermal penetration and migration of active agents.
• micro-cluster liquids include micro-cluster water, chelated minerals, chelated vitamins, creatine, creatine phosphate, taurine, osmolytes, ectoin and analogs thereof, which are described in detail below.
• creatine compounds includes creatine, creatine phosphate, and compounds, which are structurally similar to creatine or creatine phosphate, and analogs of creatine and creatine phosphate, including salts thereof such as creatine pyruvate.
• the term “creatine compounds” also includes compounds, which "mimic” the activity of creatine, creatine phosphate or creatine analogs.
• the term “mimics” is intended to include compounds, which may not be structurally similar to creatine but mimic the therapeutic activity of creatine, creatine phosphate or structurally similar compounds.
• creatine compound includes "modulators of the creatine kinase system,” for example, compounds which modulate the activity of the enzyme, or the activity of the transporter of creatine or the ability of other proteins or enzymes or lipids to interact with the system.
• treatment includes the diminishment or alleviation of at least one symptom associated or caused by the disorder being treated.
• treatment can be diminishment of several symptoms of a disorder or complete eradication of a disorder.
• the language "treating for skin disorders” includes both prevention of disorders, amelioration and/or arrest of the disorder process.
• skin disorders include, but are not limited to aging and damage resulting from sun radiation, stress, fatigue and/or free radicals.
• the micro-cluster liquids in association with creatine compounds described herein are thought to have both curative and prophylactic effects on development of damage and aging of the skin and other tissue.
• the language also includes any amelioration or arrest of any symptoms associated with the disorder process (e.g., wrinkles).
• treating wrinkles may include preventing, retarding, arresting, or reversing the process of wrinkle formation in skin, e.g., mammalian skin, preferably, human skin.
• This invention is directed to reducing free-radical and oxidative damage secondary to free-radicals and other oxidants contacting cells, cellular components or tissues.
• the micro-cluster water of the present invention has free-radical and oxidant quenching properties. Contacting cells, cellular components or tissues with the present micro-cluster water results in increased cellular longevity, decreased rates of DNA mutation, improved mitochondrial efficiency, decreased mitochondrial DNA mutation, increased collagen and fibroblast growth, amelioration of wrinkles and other skin damage; and thus anti-aging.
• Administration of the compositions of the present invention is accomplished by several methods, including ingestion topical application such as by a cosmetic product, or any other method whereby the tissue or system in need of treatment is sufficiently contacted.
• active agents therapeutic or cosmetics agents
• Conventional means for administering therapeutic or cosmetics agents to a human or animal are usually limited to some degree by biological, chemical, and physical barriers.
• physical barriers are the skin and various organ membranes that must be traversed before the agent reaches a target.
• Chemical barriers include pH variations, lipid bi-layers, and degrading enzymes. Both biologically and chemically active agents are particularly vulnerable to such barriers.
• Many active agents can be applied topically and this provides a convenient mode of administration, particularly for cosmetics agents that are typically applied to an area of the skin that is affected by a skin condition.
• the effectiveness of topical application of an active agent depends on two major factors: a) percutaneous absorption and penetration; and b) bioavailability of the penetrated active agent to the target site in the skin.
• the agents For active agents to be effectively applied topically, the agents need to penetrate the stratum corneum (the outer layer of the skin that includes layers of terminally differentiated keratinocytes) into the epidermal layers, and then be distributed and bioavailable to the target sites to provide an effect.
• This transdermal migration of active agents shall be termed transdermal administration.
• Many cosmetics agents require routine application over an extended time, and for this reason topical application is advantageous because the administration regime is relatively simple and can be achieved with a minimum of inconvenience.
• topical application is advantageous because the administration regime is relatively simple and can be achieved with a minimum of inconvenience.
• to maximize the effectiveness of the treatment as much of the cosmetic agent as possible needs to be absorbed into the skin and when the agent is applied topically by applying a cream or lotion to the skin it is common for least some of the active agent to be lost by rubbing off or evaporation.
• a cosmetic agent may preferably be selected from one or more of: anti-aging agents, anti-wrinkle agents, antioxidants, anti-scarring agents, phytoestrogens, isoflavones, coumarines, lip balms, free radical quenching agents, and antiseptic anti-acne agents.
• the term "cosmetic agent” means any compound, mixture of compounds, or preparations derived theirfrom that are intended to be placed in contact with external parts or with mucosal membranes of an animal body. (Especially a human body) with a view to cleaning, changing the appearance, protecting and/or keeping the body parts to which the agent is applied in good condition.
• the cosmetics agent is capable of diminishing, reducing or preventing the effects of one or more skin conditions including: the visible effects of aging, wrinkles, acne, age spots, scars (keloids) broken capillaries and, includes compositions which also optionally cleanse the skin, preferably in the form of liquid compositions such as liquid soaps, lotions and solutions both additives and compositions for application to skin, hair, scalp, nails, eyes or teeth.
• one or more skin conditions including: the visible effects of aging, wrinkles, acne, age spots, scars (keloids) broken capillaries and, includes compositions which also optionally cleanse the skin, preferably in the form of liquid compositions such as liquid soaps, lotions and solutions both additives and compositions for application to skin, hair, scalp, nails, eyes or teeth.
• the term "cosmaceutical” means a cosmetic agent according to the present invention, which is adapted to facilitate delivery of neutriceutical compositions comprising vitamins, minerals and osmolytes.
• the term “minerals” as used herein means the inorganic compounds normally part of the class, as known in the art. Examples of metabolically important minerals are well documented in numerous health, wellness and medical texts including for example, Sb, As, B, Br, Yb, Pd, Re, F, Ir, La, W, Cs, C, Pt, Tm, N, Ni, Ta, Tb, Fe, K, I, Co, Mo, V, Ag, Mg, Cr, Cu, Zn, Ca, Si, Sn, Ni, P and S.
• a chelating matrix delivery system is preferably used to facilitate transdermal delivery of these minerals, as part of the present compositions.
• Such a chelating matrix delivery system is described in patent 6,716,458 to Tarbet, filed August 7, 2000, which is incorporated herein by reference. The incorporation of these minerals in a chelating matrix,
• osmolyte means organic solutes accumulated by cells/tissues in response to osmotic stress.
• osmolytes increase thermodynamic stability of folded proteins and provide protection against denaturing stresses.
• examples of osmolytes includes, but is not limited to, creatines, taurins, ectoins, their derivatives and corresponding biologically compatible salts.
• Another form of the present invention provides a method of enhancing penetration of the cosmetic and/or neutriceutic agent through the skin, the method including the steps of applying to the skin a composition containing: at least one cosmetic or neutriceutic agent, and a dermal penetration enhancer.
• the topical application of this composition results in the delivery of the active agents into the stratum comeum as well as delivery of the active agents into the epidermis and dermis.
• the present micro-cluster water has increased potential energy as compared with double distilled water. Perhaps because of this increased energy, the micro-cluster water of the present invention is able to quench free-radicals and function as an anti-oxidant.
• micro-clustered composition refers to a composition which comprises micro-cluster water.
• micro-clustered which modifies any of the compositions of bio-affecting agents, body-treating agents, adjuvant or carriers, or ingredients thereof refers to micro-clustered water in that composition, i.e. which is dissolved in, mixed with, or otherwise combined with micro-cluster water.
• a micro-cluster liquid is any liquid, mixture or combination of liquids, whether or not miscible, which have been processed according to the device described and claimed in U.S. Patent 6,521,248, which is incorporated herein by reference.
• water is a major constituent in most biological processes, as well as the fluid medium through which proteins and nucleic acids interact. Apart from being known as the main medium for biological reactions, water also plays a role in , determining and stabilizing hydrophilic and lipophyllic structures. Due to water's unique capabilities, it is able to influence the efficacy of various processes. However, many aspects related to the biological function of water remain unclear. There are facts, which indicate that the biological activity of water is due to a change in physical/chemical parameters. One of the important aspects in gaining an understanding of the mechanism controlling water's biological activity is to study it at the cell level.
• the creatine kinase/creatine phosphate energy system is only one component of an elaborate energy-generating system found in tissue with high and fluctuating energy requirements.
• the components of the creatine energy system include the enzyme creatine kinase, the substrates creatine and creatine phosphate, and the transporter of creatine.
• Some of the functions associated with this system include efficient regeneration of energy in cells with fluctuating and high energy demands, energy transport to different parts of the cell, phosphoryl transfer activity, ion transport regulation, and involvement in signal transduction pathways.
• the present invention relates to methods for protecting skin tissue against age related damage or insults such as harmful UV radiation, stress and fatigue by preserving energy pools and protecting against free radical production and oxidative stress. This is achieved by administering an amount of a creatine compound or compounds together with a micro-cluster fluid, which modulates one or more of the biological pathways involved in energy and aging sufficient to prevent, reduce or ameliorate skin damage or skin aging.
• Compounds which are effective for this purpose include, micro-cluster liquids, such as micro-cluster water, osmolytes such as taurine and ectoin and the natural compound creatine in its different hydration or salt and analogs of and combinations thereof.
• the compounds can be mixed in with creams, oils, emulsions and the like to be spread readily on skin surfaces. Alternatively, the compounds also can be packaged in a supplement form for ingestion.
• the present invention also provides micro-cluster liquid based compositions containing creatine compounds in combination with a pharmaceutically or cosmetically acceptable carrier, and effective amounts of other agents which act on tissue preservation such as antioxidants (e.g., CoQlO), vitamins such as C, B 5 , B 6 , Bg, E, energy enhancing agents (for example creatine, chelated minerals, pyruvate, nicotinamide) osmolytes and skin softeners to slow the process of aging.
• antioxidants e.g., CoQlO
• vitamins e.g., CoQlO
• vitamins e.g., CoQlO
• vitamins e.g., CoQlO
• vitamins e.g., CoQlO
• vitamins e.g., CoQlO
• vitamins e.g., CoQlO
• vitamins e.g., CoQlO
• vitamins e.g., CoQlO
• C e.g., CoQl
• modulate includes any increase or decrease in the activity of any component of an affected biological pathway or system.
• Micro-cluster liquids in combination with creatine compounds are predicted to preserve tissue by boosting up energy reserves in the skin and also by arresting mechanisms involved in oxidative damage and cell death.
• Compounds which are particularly effective for this purpose include micro-cluster water in combination with creatine, creatine phosphate, and analogs thereof which are described in detail below.
• the term "creatine compounds” includes creatine, creatine phosphate, and compounds which are structurally similar to creatine or creatine phosphate, and analogs of creatine and creatine phosphate.
• the term “creatine compounds” also includes compounds, which "mimic" the activity of creatine, creatine phosphate or creatine analogs.
• mics is intended to include compounds, which may not be structurally similar to creatine but mimic the therapeutic activity of creatine, creatine phosphate or structurally similar compounds.
• creatine compound includes "modulators of the creatine kinase system,” for example, compounds which modulate the activity of the enzyme, or the activity of the transporter of creatine or the ability of other proteins or enzymes or lipids to interact with the system.
• treatment includes the diminishment or alleviation of at least one symptom associated or caused by the disorder being treated.
• treatment can be diminishment of several symptoms of a disorder or complete eradication of a disorder.
• the language "treating for skin disorders” includes both prevention of disorders, amelioration and/or arrest of the disorder process.
• skin disorders include, but are not limited to aging and damage resulting from sun radiation, stress, fatigue and/or free radicals.
• the micro-cluster liquids in association with creatine compounds described herein are thought to have both curative and prophylactic effects on development of damage and aging of the skin and other tissue.
• the language also includes any amelioration or arrest of any symptoms associated with the disorder process (e.g., wrinkles).
• treating wrinkles may include preventing, retarding, arresting, or reversing the process of wrinkle formation in skin.
• topical administration includes methods of delivery such as laying on or spreading on the skin. It involves any form of administration, which involves the skin.
• compositions suitable for topical administration include but are not limited to, ointments, lotions, creams, cosmetic formulations, and skin cleansing formulations. Additional examples include aerosols, solids (such as bar soaps) and gels.
• pharmaceutically acceptable includes drugs, medicaments or inert ingredients which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically or cosmetically effective amount is intended to include the amount of the compound sufficient to prevent onset of aging or damage to the skin or significantly reduce progression of damage in the subject being treated.
• a therapeutically or cosmetically effective amount can be determined on an individual basis and will be based, at least in part, on consideration of the severity of the symptoms to be treated and the activity of the specific analog selected if an analog is being used.
• the effective amounts of the compound may vary according to the age of the subject being treated.
• a therapeutically or cosmetically effective amount of the compound can be determined by one of ordinary skill in the art employing such factors as described above using no more than routine experimentation in health care management.
• the topical pharmaceutical compositions of the present invention may be made into a wide variety of product types. These include, but are not limited to solutions, lotions, creams, beach products, gels, sticks, sprays, pads, ointments, pastes, mousses and cosmetics. These product types may comprise several types of carrier systems including, but not limited to solutions, emulsions, gels and solids.
• topical pharmaceutical compositions of the present invention are formulated as an aerosol and applied to the skin as a spray-on, a propellant is added to a solution composition.
• propellants useful herein can be found in Sagarin, Cosmetics Science and Technology, 2nd Edition, Vol. 2, pp. 443-465 (1972).
• topical pharmaceutical compositions of the present invention may also be formulated as makeup products such as foundations.
• topical pharmaceutical compositions of the present invention may also be formulated as medicated pads. Suitable examples of these pads are fully disclosed in U.S. Pat. Nos. 4,891,22? and 4,891,228, to Thaman et al, both issued Jan. 2, 1990 the disclosures of which are incorporated herein.
• topical pharmaceutical compositions of the present invention may contain, in addition to the aforementioned components, a wide variety of additional oil-soluble materials and/or water-soluble materials conventionally used in topical compositions, at their art-established levels.
• compositions of this invention may also be present in the compositions of this invention. These include humectants, proteins and polypeptides, preservatives and an alkaline agent.
• topical compositions herein can contain conventional cosmetic adjuvants, such as dyes, pigments and perfumes.
• the topical pharmaceutical compositions of the present invention may also include a safe and effective amount of a dermal penetration enhancing agent.
• a preferred amount of penetration enhancing agent is from about 1% to about 5% of the composition.
• Another useful penetration enhancer for the present invention is the non- ionic polymer under the CTFA designation: polyacrylamide and isoparrafm and laureth-7, available as Sepigel from Seppic Corporation.
• compositions of the present invention may also be included in the compositions of the present invention.
• collagen hyaluronic acid, elastin, hydrolysates, primrose oil, jojoba oil, epidermal growth factor, soybean saponins, mucopolysaccharides, and mixtures thereof may be used.
• vitamins and minerals may also be included in the compositions of the present invention.
• Vitamin A, ascorbic acid, Vitamin B, biotin, pantothenic acid, Vitamin D, Vitamin E and mixtures thereof and derivatives thereof are contemplated.
• compositions comprising both active compounds of the present invention and a cosmetically-acceptable surfactant.
• Cosmetically-acceptable surfactant refers to a surfactant, which is not only an effective skin cleanser, but also can be used without undue toxicity, irritation, allergic response, and the like.
• the surfactant must be capable of being commingled with the active compound in a manner such that there is no interaction, which would substantially reduce the efficacy of the composition for regulating skin damage, e.g., wrinkles.
• the skin cleaning compositions of the present invention preferably contain from about 0.1% to about 20%, preferably from about 1% to about 5%, of the creatine compound (e.g., creatine, cyclocreatine or another creatine compound) and from about 1% to about 90% micro-cluster liquid, and from about 0.1% to about 10%, of a cosmetically-acceptable surfactant.
• the creatine compound e.g., creatine, cyclocreatine or another creatine compound
• the physical form of the skin cleansing compositions is not critical.
• the compositions can be, for example, formulated as toilet bars, liquids, pastes, mousses, or pads.
• the cleaning compositions of the present invention can optionally contain, at their art-established levels, materials, which are conventionally used in skin cleansing compositions.
• Sunblocks and sunscreens incorporating micro-cluster liquids and creatine compounds are also contemplated.
• the term "sun block” or “sun screen” includes compositions, which block UV light. Examples of sunblocks include, for example, zinc oxide and titanium dioxide.
• Sun radiation is one major cause of skin damage, e.g., wrinkles.
• a micro-cluster liquid and a creatine compound with a UVA and/or UVB sunscreen would be advantageous.
• sunscreens in compositions of the present invention will provide immediate protection against acute UV damage.
• the sunscreen will prevent further skin damage caused by UV radiation, while the compounds of the invention modulates existing skin damage.
• sunscreening agents are suitable for use in combination with the active compound.
• Specific suitable sunscreening agents include, for example: p-aminobenzoic acid, its salts and its derivatives (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); anthranilates (i.e., o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters); salicylates (amyl, phenyl, benzyl, menthyl, glyceryl, and dipropyleneglycol esters); cinnamic acid derivatives (methyl and benzyl esters, .alpha.
• Naphtholsulfonates sodium salts of 2-naphthol-3,6-disulfonic and of 2-naphthol-6,8- disulfonic acids
• Dihydroxy-naphthoic acid and its salts o- and p- Hydroxybiphenyldisulfonates
• Coumarin derivatives (7-hydroxy, 7-methyl, 3 -phenyl
• Diazoles (2-acetyl-3-bromoindazole, phenyl benzoxazole, methyl naphthoxazole, various aryl benzothiazoles
• Quinine salts bisulfate, sulfate, chloride, oleate, and tannate
• Quinoline derivatives (8-hydroxyquinoline salts, 2-phenylquinoline); Hydroxy- or methoxy-substituted benzophenones; Uric and vilouric acids; Tannic acid and its derivatives (e.g., hexaeth
• a safe and effective amount of sunscreen may be used in the compositions of the present invention.
• the sunscreening agent must be compatible with the active compound.
• the composition may comprise from about 1% to about 20%, preferably from about 2% to about 10%, of a sunscreening agent. Exact amounts will vary depending upon the sunscreen chosen and the desired Sun Protection Factor (SPF).
• SPF Sun Protection Factor
• compositions of the present invention may also be added to any of the compositions of the present invention to improve the skin substantivity of those compositions, particularly to enhance their resistance to being washed off by water, or rubbed off.
• a preferred agent, which will provide this benefit is a copolymer of ethylene and acrylic acid. Compositions comprising this copolymer are disclosed in U.S. Pat. No. 4,663,157, Brock, issued May 5, 1987, which is incorporated herein by reference.
• an anti-inflammatory agent is included as an active agent along with the micro-cluster liquids in association with creatine compounds of the invention.
• the anti-inflammatory agent protects strongly in the UVA radiation range (though it also provides some UVB protection as well) thereby preventing further skin damage caused by UV radiation, while
• the micro- cluster liquids in association with creatine compounds of the invention treat existing damage.
• the topical use of anti-inflammatory agents reduces photo-aging of the skin resulting from chronic exposure to UV radiation. (See U.S. Pat. No. 4,847,071, Bissett, Bush, and Chatterjee, issued JuI. 11, 1989, incorporated herein by reference; and U.S. Pat. No. 4,847,069, Bissett and Chatterjee, issued JuI. 11, 1989, incorporated herein by reference.)
• a safe and effective amount of an anti-inflammatory agent may be added to the compositions of the present invention, preferably from about 0.1% to about 10%, more preferably from about 0.5% to about 5%, of the composition.
• the exact amount of anti-inflammatory agent to be used in the compositions will depend on the particular anti-inflammatory agent utilized since such agents vary widely in potency.
• the cosmaceutical further comprises a safe and effective amount of a skin protectant.
• the skin protectant preferably comprises from about 0.001% to about 2%, more preferably from about 0.01% to about 1% of the composition.
• Useful skin protectants are disclosed in the Federal Register Vol. 48, No. 32 and include allantoin, aluminum hydroxide gel, bismuth subnitrate, boric acid, calamine, cocoa butter, corn starch, dimethicone, glycerin, kaolin, live yeast cell derivative, petrolatum, shark liver oil, sodium bicarbonate, sulfur, tannic acid, white petrolatum, zinc acetate, zinc carbonate and zinc oxide and mixtures thereof.
• Formulations of the present invention include those suitable for topical, oral, nasal, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Methods of preparing these formulations or compositions include the step of bringing into association all components of the formulation, including accessory ingredients. This mixture of ingredients is processed through the device as described in U.S. patent 6,521,248 until desired nanometer particle size and/or dissolution of hydrophobics is accomplished.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
• Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
• the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
• dosage forms can be made by dissolving or dispersing the compounds in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compounds in a polymer matrix or gel.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifmgal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form maybe brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In a further embodiment, the skin disorder is associated with free radicals, aging, sun radiation, stress or fatigue.
• the subject is afflicted with wrinkles or is at risk for a skin disorder.
• associated with free radicals includes any disorders or damage to the skin resulting directly or indirectly from free radicals.
• the free radicals may be initiated by, for example, sun radiation (e.g., UV radiation) or pollution.
• aging includes processes where there is oxidative damage, energy depletion or mitochondrial dysfunction where onset, amelioration, arrest, or elimination is effectuated by The micro-cluster liquids in association with creatine compounds described herein. Symptoms of aging include, but are not limited to, wrinkles, loss of elasticity of the skin and uneven pigmentation of the skin.
• the invention also features a composition for the treatment of the skin of a subject.
• the composition comprises an effective amount of a micro-cluster liquid combined with a creatine, creatine phosphate, a creatine compound or a salt thereof.
• the effective amount is effective to treat or prevent a skin disorder.
• the composition is suitable for topical administration.
• the composition may be formulated as a lotion, cream, or ointment, gel or solid.
• the composition also contains a sunblock or sunscreen (e.g., zinc oxide or titanium dioxide).
• the composition may be formulated as a cosmetic foundation or as a skin cleansing agent.
• the composition may contain a penetration agent.
• examples of compounds which may be incorporated into the composition of the invention include, but are not limited to, hydroxyacids, retinols, Aloe, Chamomile, or mixtures thereof.
• the skin disorder is associated with free-radicals, aging, sun radiation, stress or fatigue.
• the invention contemplates co-administering to the subject an effective amount of a skin preserving agent.
• skin preserving agents include antioxidants, such as micro-cluster water, ascorbic acid, vitamins, coenzyme QlO (CoQlO) and its, derivatives, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• antioxidants such as micro-cluster water, ascorbic acid, vitamins, coenzyme QlO (CoQlO) and its, derivatives, cyste
• Preferred anti-oxidants include, CoQlO and vitamin E.
• Other examples of skin preserving agents include energy-enhancing agents (e.g., ATP, nicotinamide or pyruvate), vitamins (e.g., E, C, B5, B6, and B9) and vitamin precursors.
• energy enhancing agents also includes stimulants of mitochondrial function or ATP production elsewhere in the cell. Examples include intermediates such as, for example, pyruvate, nicotinamide and CoQlO.
• the creatine content and the efficiency of the creatine kinase system decreases with aging. Aging and several insults result in oxidative stress state and energy compromise. Minimizing the rate of production of molecules associated with oxidative damage correlates well with a decrease in oxidative damage. Such minimization combined with energy boosting effects should slow damage to tissue during aging or exposure to insults. Creatine and analogs of creatine that modify the rate of ATP synthesis through creatine kinase could sustain energy production, mitochondrial function, and protect against free radical production. Such effects could have positive impact against aging or insult related skin damage.
• Creatine is taken by athletes to boost muscle function during burst activity (for review see Wyss and Kaddurah-Daouk 1999) and during competitions. Creatine was shown to have neuroprotective properties, in several animal models of neurodegenerative diseases (Matthews et al., 1988; Kliveny et al 1999; Matthews et. al., 1999).
• micro-cluster water has been shown to improve cellular energy metabolism.
• topical application of micro-cluster water has been shown to provide a significant decrease in mtDNA mutation rates.
• Creatine compounds useful in the present invention include compounds which modulate one or more of the structural or functional components of the creatine kinase/phosphocreatine system.
• Compounds which are effective for this purpose include creatine, creatine phosphate and analogs thereof, compounds which mimic their activity, and salts of these compounds as defined above. Exemplary creatine compounds are described below.
• Creatine also known as N-(aminoiminomethyl)-N-methylglycine; methylglycosamine or N-methyl-guanido acetic acid
• Creatine is a well-known substance.
• Cyclocreatine is an essentially planar cyclic analog of creatine. Although cyclocreatine is structurally similar to creatine, the two compounds are distinguishable both kinetically and thermodynamically. Cyclocreatine is phosphorylated efficiently by creatine kinase in the forward reaction both in vitro and in vivo. Rowley, G. L., J. Am. Chem. So ' c. 93: 5542-5551 (1971); McLaughlin, A. C. et. al., J. Biol. Chem. 247, 4382-4388 (1972).
• the phosphorylated compound phosphocyclocreatine is structurally similar to phosphocreatine; however, the phosphorous-nitrogen (P-N) bond of cyclocreatine phosphate is more stable than that of phosphocreatine. LoPresti, P. and M. Cohn,
• Guanidino acetate is yet another analog of creatine and is a precursor of creatine in its biosynthetic pathway.
• Guanidino benzoic acids are structurally related to creatine.
• compounds that attach amino acid like molecules covalently to creatine are creatine compounds of interest. Examples are creatine-ascorbate and creatine-pyruvate. Other types of molecules could be covalently attached. -21-
• aminoimidazolidine modifies the flow of energy of cells in stress and may interfere with ATP utilization at sites of cellular work.
• micro-cluster water has been shown to improve cellular energy metabolism.
• topical application of micro-cluster water has been shown to provide a significant decrease in mtDNA mutation rates.
• Creatine compounds useful in the present invention include compounds which modulate one or more of the structural or functional components of the creatine kinase/phosphocreatine system.
• Compounds which are effective for this purpose include creatine, creatine phosphate and analogs thereof, compounds which mimic their activity, and salts of these compounds as defined above. Exemplary creatine compounds are described below.
• Creatine also known as N-(aminoiminomethyl)-N-methylglycine; methylglycosamine or N-methyl-guanido acetic acid
• Creatine is a well-known substance.
• Cyclocreatine is an essentially planar cyclic analog of creatine. Although cyclocreatine is structurally similar to creatine, the two compounds are distinguishable both kinetically and mermodynamically. Cyclocreatine is phosphorylated efficiently by creatine kinase in the forward reaction both in vitro and in vivo. Rowley, G. L., J. Am. Chem. Soc. 93: 5542-5551 (1971); McLaughlin, A. C. et. al., J. Biol. Chem. 247, 4382-4388 (1972).
• the phosphorylated compound phosphocyclocreatine is structurally similar to phosphocreatine; however, the phosphorous-nitrogen (P--N) bond of cyclocreatine phosphate is more stable than that of phosphocreatine. LoPresti, P. and M. Cohn,
• Guanidino acetate is yet another analog of creatine and is a precursor of creatine in its biosynthetic pathway. Guanidino benzoic acids are structurally related to creatine. Also compounds that attach amino acid like molecules covalently to creatine are creatine compounds of interest. Examples are creatine-ascorbate and creatine-pyruvate. Other types of molecules could be covalently attached. -22-
• Creatine analogs and other agents which act to interfere with the activity of creatine biosynthetic enzymes or with the creatine transporter are useful in the present method of treating or preventing age related damage.
• the effects of such compounds can be direct or indirect, operating by mechanisms including, but not limited to, influencing the uptake or biosynthesis of creatine, the function of the creatine phosphate shuttle, enzyme activity, or the activity of associated enzymes, or altering the levels of substrates or products of a reaction to alter the velocity of the reaction.
• Molecules that regulate the transporter of creatine, or the association of creatine kinase with other protein or lipid molecules in the membrane, the substrates concentration creatine and creatine phosphate also are useful in preventing and/or treating age related damage to tissue such as skin.
• Compounds which are useful in the present invention can be substrates, enzyme activity modifiers or substrate analogs of creatine kinase.
• modulators of the enzymes that work in conjunction with creatine kinase now can be designed and used, individually, in combination or in addition to creatine compounds. Combinations of creatine compounds with other supplements or other drugs is proposed.
• the pathways of biosynthesis and metabolism of creatine and creatine phosphate can be targeted in selecting and designing compounds which may modify energy production or high energy phosphoryl transfer through the creatine kinase system.
• Compounds targeted to specific steps may rely on structural analogies with either creatine or its precursors. Novel creatine analogs differing from creatine by substitution, chain extension, and/or cyclization may be designed.
• the substrates of multisubstrate enzymes may be covalently linked, or analogs which mimic portions of the different substrates may be designed.
• Non-hydrolyzable phosphorylated analogs can also be designed to mimic creatine phosphate without sustaining ATP production.
• Creatine, creatine phosphate and many creatine analogs are commercially available. Additionally, analogs of creatine maybe synthesized using conventional techniques. -23-
• Creatine compounds which currently are available or have been synthesized include, for example, creatine, b-guanidinopropionic acid, guanidinoacetic acid, creatine phosphate disodium salt, cyclocreatine, homocyclocreatine, phosphinic creatine, homocreatine, ethylcreatine, cyclocreatine phosphate dilithium salt and guanidinoacetic acid phosphate disodium salt, 4 guanidino benzoic acid and derivatives, creatine-pyruvate, creatine-ascorbate among others.
• administration is intended to include routes of administration which allow the inventive compositions to perform their intended function(s).
• the cytogenetic method represents one approach for evaluating the potential mutagenic effects of water. This approach is based on determination of the frequency of chromosome aberrations, sister chromatid exchange (SCE), and cell cycle duration. The method was used in testing the cytogenetic effects of Micro-cluster research water having the trade name AQUA RXTMin the U.S. market. This water was provided by Bio-Hydration Research Lab (USA). Micro-cluster water is produced through a multistep process according to U.S. patent NO.
• 6,521,248 which provides research water with unique attributes and a purity of less than 0.5 ppm of total dissolved substances (TDS).
• Medicinal grade oxygen is added to the water in a final step to pressurize the plastic bottles for shipment.
• Cell culture medium was prepared by dissolving RPMI 1640 (Gibco) powder in standard deionized water — 18 Mohm (control) or Micro-cluster water. Experiments were conducted with human lymphocytes, which were cultured in accordance with standard protocol. Cells are fixed after 48 hours of culturing in order to determine the frequency of chromosome aberrations. Upon determining the SCE frequency, after 48 hours 5-BDU (10 mg/ml) is added to the cell culture. Cells are fixed after 80 hours of culturing.
• Specimen preparation and staining are done according to procedures known in the art. Experiments were performed twice for each of the 3 donors. 1200 metaphases are analyzed to determine the chromosome aberrations in the control and in Micro-cluster water. -24-
• Oxidative injury involves the activation of nitric oxide production, and peroxynitrite which results in nitration of proteins.
• the nitration of proteins could be determined by measuring the ratio of 3-nitrotryrosine to tyrosine.
• the FALS mice are transgenic animals that express a mutant form of Cu/Zn superoxide dismutase found in patients with familial ALS (Amyotrophic Lateral Sclerosis). These animals develop ALS symptoms with gradual motor neuron loss, muscle weakness, and die within 135 days. Oxidative stress has been associated with the death of motor neurons. Levels of 3-nitrotyrosine are significantly increased in the spinal cords of these mice (Ferrante 1997).
• transgenic mice with the G93A mutation and the littermate controls were fed 1% creatine or unsupplemented diets at days 70 of age and then killed at 120 days of age for measurements of 3-nitrotyrosine as described (Ferrante 1997). Creatine ingestion can significantly inhibit the higher levels of 3 nitrotyrosine/tyrosine levels in lower spinal cords of transgenic FALS mice.
• Example 2 Effect of 1 % Creatine Supplementation on Hydroxyl Radical Production as Measured by Rate of Conversion of Salicylate to its by Products in FALS Mice.
• the level of free radical production in vivo can be determined using the microdialysis technique (Matthews et al 1998).
• Administration of the mitochondrial toxin 3-nitropropionic acid results in a significant increase in the conversion of salicylate to 2,3-DHBA in the striatum, which is blocked in mice over expressing Cu, Zn SOD (Bogdanov et. al., 1998).
• the salicylate hydroxyl radical-trapping method was used for measuring levels of hydroxyl radicals in striatal tissue after malonate injections. Eight animals in each group were fed either a normal diet or a diet enriched with 1% creatine or 1% cyclocreatine for two weeks before intrastriatal malonate injections. Animals were inj ected with 200 mg/kg salicylate intraperitoneally just before the malonate injections and were killed 1 hour later. The striata were then dissected rapidly from a 2-mm thick slice and placed in 0.25 ml of chilled 0.1 M perchloric acid. Samples were subsequently sonicated, frozen rapidly and thawed and centrifuged twice.
• the duration of the cell cycle is calculated as 32 hours divided by the average number of divisions.
• the cell cycle duration is 21.2 hours for both types of water, which is in agreement with literature data.
• micro-cluster water doesn't result in mutagenic effects compared to standard deionized water. Based on the data obtained, it appears that Micro-cluster water has a stabilizing effect, which results in both a lower frequency of sister chromatid exchanges and chromosome aberrations compared to standard deionized water.
• This example examines the influence of Micro-cluster water on intracellular pH of mice peritoneal macrophages and to also assess the cell membrane status under short and long term exposure to the water.
• Fluoresceindiacetate FscDA, Sigma
• Ethidium bromide EthBr, Sigma
• macrophages were incubated in 140 MM KCl; IMM CaCl 2 ; 0.5 MM MgCl 2 ; and 20 MM HEPES medium.
• Intracellular pH values have varied within a range of 6.8 to 7.6.
• Intracellular pH has been adjusted to the pH of the medium by adding the ionophore antibiotic nigericine (Sigma) 5 mg/ml, which has the ability to exchange
• Nigericine has a high affinity for K . This property allows it to stabilize to the following transmembrane equilibrium: Where i and o designate internal and external concentrations respectively. Hence intracellular pH will be close to the extracellular pH in the medium, having the same K + concentration outside and inside the cells.
• Incubation media Hanks solution (1OMM Hepes) pH 7.2; standard lab medium prepared on double distilled water with 1OMM Hepes pH 7.2; standard lab medium prepared on Micro-cluster water with 1OMM Hepes pH 7.2;
• the increase in pH is the result of quenching metobolic oxidants.
• the quenching of a hydroxyl radical would result in formation of hydroxide, causing an increase in pH.
• the quenching of other free-radicals and oxidants results in chemical species which increase the pH.
• the reduction of these free- radicals and oxidants prevents their deleterious interaction with mitochondria or other biological components. This results in decreased mutation to mitochondria DNA and other DNA and cell membranes.
• This reduction in free-radicals, oxidants and the damage they cause provides increased health, blood oxygen levels and more efficient oxygen use.
• the decreased rate of mitochondrial decay and destruction results in increased energy secondary to increased population of healthy mitochondria.
• micro-cluster water results in decreased oxidative damage.
• inventive water provides anti- aging results through decreased damage to mitochondrial DNA, and increased efficiency in related energetics.

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