WO2009084743A1 - 治療または予防のための外用剤 - Google Patents
治療または予防のための外用剤 Download PDFInfo
- Publication number
- WO2009084743A1 WO2009084743A1 PCT/JP2009/050010 JP2009050010W WO2009084743A1 WO 2009084743 A1 WO2009084743 A1 WO 2009084743A1 JP 2009050010 W JP2009050010 W JP 2009050010W WO 2009084743 A1 WO2009084743 A1 WO 2009084743A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- external preparation
- hydrogen
- agent
- metal
- solution
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/02—Medicinal preparations containing materials or reaction products thereof with undetermined constitution from inanimate materials
-
- 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
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- 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
- A61K33/24—Heavy metals; Compounds thereof
-
- 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
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/242—Gold; Compounds thereof
-
- 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
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds 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
- A61K47/06—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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P17/18—Antioxidants, e.g. antiradicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to an external preparation for treatment or prevention.
- Oxidative stress derived from active oxygen and free radicals is involved in many diseases and diseases.
- a method utilizing the antioxidant power of active hydrogen is known (patented) Reference 1).
- the reduction of the antioxidant targets that are in an oxidized state due to electron deficiency or that are to be protected from oxidation are filled with electrons.
- Antioxidant methods have been proposed to bring it to a state.
- Patent Documents 2 and 3 a method of generating hydrogen molecules by bringing metal or magnesium into contact with water or an acid is known.
- the problem to be solved by the present invention is to provide an external preparation that is not limited by the solubility of hydrogen molecules in a solvent (solvent) when the reducing power of active hydrogen is used as an external preparation for treatment or prevention. It is to be.
- the active hydrogen obtained by generating active hydrogen or activating hydrogen molecules is directly supplied to a site in an oxidized state or a site to be protected from oxidation due to electron deficiency, thereby filling the site with electrons.
- the above-described problem is solved by setting the reduction state.
- the reducing power of active hydrogen can be used as an external preparation for treatment or prevention.
- Example 10 is a graph showing test results of Examples 3 to 9. It is a graph which shows the test result of Example 10. It is a graph which shows the result (whole) of a dermatitis inhibitory action test. It is a graph which shows the result (back part) of a dermatitis suppression action test. It is a graph which shows the result (auricle part) of a dermatitis suppression action test. It is a graph which shows the result of the comparative reference example of a dermatitis suppression action test. It is an ESR spectrum of a control system for hydroxy radical elimination measurement. It is an ESR spectrum of a Mg supernatant liquid system for measurement of hydroxy radical elimination. It is a Mg-based ESR spectrum for measurement of hydroxy radical elimination. It is the Mg type
- an active hydrogen is applied to an antioxidant target that is a target site (for example, an antioxidant target that is in an oxidized state due to lack of electrons in human or animal skin or mucous membrane, or an antioxidant target that is to be protected from oxidation).
- an agent for external use for treatment or prevention containing an agent that activates hydrogen generated while generating hydrogen molecules with a catalyst or the like (both are active hydrogen generators) can be used.
- Such external preparations can be composed of multiple agents.
- the first agent contains an electron donor or a hydride ion donor
- the second agent contains a substance containing a proton donor
- the first agent and the second agent are targeted for oxidation.
- the active hydrogen can be given to the target site through the contact at.
- a catalyst to any one of the multiple agents, hydrogen molecules generated by a reaction between active hydrogen and protons or a reaction between active hydrogens can be activated again (the target site thereby). To give active hydrogen).
- the “active hydrogen generator” in the present specification is an agent that can generate active hydrogen molecules through any means such as chemical, physical, electrical, and mechanical, or generates hydrogen molecules and a catalyst.
- the reaction to active hydrogenation is promoted through the generation of hydrogen molecules, or the generation of hydrogen molecules and the oxidation of hydrogen molecules to radicals or active oxygen with strong oxidizing power (hydrogen abstraction).
- Examples include compounds containing hydrogen elements such as hydrocarbon compounds and organic hydrides (hydrogen compounds), substances having properties of absorbing and releasing hydrogen molecules such as hydrogen storage alloys and liposomes, and the like, and It is a concept that includes a substance that does not have hydrogen itself, but acts on the hydrogen compound or hydrogen storage alloy, and can generate hydrogen.
- electron donor refers to a substance that emits electrons and delivers the electrons to protons. Such electron donors are characterized by delivering electrons directly to protons, characterized by delivering electrons once to a solvent and then delivering the electrons to protons, Including a catalyst that facilitates transfer and a catalyst that transfers electrons to protons after being transferred to electrons once.
- Examples of electron donors are "metals” including alkali metals and alkaline earth metals, among which lithium, rubidium, potassium, barium, strontium, calcium, sodium, magnesium, aluminum, manganese, zinc, chromium, iron, cadmium
- metals having a higher ionization tendency than hydrogen such as cobalt, nickel, tin, lead, and alloy compounds, complex compounds, and mixtures of these metals.
- this does not preclude the use of metals other than these, and alloy compounds, complex compounds of metals other than these, and mixtures other than these.
- metal magnesium, magnesium hydride, zinc and the like are preferable metals in consideration of safety in handling, safety to living bodies, and the like.
- hydride ion donor refers to a substance that releases hydride ions and delivers the hydride ions to protons. Such a hydride ion donor is characterized in that it passes hydride ions directly to protons, and is characterized in that it releases hydride ions once to a solvent and then delivers the hydride ions to protons. And a catalyst that facilitates the transfer of hydride ions to protons, and one that is characterized in that hydride ions are once transferred to protons and then transferred to protons.
- hydride ion donors examples include metal hydrides such as calcium hydride and magnesium hydride obtained through hydrogen gas through metal, and group 13 / group 14 elements such as sodium borohydride. Hydrides of the indicated elements are included.
- proton donor refers to a substance that donates protons in a solvent and a substance that ionizes by both donating and accepting protons without self-dissociation, even if it does not donate free protons.
- it is a concept including a compound containing a hydrogen element, that is, a hydrogen compound.
- amphoteric metal such as zinc, aluminum, lead, or tin
- hydrogen derived from a hydroxyl group can be reduced.
- a hydroxyl compound is also a proton in this specification. It can be included in the concept of a donor.
- proton donors include, but are not limited to, amphoteric and protic solvents such as water, formic acid, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and acetic acid. It is.
- Hydrogen molecules are generated when a substance containing an electron donor or hydride ion donor comes into contact with a substance containing a proton donor. Although not limited to this, the process is basically explained by the following reaction formula.
- reducing protons is a concept that includes reducing free protons, non-free protons, or proton donors themselves that are donated by proton donors.
- it is a concept including reduction of a compound containing a hydrogen element, that is, a hydrogen compound, by a hydrogen reducing agent of the hydrogen compound.
- “acid” refers to a chemical species such as citric acid, acetic acid, succinic acid, gluconic acid, lactic acid, malic acid, phosphoric acid, hydrochloric acid, sulfuric acid or the like in order to increase the proton donating property of the proton donor.
- acids solutions created by electrochemical means such as decomposition, but these examples are not intended to limit the invention.
- a “basic substance” such as sodium hydroxide can be used.
- Catalyst in the present specification includes all those having a function of promoting the reaction of decomposing generated hydrogen molecules into active hydrogen as a product. Examples include noble metal fine particles, metal complexes, hydrogen oxidoreductase hydrogenase, or active site model compounds thereof, ultrasonic waves, electromagnetic waves, and the like.
- the noble metal fine particles of the present specification are platinum, palladium, rhodium, iridium, ruthenium, gold, silver, rhenium, and salts, alloy compounds, complex compounds of these noble metal elements, It is a concept including the noble metal fine particles themselves and a mixture thereof.
- the precious metal fine particles (catalyst) referred to in the present specification are assumed to be particles having a diameter in the range of 1 nm to 0.5 ⁇ m, which are generally said to exhibit an essential behavior as a colloid.
- the particle diameter that increases the catalytic activity of the Pt colloid is preferably 1 to 10 nm, more preferably 4 to 6 nm. This is a particle size that can be derived from the trade-off relationship between exerting the original properties as a noble metal and increasing the surface area with the aim of improving catalytic activity.
- active hydrogen includes such a reactive property. Also included are hydrogen molecules that are forcibly activated by high radicals.
- a catalyst for activating hydrogen molecules is not necessarily included in the constituent elements.
- “hydrogen in the nascent state” such as e ( ⁇ ) in the above formula (a) and H ( ⁇ ) in the formula (b) can be generated in the process of hydrogen generation. It is desirable to use an active hydrogen generator.
- the advantage of this external preparation that a large amount of active hydrogen can be generated in the target antioxidant target without containing hydrogen molecules in advance has changed. Absent.
- antioxidant target in the present specification includes all antioxidant targets that are in an oxidation state due to electron deficiency or that are desired to be protected from oxidation.
- antioxidant targets related to human diseases include liver and kidney damage due to drugs and harmful substances, ischemic reperfusion injury, cardiovascular diseases such as arteriosclerosis, gastric ulcer, stomach Digestive system diseases such as mucosal disorders, respiratory diseases, arteriosclerosis, diabetic complications (eg hypertension, cerebral infarction, myocardial infarction, etc.), cataracts, skin diseases, various inflammatory diseases, neurological diseases, cancer, aging, There are menopause, ED (erectile dysfunction), depression, periodontal disease, osteoporosis, rheumatism and other autoimmune diseases, stiff shoulders, coldness, hypertension, senile dementia and the like.
- cardiovascular diseases such as arteriosclerosis, gastric ulcer, stomach Digestive system diseases such as mucosal disorders, respiratory diseases, arteriosclerosis, diabetic complications (eg hypertension, cerebral infarction, myocardial infarction, etc.), cataracts, skin diseases, various inflammatory diseases, neurological diseases, cancer, aging, There are menopause, ED (erectile
- the skin area is exemplified by acne, blotches, wrinkles, or liver spots, sparrow egg spots, sunburst black spots, dullness derived from oxidation or aging or photoaging of the skin or mucous membranes, regardless of the epidermis or dermis.
- dermatologic subjects with direct or indirect involvement of oxidative stress include trauma, eczema, urticaria, erythema, purpura / cutaneous vasculitis, vasculitis in general, Abnormal keratinization, blistering, pustulosis, metabolic disorders, abnormal skin formation, granulomatous disease, collagen disease, infection, nevi, nevi, benign tumor / pigmentation, malignant tumor, sebaceous gland, sweat gland Diseases, hair diseases, nail diseases, actinic keratosis, xeroderma pigmentosum, burns, pressure ulcers, and various skin symptoms such as redness, crusts, dryness, edema, abrasions, itching, and pain. It is not limited to.
- the “external preparation” of the present specification includes, in addition to an agent administered or applied to a body surface such as skin or mucous membrane, for example, an organ, blood vessel, nerve tissue, etc. exposed by incising the body during surgery, etc.
- agents that are administered or applied to various parts of the body that are not exposed to the outside are also included in the concept.
- an organ preservative used for organ preservation or organ transplantation is also included in the concept.
- the present invention does not hinder the blending of existing percutaneous absorption enhancers or other commonly used ingredients for external use to help the action deeper in the skin.
- the dispersant is particularly important when the external preparation for treatment or prevention takes a shape that holds a metal or a metal hydride in a solvent. This is because, in order to uniformly disperse the metal or metal hydride in a solvent (dispersion medium) without precipitation, it is desirable to use a dispersant while reducing the particle diameter of the metal. Because.
- a dispersant in addition to cellulose derivatives such as hydroxypropylcellulose and methylcellulose, there are many available ones such as glycerin (also a moisturizing agent), sodium alginate, and sodium polyacrylate.
- glycerin also a moisturizing agent
- sodium alginate sodium polyacrylate
- agar, collagen, gelatin and the like can be used.
- the metal or metal hydride As a procedure for dispersing a metal or metal hydride in a solvent (dispersion medium), first, the metal or metal hydride is put in a solvent (dispersion medium) and left for several hours to one day. In this way, after forming a passive film on the surface of the metal or metal hydride, a dispersant is added. At this time, the smaller the particle size of the metal or metal hydride and the larger the surface area, the longer it takes to form the passive film.
- an oil coating process or a microencapsulation process may be performed to further block contact with the solvent (dispersion medium).
- the metal or metal hydride it is not preferable to add the metal or metal hydride to the solvent (dispersion medium) to which the dispersant is added before the passive film is formed on the metal or metal hydride. This is because when a protic solvent such as water is used as the solvent (dispersion medium), the metal or metal hydride slowly reacts with the protic solvent and slowly releases hydrogen, so that the solvent is viscous. This is because hydrogen bubbles are foamed and hinder uniform dispersion of metal particles.
- the dispersant has a role of increasing the retention in the antioxidant target and a role of not releasing hydrogen and active hydrogen generated in the antioxidant target into the atmosphere. is doing.
- a solvent dispersion medium
- the blending ratio of the nonpolar solvent and / or the aprotic solvent in the protic solvent is 1% by weight or more, preferably 20% by weight or more, more preferably 30% by weight or more, and particularly preferably 50% by weight or more. .
- the amount of metal or metal contained in the solvent is calculated, and the amount of the protic solvent in the solvent (dispersion medium) is less than that amount. You may adjust the compounding quantity of a solvent.
- nonpolar solvents include, but are not limited to, hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, methylene chloride, etc. in addition to the above-mentioned acetone.
- aprotic solvents include, but are not limited to, the above DMSO, tetrahydrofuran, acetonitrile, N, N-dimethylformamide and the like.
- Another method for preventing the reaction between the metal or metal hydride and the protic solvent in the solvent (dispersion medium) is to cover the metal or metal hydride with a passive film, or to disperse the solvent (dispersion).
- a non-polar solvent or aprotic solvent to the solvent
- a hydroxide that ionizes in a protic solvent such as sodium hydroxide to release hydroxide ions based on the law of chemical equilibrium. Therefore, the reaction (positive reaction) that generates hydrogen molecules while generating hydroxides (hydroxide ions) may be suppressed in advance.
- the liquid property of the solvent (dispersion medium) at that time is alkaline with a pH of 7 to 14, preferably 7.5 to 13.5, more preferably 8 to 13, and particularly preferably 8.5 to 12.5. Is desired.
- known chelating agents and ion-exchange sequestering agents may be appropriately blended.
- the generated active hydrogen or the hydrogen molecule activated via the catalyst is an antioxidant object that is in an oxidized state due to electron deficiency or an antioxidant object that wants to protect against oxidation, such as skin or
- the target anti-oxidation target site such as mucous membrane wrinkles, stains, and darkening, is reduced to a state in which electrons are satisfied. Prior to reaching the oxidation target, there is no concern that active hydrogen is wasted on dissolved oxides.
- the outstanding feature of the external preparation for treatment or prevention according to the present invention is that the hydrogen molecule or the active hydrogen is not first contained in the solvent, but is generated only at the time of administration.
- Generation of hydrogen or activation of hydrogen through a catalyst basically occurs in the target antioxidant target, so that active hydrogen is less wasted by oxidants other than the target, and many of them are target sites. It is mentioned that it is directed against the antioxidant object.
- any one or more of the multiple agents constituting the external preparation for treatment or prevention of the present invention may contain an existing component, so that the synergistic effect of such component and hydrogen or active hydrogen Can also be expected.
- Examples of such components are not intended to limit the present invention, but may be components used in the treatment of the diseases and diseases described above.
- the liquid containing the metal magnesium fine powder as the first agent and the citric acid solution or the citric acid solution containing the platinum fine particles as the second agent are put in separate containers and stored until use.
- the container has a space for separately containing the two agents, and the two agents are released at the same time by pushing the nozzle at the top of the container, and the two agents contact each other for the first time.
- a dual dispenser type container may be used.
- the first agent and the second agent When using an external preparation for the treatment or prevention of an antioxidant target that is the target site of the skin or mucous membrane, apply the first agent and the second agent to the antioxidant target at an appropriate ratio, Leave for a few seconds to tens of minutes.
- the first agent and the second agent are preferably given appropriate viscosity by a dispersant or the like.
- the dispersant can also function as a protective film for the generated active hydrogen or hydrogen molecules.
- the first agent and the second agent applied to the antioxidant object and mixed with each other start to release active hydrogen and hydrogen molecules.
- the mechanism is that the passive film covering the metal magnesium fine powder in the first agent is removed by the acid in the second agent, and the exposed active surface of the metal magnesium reacts with water or hydrated protons. It is assumed that magnesium hydroxide is produced while releasing active hydrogen and hydrogen molecules.
- H ( ⁇ ) is a substance called a hydride ion.
- the diameter of hydride ions is 3 angstroms, about 3 times larger than H. The reason is thought to be that the electron cloud spreads due to repulsion between electrons because two electrons coexist in the 1s orbit. A wide electron cloud means that electrons are easily removed.
- the acid plays a role of removing the passive film from the metallic magnesium, in addition to the role of supplying the hydrated proton.
- passive films can be considered as a mixture of oxides and hydroxides, but acids prevent the formation of passive films of these oxides and hydroxides and the formed passive films It is assumed that it has the effect
- the metal magnesium particle size should be made as small as possible to increase the surface area contributing to the reaction, and mechanical stimuli such as finger pressure should be actively used to expose the active surface of the metal magnesium. .
- active hydrogen or hydrogen molecules activated via a catalyst can be used to target an antioxidant object that is the target site of the skin or mucosa where such generation or activation is taking place.
- the reduction state is filled with electrons.
- the generation of active hydrogen or the activation of hydrogen molecules and the consumption of activated hydrogen (active hydrogen) occur almost simultaneously on the target antioxidant target, so that they can exist stably. Therefore, it is possible to actually use the reducing power of active hydrogen, which is difficult to use effectively for living bodies.
- the antioxidant target which is the target site of the skin or mucous membrane, is automatically brought into a reduced state filled with electrons.
- the first agent and the second agent are permeated so as to be applied to the antioxidant target as the target site.
- the external preparation for treatment or prevention is given viscosity
- the first agent and the second agent are thoroughly mixed in advance, and the resulting creamy mixture is applied to the antioxidant target. May be.
- mechanical stimulation by such finger pressure also has the effect of removing the passive film of metallic magnesium, if the mechanical stimulation is applied again by finger pressure, etc., when the release of hydrogen bubbles is attenuated, The active surface of magnesium can be exposed again.
- the metal used in the external preparation for this treatment or prevention regardless of the above description regarding the preferred particle size of the noble metal fine particles Maintaining fine powders or precious metal fine particles with a size larger than that which penetrates the skin, for example, pores or particle sizes that do not sink into exocrine glands such as sweat glands and sebaceous glands, and then increase the activity by micronization
- the particle size may be adjusted to a maximum, for example, 0.5 ⁇ m to 1000 ⁇ m, preferably 1 ⁇ m to 500 ⁇ m, more preferably 1 ⁇ m to 250 ⁇ m, and particularly preferably 1 ⁇ m to 150 ⁇ m.
- the particle size is reduced to a size that penetrates the skin, and the antioxidation target is to be reduced from a deeper part of the skin. You can also. In order to obtain such a particle size, it is possible to refer to the description relating to the particle size of the preferred noble metal fine particles described above. In any case, the present invention can include various particle sizes of fine powder of metal or metal hydride, or noble metal fine particles.
- a patch-type external preparation for treatment or prevention can be considered.
- a layer containing zinc powder is used as a first adhesive layer in contact with the skin, and a second adhesive layer containing a citric acid solution or a citric acid solution containing platinum fine particles is formed thereon as a plastic layer. Install it with a board in between.
- a patch type therapeutic or preventive agent having such a structure is applied to an antioxidant target that is a target site of skin or mucous membrane, and when the plastic plate is removed, the first layer and the second layer are in contact with each other, At the same time as generating active hydrogen or activating hydrogen molecules, electrons are supplied to the antioxidant object.
- the second adhesive layer is covered with a cover made of a material that is difficult to escape hydrogen molecules such as aluminum.
- the first adhesive layer may be an upper layer and the second adhesive layer may be a lower layer. Platinum fine particles may be contained in the first adhesive layer.
- Zinc is exemplified here, as will be described later, the generation of active hydrogen or activation of hydrogen molecules by zinc is slower than that of metals such as magnesium, for example.
- the active ingredient is suitable for a dosage form such as a patch where it is desirable to release the active ingredient slowly.
- this example does not limit the active hydrogen generator or metal that can be used for the patch.
- vaginal external preparation for treatment or prevention can be considered.
- a citric acid solution or a citric acid solution containing fine platinum particles is applied to an antioxidant target, which is a target site of the skin or mucous membrane, and a powder containing metal magnesium fine powder is applied on the top thereof. It is popular. Then, the citric acid solution and the metal magnesium fine powder react to generate active hydrogen or activate hydrogen molecules, and at the same time supply electrons to the antioxidant target.
- a structure may be adopted in which a citric acid solution is applied to an antioxidant target that is a target site of the skin or mucous membrane, and a powder containing metal magnesium fine powder and, if necessary, platinum fine particles is deposited on the upper part thereof to a fingertip size. .
- the antioxidation target which is the target site of the skin or mucous membrane, is composed of a metal magnesium fine powder, citric acid and, if necessary, a powder containing platinum fine particles on the fingertip size, and an appropriate amount of solvent is dripped there. You may take.
- an oral preparation of an external preparation for treatment or prevention can be considered.
- an oral drug containing fine metal magnesium powder and, if necessary, precious metal fine particles such as platinum fine particles is administered to an antioxidant target which is a target site of the gastric mucosa.
- gastric juice which is an acid solution reacts with metal magnesium fine powder to generate active hydrogen or activate hydrogen molecules, and at the same time supply electrons to the antioxidant target. It is desirable that such an oral drug is appropriately coated with a gastric soluble capsule or the like.
- Example 1 Metal magnesium powder (particle size: 212 to 600 ⁇ m, 99.9%) (a reagent manufactured by Wako Pure Chemical Industries, Ltd.) was used as the first agent.
- Second agent Citric acid (C 6 H 8 O 7 , Wako Pure Chemical Industries, Ltd.) in a solution obtained by dissolving 0.05 g of a platinum colloid 4 wt% solution made by Tanaka Kikinzoku in 100 mL of distilled water manufactured by Wako Pure Chemical Industries, Ltd. The solution to which 3 g (made by company) was added was used as the second agent.
- the first agent and the second agent were stored in separate plastic containers.
- methylene blue (tetramethylthionine chloride; C 16 H 18 ClN 3 S ⁇ 3 (H 2 O), manufactured by Wako Pure Chemical Industries, Ltd.) solution (hereinafter referred to as MB solution) was placed on the plate. After that, 0.01 g of the first agent and 0.5 mL of the second agent were dropped in this order.
- MB solution methylene blue (tetramethylthionine chloride; C 16 H 18 ClN 3 S ⁇ 3 (H 2 O)) solution
- antioxidant 0.5 mL of water was dropped on it.
- Example 1 Comparative Example 1 for 5 seconds Not erased [Preservation evaluation test by color change of DPPH radical] [Example 2]
- First agent Metal magnesium powder (particle size: 212 to 600 ⁇ m, 99.9%) (a reagent manufactured by Wako Pure Chemical Industries, Ltd.) was used as the first agent.
- Second agent Citric acid (C 6 H 8 O 7 , Wako Pure Chemical Industries, Ltd.) in a solution obtained by dissolving 0.05 g of a platinum colloid 4 wt% solution made by Tanaka Kikinzoku in 100 mL of distilled water manufactured by Wako Pure Chemical Industries, Ltd. The solution to which 3 g (made by company) was added was used as the second agent.
- the first agent and the second agent were stored in separate plastic containers.
- DPPH solution Calbioche DPPH (1, 1-diphenyl-2-picrrylhydrazyl) solution having a concentration of 0.16 g / L was placed in a graduated cylinder. 0.5 mL of the agent was sequentially dropped on it.
- Example 2 60 seconds comparative example 2 No fading [consideration of examples] Methylene blue is blue when it is in the oxidized form, but when it is reduced to become reduced methylene blue (leucomethylene blue), the blue color disappears. Therefore, if any reagent is treated with oxidized methylene blue and then the blue color disappears, the reagent can be regarded as having reducing power.
- the reagent is considered to have radical scavenging activity or antioxidant power. be able to.
- the external preparation for treatment or prevention according to the present invention erases the blue color of methylene blue and fades the deep red color of the DPPH radical even after being stored in a plastic container for 72 hours.
- the antioxidant waters of Comparative Examples 1 and 2 did not erase the blue color of methylene blue and did not fade the deep red color of the DPPH radical.
- Antioxidant water containing hydrogen molecules and platinum fine particles will be able to reduce methylene blue or DPPH radical, which is the object of oxidation, as soon as it is made, but it must be stored in a plastic container for a long time. Then, the hydrogen molecules in the container are gradually lost to the atmosphere, and the hydrogen molecules react with oxygen and other oxides dissolved from the atmosphere through the platinum fine particles as a catalyst. Therefore, most of the hydrogen molecules remain when the target antioxidant target (methylene blue, DPPH radical) is encountered after 72 hours. On the other hand, in the preparation for external use for treatment or prevention according to the present invention, it is not necessary to pay attention to the preservability of hydrogen molecules, which are substances that are inherently difficult to preserve.
- the antioxidant water there is a restriction that the hydrogen molecules are contained in the solvent water in advance, so that hydrogen molecules having a saturation solubility in the solvent or higher cannot be used.
- the solubility of hydrogen molecules in water is only 1.6 mg / L at 20 ° C. and 1 atm, and there is little to have a meaningful action on a living body.
- the external preparation for treatment or prevention according to the present invention has many advantages that cannot be obtained simply by using antioxidant water as an external preparation for treatment or prevention.
- Test procedure As a basic test procedure, first prepare 1g of each test substance, perform the hydrogen generation operation for the necessary ones, and apply dropwise the methylene blue aqueous solution adjusted to a certain concentration there. . If those test substances have reducing power, the dropped blue methylene blue will be reduced and become colorless, but gradually increase the input amount of methylene blue aqueous solution, and when the reducing agent in the test substance is consumed, Color change from blue to colorless in methylene blue cannot be observed. The reducing power of each substance is evaluated from the total amount of methylene blue aqueous solution dropped to this point for each test substance.
- methylene blue aqueous solutions to be added dropwise those of 50 mg / L (volume molar concentration: 156.3 ⁇ M), those of 1 g / L (volume molar concentration: 316.5 ⁇ M), and 2.5 g / L (volume molar concentration: 7816. 3 ⁇ M) is prepared.
- three types of methylene blue aqueous solutions having different concentrations were prepared, because there was too much difference in reducing power among the test substances, so that three types of methylene blue were used depending on the reducing power of each test substance. This is because higher test accuracy can be expected.
- the container used was a 20 mL capacity test tube. Add 1 g of the test substance to the test tube, and then add 1 mL of methylene blue aqueous solution dropwise with a pipette. When 1 mL is added, the test tube is shaken lightly and stirred, and visually observed for color reaction. The color reaction of methylene blue is reversible, and once methylene blue that has been reduced and becomes colorless is returned to blue when oxidized in the atmosphere, it is necessary to drop methylene blue quickly.
- Alfa Aesar 50 mg magnesium powder (-100 + 200 mesh, 99.6%) as the first agent, platinum colloid 4 wt% solution made by Tanaka Kikinzoku Kogyo Co., Ltd. 950 mg diluted 200-fold with purified water treated through the process (platinum colloid concentration 200 mg / L, the same applies below) and citric acid added to 20% concentration (200 g / L, the same applies below) was the second agent.
- a mixture of the first agent and the second agent was used as a test substance, and after adjusting the test substance, a methylene blue aqueous solution was dropped by a pipette 1 mL at a time while visually observing the color change of the test substance.
- the amount of methylene blue solution dropped until no color change was confirmed was 6 mL for 2.5 g / L concentration and 3 mL for 1 g / L, and the total amount of reduced methylene blue was 56.3 ⁇ mol. It was.
- Example 4 50 mg of zinc powder (particle size: about 6 ⁇ m) manufactured by Wako Pure Chemical Industries, Ltd. is passed through the first agent, platinum colloid 4 wt% solution manufactured by Tanaka Kikinzoku Kogyo Co., Ltd., and Fujisawa city tap water are passed through an ion exchange column manufactured by Organo. Diluted 200 times with purified water treated in this manner, and 950 mg of citric acid added to a concentration of 20% is used as the second agent.
- a mixture of the first agent and the second agent was used as a test substance, and after adjusting the test substance, a methylene blue aqueous solution was dropped by a pipette 1 mL at a time while visually observing the color change of the test substance.
- the amount of the methylene blue solution dropped until no color change was confirmed was 12 mL for 2.5 g / L concentration and 2 mL for 1 g / L, and the total amount of methylene blue reduced was 100.0 ⁇ mol. It was.
- Example 5 In purified water treated with Wako Pure Chemical Industries, Ltd. 50 mg calcium granule as the first agent, platinum colloid 4 wt% solution, manufactured by Tanaka Kikinzoku Kogyo Co., Ltd., passed through an ion exchange column manufactured by Organo Co., Ltd. The second agent is 950 mg diluted 200-fold.
- a mixture of the first agent and the second agent was used as a test substance, and after adjusting the test substance, a methylene blue aqueous solution was dropped by a pipette 1 mL at a time while visually observing the color change of the test substance.
- the dripping amount of the methylene blue aqueous solution until no color change could be confirmed was 6 mL at a concentration of 2.5 g / L, and the total amount of methylene blue was 46.9 ⁇ mol.
- Example 6 Merck sodium borohydride 50 mg as the first agent, Tanaka Kikinzoku Kogyo Co., Ltd. platinum colloid 4 wt% solution 200 times with purified water treated with Fujisawa city tap water through an organo ion exchange column 950 mg diluted to 2 is used as the second agent.
- a mixture of the first agent and the second agent was used as a test substance, and after adjusting the test substance, a methylene blue aqueous solution was dropped by a pipette 1 mL at a time while visually observing the color change of the test substance.
- the dripping amount of the methylene blue aqueous solution until no color change could be confirmed was 6 mL at a concentration of 2.5 g / L, and the total amount of methylene blue was 46.9 ⁇ mol.
- Example 7 Purified water treated with 50 mg calcium hydride manufactured by Wako Pure Chemical Industries, Ltd. as the first agent, platinum colloid 4 wt% solution manufactured by Tanaka Kikinzoku Kogyo Co., Ltd., and Fujisawa city tap water through an ion exchange column manufactured by Organo.
- the second drug is 950 mg diluted 200 times.
- the first agent and the second agent were mixed together and an attempt was made to add methylene blue dropwise.
- the reaction between the first agent and the second agent was so intense that hydrogen was added at the moment when the first agent and the second agent contacted each other. Since water spattered during generation and the reaction ended instantaneously, measurement was not possible.
- Example 8 50 mg of magnesium powder (-100 + 200 mesh, 99.6%) manufactured by Alfa Aesar (ALF) is used as the first agent, a 4 wt% palladium colloid solution manufactured by Tanaka Kikinzoku Kogyo Co., Ltd., and Fujisawa City tap water is used as an ion exchange column manufactured by Organo. Dilute 200-fold with purified water treated through, and add 950 mg citric acid to a concentration of 20% as the second agent.
- ALF Alfa Aesar
- a mixture of the first agent and the second agent was used as a test substance, and after adjusting the test substance, a methylene blue aqueous solution was dropped by a pipette 1 mL at a time while visually observing the color change of the test substance.
- the amount of the methylene blue solution dropped until the color change could not be confirmed was 4 mL for 2.5 g / L concentration and 3 mL for 1 g / L, and the total amount of methylene blue reduced was 40.3 ⁇ mol. It was.
- Alfa Aesar (ALF) Magnesium Powder (-100 + 200 mesh, 99.6%) 50 mg as the first agent, Fujisawa City tap water passed through Organo ion exchange column, purified water treated with 20% concentration of citric acid 950 mg added so as to become the second agent.
- a mixture of the first agent and the second agent was used as a test substance, and after adjusting the test substance, a methylene blue aqueous solution was dropped by a pipette 1 mL at a time while visually observing the color change of the test substance.
- the amount of the methylene blue aqueous solution added until no color change could be confirmed was 1 mL at a concentration of 50 mg / L, and the total amount of methylene blue reduced was 0.2 ⁇ mol.
- a platinum colloid 4 wt% solution manufactured by Tanaka Kikinzoku Kogyo Co., Ltd. is 200 mg / L.
- a test substance 1 mL of the colloidal platinum colloid was added to the test substance, and after adjusting the test substance, a methylene blue aqueous solution was added dropwise by 1 mL while observing the color change of the test substance visually.
- the amount of the methylene blue aqueous solution dropped until no color change could be confirmed was 2 mL at a concentration of 50 mg / L, and the total amount of reduced methylene blue was 0.3 ⁇ mol.
- a platinum colloid 4 wt% solution manufactured by Tanaka Kikinzoku Kogyo Co., Ltd. is diluted 200-fold with purified water obtained by treating Fujisawa city tap water through an ion exchange column manufactured by Organo Co., Ltd., and the citric acid concentration becomes 20%.
- the methylene blue aqueous solution was added dropwise with a pipette by 1 mL while visually observing the color change of the test substance. 1 mL of L-concentration methylene blue aqueous solution could not be made transparent.
- test results are shown in Table 3 and a graph is shown in FIG.
- Example 4 the external preparation using zinc as the first agent in Example 4 reduced most methylene blue.
- the generation rate of hydrogen bubbles was fairly moderate. From this, it is considered that in Example 4, the generated hydrogen molecules did not escape to the atmosphere, and the generated hydrogen molecules could be effectively directed to methylene blue reduction.
- Example 5 using calcium, Example 6 using sodium borohydride, and Example 7 using calcium hydride were very reactive, and added citric acid to the first agent. At least it reacts vigorously with neutral water. Especially, since the calcium hydride of Example 5 reacted strongly only by touching the water surface, data could not be taken in this test method.
- Test procedure The test procedure was carried out in accordance with the test procedure of the reducing power evaluation test based on the color change of methylene blue. That is, 1 cc of the test substance and 1 cc DPPH solution were placed in the cell, and it was visually confirmed whether the DPPH solution in the cell changed to an amber color. If the DPPH in the cell changes from purple to amber, the test substance has reduced DPPH radicals in the solution.
- the concentration of the DPPH solution was gradually increased, and the antioxidant power between the test substances was compared based on the DPPH concentration up to the point when no change to amber color could be confirmed.
- hydrogen reacts with oxygen in the liquid or the atmosphere. Since a large amount of hydrogen is generated inside the cell due to its nature, it is impossible to cover the cell, without removing oxygen and without covering the cell. In order to unify the conditions, the same applies to the comparative example.
- DPPH manufactured by Calbioche was used, and ethanol manufactured by Wako Pure Chemical Industries, Ltd. was used as the solvent. Starting from 25 mg / L, 50 mg / L, 100 mg / L, 200 mg / L, 400 mg / L, 500 mg / L and the maximum concentration of DPPH radicals that can be dissolved in ethanol in units of 100 mg / L and thereafter 5000 mg / L I gave it up.
- Alfa Aesar 50 mg magnesium powder (-100 + 200 mesh, 99.6%) as the first agent, platinum colloid 4 wt% solution made by Tanaka Kikinzoku Kogyo Co., Ltd. 950 mg diluted 200-fold with purified water treated through, and added with citric acid to a concentration of 20% was used as the second agent.
- a mixture of the first and second agents is used as the test substance, and after adjusting the test substance, the DPPH solution is dripped alternately until the color change cannot be confirmed in order from the lowest concentration.
- the color change could be confirmed up to 5000 mg / L.
- Test results The above test results are shown in Table 4 and a graph is shown in FIG.
- Example 10 the DPPH concentration that Example 10 was able to reduce was 5000 mg / L, which is the solubility limit, but it should potentially be able to reduce DPPH at a much higher concentration. It is.
- 4.17 mg of hydrogen is generated from 50 mg of magnesium, which is about 2600 times the amount of hydrogen contained in 1 g of saturated hydrogen water at 20 ° C. and 1 atm. It is.
- the amount of hydrogen generated from the hydrogen generating agent used as an external preparation for treatment or prevention in this specification can be calculated as follows.
- the reaction formula Mg + 2H2O ⁇ Mg (OH) 2 + H2 shows that 1 mol (2 g) of hydrogen is generated per 1 mol (24 g) of magnesium.
- 1 L of the external preparation for treatment or prevention it is not intended to limit the present invention.
- the composition ratio is 1: 4, and the composition is composed of the first agent 200 g and the second agent 800 g. Can do.
- the concentration of metallic magnesium contained in the first agent is 5 wt%, for example, the amount of metallic magnesium itself used is 10 g.
- the amount of metallic magnesium itself used is 10 g.
- 1 mol (2 g) of hydrogen is generated with respect to 1 mol (24 g) of magnesium. Therefore, the amount of hydrogen generated from 10 g of metal magnesium can be calculated to be about 830 mg. .
- This numerical value is only a calculated value.
- hydrogen molecules are dissolved in water at 20 ° C. and 1 atm, only about 1.6 mg / L can be dissolved.
- the advantages are clear.
- hydrogen reacts with dissolved oxides such as oxygen at the stage where the catalyst coexists, so that the amount of hydrogen that can actually be used is further reduced during use. Needless to say.
- the respective compositions are as follows, for example: become.
- First agent Magnesium powder MG100 (150 ⁇ m or less) (Kanto Metal Co., Ltd.) 5.0 wt% Metroles (methylcellulose) SNB-30T (Shin-Etsu Chemical Co., Ltd.) 2.0wt% Glycerin (Toho Pharmaceutical Co., Ltd.) 10.0wt% Calfa (Grapefruit Seed Extract, Preservative) (Calfa Chemical Co., Ltd.) 0.05wt% Purified water 82.95wt% Second agent: Platinum colloid 4wt% solution (Tanaka Kikinzoku Kogyo Co., Ltd.) 0.32wt% (platinum colloid concentration is 128mg / L) Citric acid (Wako Pure Chemical Industries, Ltd.) 10.0wt% Hydroxypropyl cellulose (Nippon Soda Co., Ltd.) 0.5wt% Glycerin (Toho Pharmaceutical Co., Ltd.) 5.0wt% Calfa (Grapefruit Seed Extract, Preservative) (Cal
- the magnesium Since the specific gravity of magnesium is greater, if the viscosity is weak, the magnesium will gradually sink and cannot be made into a stable product. In this sense, the smaller the particle size of the magnesium powder, the better. If possible, the one of about 150 ⁇ m or less used in this example is desirable. Further, the type and concentration of the thickening dispersant are required to stably hold the magnesium in the gel. Therefore, it is desirable to add an anti-settling agent such as polyethylene oxide, amide wax, dry silica as required.
- an anti-settling agent such as polyethylene oxide, amide wax, dry silica as required.
- platinum colloid is adopted as the noble metal fine particle catalyst, but naturally it is not limited to platinum colloid, and as described in part in Examples, palladium colloid or Precious metal fine particles such as gold colloid, alloy compounds or metal complexes thereof, or hydrogen oxidoreductase are also candidates.
- the citric acid in the composition of the second agent is desirably contained at a concentration sufficient to dissolve all the magnesium powder in the first agent when mixed with the first agent.
- the first agent is alkaline at a pH of around 11, and the second agent is strongly acidic at a pH of slightly less than 2. When this is mixed at a ratio of 1: 2, the pH is about 3 acidic.
- the passive film formed on the magnesium surface in the first agent is broken by the citric acid of the second agent, ⁇ Formula 8 >> Mg + 2H2O ⁇ Mg (OH) 2 + H2
- the reaction starts. By this reaction, the pH, which was about 3 immediately after mixing, is pulled in the alkaline direction (action of hydroxide ions).
- the citric acid concentration is sufficient, and the pH after all of the magnesium has reacted is about 4 acidic.
- the first agent when a substance that generates a hydroxyl group by reaction with a support agent, such as metallic magnesium, is used as the first agent, the first agent has a pH of 7 to 14, more specifically, a pH of 9 to 12, and more particularly, a pH of 11
- the second agent intended to neutralize the alkali of the first agent, neutralize the alkalinization associated with the reaction between the first agent and the second agent, and supply protons to the system Can be said to exhibit an acidity of pH 1 to 7, more particularly pH 1 to 4, more particularly pH 1 to 3, particularly particularly pH 2. Even after the first agent and the second agent are mixed and the reaction is completed, for example, even when 72 hours have elapsed after mixing, the liquidity of the mixed solution is still reduced by the acid of the second agent. It is preferable to maintain weak acidity to acidity.
- Test procedure 1.1 Preparation of atopic dermatitis model (first trigger) After shaving the back and auricle of NC / Nga mice with a clipper and electric shaver, apply an appropriate amount of hair remover (trade name: manufactured by Epirat, Kanebo) and remove the hair.
- hair remover trade name: manufactured by Epirat, Kanebo
- Biosta AD manufactured by Biosta Co., Ltd.
- a salmon mite-derived induced ointment evenly on the back and auricle on the back of the tip of the micropipette.
- Dermatitis severity score chart (a) Redness / bleeding (observation of redness and bleeding symptoms on the back) 0: Asymptomatic; no redness or bleeding symptoms on back 1: Mild; Redness locally on back, no bleeding due to continuous abrasion 2: Moderate; Redness is scattered on the back or bleeding due to continuous abrasion is not observed 3: Severe; Redness on the back as a whole or bleeding with continuous abrasion (b) Crust formation / drying (observation of crust formation and dryness on the back) 0: Asymptomatic; no crust formation or dryness on back 1: Mild; Locally recognized on the back, slightly whitened skin, and slight exfoliation of the skin 2: Moderate; scattered on the back or apparently exfoliated exfoliated 3: Severe; condition with crusts on the back as a whole or apparently exfoliation of keratin (c) edema 0: Asymptomatic; no thickness on left and right pinna 1: Mild; Slight thickness on either the left or
- First agent Kanto Metals Co., Ltd. magnesium powder MG100 (150 ⁇ m or less) 5.0 wt%, Shin-Etsu Chemical Co., Ltd. Metroses (methylcellulose) SNB-30T 2.0 wt%, Toho Pharmaceutical Co., Ltd. glycerin 10.0 wt% %, Calfa Chemical Co., Ltd. 0.05 wt%, and Fujisawa City tap water passed through Organo Corporation ion exchange column 82.95 wt% purified composition.
- Second agent 0.32 wt% of platinum colloid 4 wt% solution manufactured by Tanaka Kikinzoku Kogyo Co., Ltd., 10.0 wt% of citric acid manufactured by Wako Pure Chemical Industries, Ltd., 0.5 wt% of hydroxypropyl cellulose manufactured by Nippon Soda Co., Ltd.
- Composition 5.0% by weight of glycerin manufactured by Toho Pharmaceutical Co., Ltd., 0.05% by weight of Calfa Chemical Co., Ltd. by Calfa Chemical Co., Ltd. Composition.
- the first agent and the second agent were mixed at a weight ratio of 1: 2, and 100 mg of a foaming creamy mixture was immediately applied.
- Example 5 The first product of Example 11 and the second agent were mixed and allowed to stand for 72 hours or longer, and the reaction product from which hydrogen was released was regarded as the base of Example 11 and 100 mg was applied.
- the biosta AD model is a model in which lesions are observed in the back and auricle of the mouse. In order to make an evaluation close to human skin, it is better to give more importance to the healing effect of back skin lesions than to soft mouse pinna.
- Example 11 the significant dermatitis improving effect of Example 11 was confirmed on the back of the mouse, suggesting that the dermatitis improving effect on human of Example 11 can be expected.
- FIG. 6 shows changes in the dermatitis score by transdermal administration of Locoid ointment (registered trademark, manufactured by Torii Pharmaceutical Co., Ltd., steroid rank IV group, mild).
- Example 11 may have a strong dermatitis improving effect that is almost the same as or higher than that of locoid ointment.
- the first layer containing a metal or a metal hydride and the second layer containing a citric acid solution (and platinum fine particles as necessary) face each other through a partition plate such as a plastic plate.
- a partition plate such as a plastic plate.
- fabric products such as pillows and cushions can be designed using the same configuration. That is, by pulling out the partition plate at bedtime or the like, the first layer and the second layer come into contact with each other, and hydrogen molecules or active hydrogen is generated.
- the fabric products supplied can be designed.
- Such fabric products can be used, for example, in the prevention / treatment of disease disorders involving oxidative stress such as cognitive impairment or cerebral infarction or pressure ulcers.
- a powder containing metal or metal hydride and citric acid is mixed with an aprotic solvent or a nonpolar solvent as necessary, and hydrogen is passed through moisture such as sweat that exudes from a contact site such as the head.
- a configuration in which molecules or active hydrogen is generated at the site can also be adopted.
- “sealing therapy” used when a steroid is applied to the skin for the treatment of atopic dermatitis or the like can be combined. That is, when applying this external preparation, in order to allow hydrogen molecules or active hydrogen to permeate through the skin or mucous membrane, it can be covered with a wrap or sheet made of polyethylene, polyvinylidene chloride or the like together with the application of the external preparation. . At this time, in order to further improve the sealing performance of hydrogen, the material of the wrap or the sheet is preferably made of a material hardly permeable to gas such as hydrogen gas (aluminum or the like).
- a well-known liposome can be used as an external preparation.
- Liposomes are artificial cell-like fine particles composed of phospholipids that constitute the cell membrane of a living body, and can include water-soluble and fat-soluble drugs. Since it is highly biocompatible and can be transported in the body while protecting the drug from decomposing enzymes, it is also used as a transporter for compounds such as drugs.
- the present invention is not limited to this, but liposomes having hollow interiors, such as hollow liposomes, can be preferably used. That is, the liposome suspension is deaerated as necessary by reducing the pressure, and the suspension of the suspension is added under an appropriate atmospheric pressure environment (for example, 1 to 10 atmospheres or 1.5 to 10 atmospheres).
- the hydrogen-containing liposome suspension is mixed with a second agent containing a substance (for example, alcohol such as ethanol or a surfactant) having an action of destroying a membrane constituting the liposome, or ultrasonic or other physical Hydrogen can be generated in the skin or mucous membrane by disrupting the membrane with a specific force.
- a substance for example, alcohol such as ethanol or a surfactant
- the membrane constituting the liposome can be destroyed.
- an effective external preparation can be configured such that attack (oxidation) directly leads to counterattack (antioxidation).
- Atomized magnesium powder (-400 mesh) 50mg made by Tangshan Weihao Magnesium Powder Co., Ltd. is the first agent, platinum colloid 4wt% solution made by Tanaka Kikinzoku Kogyo Co., Ltd. Diluted 200-fold with purified water treated through, and 950 mg of citric acid added to a concentration of 20% was used as the second agent.
- a mixture of the first agent and the second agent was used as a test substance, and after adjusting the test substance, a methylene blue aqueous solution was dropped by a pipette 1 mL at a time while visually observing the color change of the test substance.
- the amount of the methylene blue solution dropped until no color change was confirmed was 7 mL for 2.5 g / L concentration and 2 mL for 1 g / L, and the total amount of methylene blue reduced was 61.0 ⁇ mol. It was.
- Example 13 Purified water treated with Alfa Aesar (ALF) 50 mg of magnesium hydride as the first agent, platinum colloid 4 wt% solution manufactured by Tanaka Kikinzoku Kogyo Co., Ltd., and Fujisawa city tap water through an ion exchange column manufactured by Organo.
- the second drug is 950 mg diluted 200 times.
- a mixture of the first agent and the second agent was used as a test substance, and after adjusting the test substance, a methylene blue aqueous solution was dropped by a pipette 1 mL at a time while visually observing the color change of the test substance.
- the amount of the methylene blue aqueous solution dropped until no color change could be confirmed was 4 mL at a concentration of 2.5 g / L, and the total amount of methylene blue was 31.3 ⁇ mol.
- Test procedure As a basic test procedure, first prepare 1g of each test substance, perform the hydrogen generation operation for the necessary ones, and apply dropwise the DPPH radical solution adjusted to a certain concentration. Go. If those test substances have antioxidant power, the dropped purple DPPH radical solution will be reduced and become amber, but the amount of DPPH radical solution input will gradually increase, and the antioxidant in the test substance When all of is consumed, the color change from purple to amber in the DPPH radical solution cannot be observed. The antioxidant power of each substance is evaluated from the total amount of DPPH radical solution dropped to this point in each test substance.
- a DPPH radical solution to be dropped Available in 0.1 g / L (volume molar concentration: 0.253 mM), 1 g / L (volume molar concentration: 2.53 mM), and 5 g / L (volume molar concentration: 12.65 mM) To do.
- three types of DPPH radical solutions having different concentrations were prepared because there was too much difference in the antioxidant power among the test substances. This is because higher experimental accuracy can be expected by using different radical solutions.
- the container used was a 20 ml test tube. Add 1 g of the test substance to the test tube, and then add 1 ml of DPPH radical solution dropwise with a pipette. For every 1 ml of dripping, the test tube is shaken lightly and stirred, and visually observed for color reaction.
- the color reaction of the DPPH radical is irreversible, and DPPH that has been once reduced and turned amber does not return to purple even when oxidized in the atmosphere. However, considering that hydrogen is consumed by oxygen in the atmosphere, it is necessary to drop the DPPH radical solution quickly.
- Alfa Aesar 50 mg magnesium powder (-100 + 200 mesh, 99.6%) as the first agent, platinum colloid 4 wt% solution from Tanaka Kikinzoku Kogyo Co., Ltd. 950 mg diluted 200-fold with purified water treated through, and added with citric acid to a concentration of 20% was used as the second agent.
- a mixture of the first agent and the second agent was used as a test substance, and after adjustment of the test substance, a DPPH radical solution was added dropwise with a pipette by 1 ml while visually observing the color change of the test substance.
- the dripping amount of the DPPH radical solution until the color change could not be confirmed was 3 ml at 5 g / L concentration and 1 ml at 1 g / L, and the total of reduced DPPH radicals was 40.48 ⁇ mol. It was.
- Example 15 Purified water treated with 50 mg of zinc powder manufactured by Wako Pure Chemical Industries, Ltd. as the first agent, and 4 wt% platinum colloid solution manufactured by Tanaka Kikinzoku Kogyo Co., Ltd. by passing Fujisawa city water through an ion exchange column manufactured by Organo.
- the second agent was 950 mg diluted 200-fold and citric acid added to a concentration of 20%.
- a mixture of the first agent and the second agent was used as a test substance, and after adjustment of the test substance, a DPPH radical solution was added dropwise with a pipette by 1 ml while visually observing the color change of the test substance.
- the amount of the DPPH radical solution dropped until no color change could be confirmed was 4 ml for the 5 g / L concentration and 3 ml for the 1 g / L concentration, and the total of the reduced DPPH radicals was 58.19 ⁇ mol. It was.
- Example 16 In purified water treated with Wako Pure Chemical Industries, Ltd. 50 mg calcium granule as the first agent, platinum colloid 4 wt% solution, manufactured by Tanaka Kikinzoku Kogyo Co., Ltd., passed through an ion exchange column manufactured by Organo Co., Ltd. The second agent was 950 mg diluted 200-fold.
- a mixture of the first agent and the second agent was used as a test substance, and after adjustment of the test substance, a DPPH radical solution was added dropwise with a pipette by 1 ml while visually observing the color change of the test substance.
- the dripping amount of the DPPH radical solution until the color change could not be confirmed was 3 ml at 5 g / L concentration and 1 ml at 1 g / L, and the total of reduced DPPH radicals was 40.48 ⁇ mol. It was.
- Example 17 Merck sodium borohydride 50 mg as the first agent, Tanaka Kikinzoku Kogyo Co., Ltd. platinum colloid 4 wt% solution 200 times with purified water treated with Fujisawa city tap water through an organo ion exchange column 950 mg diluted to 2 was used as the second agent.
- a mixture of the first agent and the second agent was used as a test substance, and after adjustment of the test substance, a DPPH radical solution was added dropwise with a pipette by 1 ml while visually observing the color change of the test substance.
- the amount of the DPPH radical solution dropped until no color change could be confirmed was 4 ml for the 5 g / L concentration and 1 ml for the 1 g / L concentration, and the total of the reduced DPPH radicals was 53.13 ⁇ mol. It was.
- Example 18 50 mg of Alfa Aesar (ALF) magnesium powder (-100 + 200 mesh, 99.6%) as the first agent, 4% by weight of palladium colloid from Tanaka Kikinzoku Kogyo Co., Ltd. 950 mg diluted 200-fold with purified water treated through, and added with citric acid to a concentration of 20% was used as the second agent.
- ALF Alfa Aesar
- a mixture of the first agent and the second agent was used as a test substance, and after adjustment of the test substance, a DPPH radical solution was added dropwise with a pipette by 1 ml while visually observing the color change of the test substance.
- the amount of the DPPH radical solution dropped until no color change could be confirmed was 2 ml for the 5 g / L concentration and 1 ml for the 1 g / L concentration, and the total of the reduced DPPH radicals was 27.83 ⁇ mol. It was.
- Alfa Aesar Magnesium Powder (-100 + 200 mesh, 99.6%) 50mg, first water, Fujisawa city tap water passed through an ion exchange column made by Organo Corporation, citric acid 20% concentration 950 mg added so as to be the second agent.
- a mixture of the first agent and the second agent was used as a test substance, and after adjustment of the test substance, a DPPH radical solution was added dropwise with a pipette by 1 ml while visually observing the color change of the test substance.
- the amount of the DPPH radical solution dropped until no color change could be confirmed was 5 ml at a concentration of 0.1 mg / L, and the total amount of reduced DPPH radicals was 1.27 ⁇ mol.
- a platinum colloid 4 wt% solution manufactured by Tanaka Kikinzoku Kogyo Co., Ltd. is diluted 200-fold with purified water obtained by treating Fujisawa city tap water through an ion exchange column manufactured by Organo Co., Ltd., and the citric acid concentration becomes 20%.
- the DPPH radical solution was dropped with a pipette 1 ml at a time while visually observing the color change of the test substance. 1 ml of DPPH radical solution with a concentration of 1 g / L could not be made transparent.
- OH radical generation system includes Fenton reaction system and hydrogen peroxide photolysis system.
- OH radicals and Fe (III) are generated by the reaction of Fe (II) and hydrogen peroxide.
- Apparatus JES-FR30 free radical monitor manufactured by JEOL was used for measurement of ESR spectrum.
- the measurement conditions are as follows. Magnetic field: 336 ⁇ 5 mT, microwave output: 4 mW, magnetic field modulation: 0.1 mT, amplification factor: appropriately adjusted.
- a manganese marker was used to adjust the third and fourth signals from the low magnetic field side so that the signals were recorded within the aforementioned magnetic field range.
- irradiation was performed at an illuminance of 10000 lx using a xenon lamp (HAYASHI, Luminer Ace, LA-100UV).
- a method for generating adducts such as DMPO-OH by generating OH radicals was as follows. In a glass test tube, 160 mL of citric acid, 20 mL of DMPO aqueous solution, and 20 mL of hydrogen peroxide solution were taken and irradiated with light with a xenon lamp for 5 s. Immediately after the solution was collected in a hematocrit tube, measurement of ESR spectrum was started about 30 s.
- the foaming Mg system take 5 mg of the metal powder that corresponds to the glass test tube and mix it with 160 mL of the above citric acid, 20 mL of DMPO aqueous solution, and 20 mL of hydrogen peroxide solution (total amount). 200 mL) was added, and light irradiation was performed immediately for 5 s. After the foaming was slightly settled, the solution was transferred to a hematocrit tube, and the ESR spectrum was measured after about 30 s.
- FIG. 8 is an ESR spectrum in which a so-called supernatant liquid separated from the foaming site is observed instead of the foaming site as an initial stage in which hydrogen gas is generated. Compared with the control system of FIG. 7, the signal intensity of DMPO-OH is not decreased, and the signal of DMPO-H is not observed.
- the hydrogen molecule generated by the external preparation (or a solution containing hydrogen molecules) is not brought into contact with the skin or mucous membrane, but the external preparation itself is held on the skin or mucous membrane. It is understood that it is important to generate hydrogen (active hydrogen) or to contact the site in the process of generating hydrogen (active hydrogen). Even if the external preparation is brought into contact with the skin at the stage where the generation has ended, even if hydrogen molecules may touch the site, hydrogen in the nascent state derived from the generation (foaming) of hydrogen It is because the effect of is not expected.
- the concept of active hydrogen in the present application includes not only hydrogen molecules (atomic hydrogen and hydride ions) activated by a catalyst, but also hydrogen molecules are forcibly oxidized (hydrogen) by radicals having strong oxidizing power such as hydroxy radicals.
- hydrogen molecules are forcibly oxidized (hydrogen) by radicals having strong oxidizing power such as hydroxy radicals.
- an active hydrogen generator such as a metal or a metal hydride
- the concept includes atomic hydrogen, hydride ions, or electrons themselves at the moment when hydrogen is generated.
- composition example in the case where this invention is comprised as an external preparation which does not contain a catalyst is given.
- usability as an external preparation and a dosage form balance (equivalent amount is extruded from a dual dispenser container, or a capsule-like first agent is dissolved.
- the first agent and the second agent have a weight ratio of 0.001 to 10,000, preferably 0. It is assumed that it is used in a ratio of 0.01 to 1000, more preferably 0.1 to 100, and particularly preferably 0.5 to 50, but is not limited thereto.
- First agent Atomized magnesium powder (-400 mesh) (Tangshan Weihao Magnesium Powder Co., Ltd.) 2.0wt% Hydroxypropylcellulose (Nippon Soda Co., Ltd.) 2.0wt% Glycerin (Toho Pharmaceutical Co., Ltd.) 10.0wt% Calfa (Grapefruit Seed Extract, Preservative) (Calfa Chemical Co., Ltd.) 0.05wt% AEROSIL200 (Nippon Aerosil Co., Ltd.) 2.0% Dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.) 42.0wt% Purified water 41.95wt% Or First agent: Magnesium hydride (Alfa Aesar) 1.0wt% Metroles (methylcellulose) SNB-30T (Shin-Etsu Chemical Co., Ltd.) 2.0wt% Glycerin (Toho Pharmaceutical Co., Ltd.) 10.0wt% AEROSIL200 (Nippon Aerosil Co., Ltd., anti
- 0.001 to 100 wt% preferably 0.01 to 50 wt%, more preferably 0.10 to 25 wt%, particularly preferably 0.25 to 10 wt%, but is not limited thereto.
- the content thereof is 0.01 to 99 wt%, preferably 0 in consideration of the reactivity of the metal or metal hydride used, the proton donating property of the acid, and the like. 25 to 90 wt%, more preferably 0.5 to 60 wt%, and particularly preferably 1 to 30 wt%, but is not limited thereto.
- the content takes into consideration the reaction rate, material cost, etc. However, it is 0.005 to 500,000 mg / L, preferably 0.05 to 50000 mg / L, more preferably 0.5 to 5000 mg / L, and particularly preferably 5 to 500 mg / L, but is not limited thereto. Further, when the anti-settling agent is contained in the first agent, the content thereof is 0.01 to 50 wt%, preferably 0.25 in consideration of the specific gravity or the amount of use of the metal or metal hydride to be used.
- the content is 1 wt% or more in consideration of the use amount of a metal or a metal hydride, reactivity with a protic solvent, and the like. However, it is preferably 25 wt% or more, more preferably 50 wt% or more, and particularly preferably 75 wt% or more, but is not limited thereto.
- the viscosity of the first agent is 1 to 64000000 mPA ⁇ s, preferably 10 to 6400000 mPA, taking into consideration the dosage form and thixotropy. S, more preferably 100 to 640000 mPA ⁇ s, particularly preferably 1000 to 64000 mPA ⁇ s, but is not limited thereto.
- the viscosity of the second agent is 1 to 64000000 mPA ⁇ s, preferably 2 to 6400000 mPA, taking into consideration the dosage form and thixotropy. S, more preferably 3 to 640000 mPA ⁇ s, particularly preferably 4 to 64000 mPA ⁇ s, but is not limited thereto.
- the viscosity of the mixture of the first agent and the second agent is from 1.25 to 256000 mPA ⁇ s, preferably from 2.5 to 192000 mPA ⁇ s, more preferably from 5 to 128000 mPA ⁇ s, particularly preferably from 10 to Although it is 64000 mPA ⁇ s, it is not limited to this.
- the aprotic solvent is a metal or a metal. It shows how to suppress the hydride decay over time. Since the purpose of this experiment is as described above, the amount of hydrogen described in this experiment has little correlation with the actual amount of hydrogen generated by the metal or metal hydride. Keep it. In fact, this experiment was carried out in a handmade and loose environment as described below. However, if the purpose is to accurately measure the hydrogen content in the container headspace, the above-mentioned water displacement method is used. It goes without saying that it should be adopted.
- DMSO dimethyl sulfoxide
- Test Procedure Each test substance was placed in a 420 cc glass container, and the opening was covered with a polyvinylidene chloride wrap. Furthermore, it was covered with aluminum foil, and a semi-sealed state was created by firmly fixing the periphery of the container with rubber bands from the top of the aluminum foil. After about 17 hours, a hole was carefully drilled in the wrap and foil, a hose was inserted, and the hydrogen concentration accumulated in the head space portion of the glass container was measured with a dissolved hydrogen meter “DHDI-1” manufactured by Toa DKK Corporation.
- DHDI-1 dissolved hydrogen meter
- the dissolved hydrogen meter is a device for measuring dissolved hydrogen in the liquid phase, but in order to avoid damaging the machine by pumping up magnesium hydride dispersed in the test substance, the purpose of this experiment is accurate. In view of the fact that there is no hydrogen measurement, such a method was adopted.
- Test substance Test substance 1 Purified by treating DMSO (manufactured by Wako Pure Chemical Industries, Ltd.) 17.50 g, magnesium hydride (manufactured by Alfa Aesar) 0.25 g, Fujisawa city tap water through an ion exchange column made by Organo 7.50 g water.
- Test substance 2 12.50 g of DMSO (manufactured by Wako Pure Chemical Industries, Ltd.), 0.25 g of magnesium hydride (manufactured by Alfa Aesar), purified water 12 treated by passing Fujisawa city tap water through an ion exchange column made by Organo .50 g.
- Test substance 3 purified water 17 treated with DMSO (manufactured by Wako Pure Chemical Industries, Ltd.) 7.50 g, magnesium hydride (manufactured by Alfa Aesar) 0.25 g, Fujisawa city tap water through an ion exchange column manufactured by Organo .50 g.
- DMSO manufactured by Wako Pure Chemical Industries, Ltd.
- magnesium hydride manufactured by Alfa Aesar
- Test substance 4 purified water 25 treated by passing DMSO (manufactured by Wako Pure Chemical Industries, Ltd.) 0.00g, magnesium hydride (manufactured by Alfa Aesar) 0.25g, Fujisawa city tap water through an ion exchange column manufactured by Organo .00g.
- DMSO manufactured by Wako Pure Chemical Industries, Ltd.
- magnesium hydride manufactured by Alfa Aesar
- Fujisawa city tap water through an ion exchange column manufactured by Organo .00g.
- the hydrogen concentration in the glass container headspace containing the test substance 1 was 0.002 ppm.
- the hydrogen concentration in the glass container headspace containing the test substance 2 was 0.007 ppm.
- the hydrogen concentration in the glass container headspace containing the test substance 3 was 0.017 ppm.
- the hydrogen concentration in the glass container headspace containing the test substance 4 was 0.058 ppm.
- the weight ratio of the aprotic solvent or the nonpolar solvent to the protic solvent in the first agent is 0 or more, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 when the protic solvent is 1.
- 7 or more, 8 or more, 9 or more and 10 or more are desirable, and the total amount or almost the total amount of the solvent (dispersion medium) in the first agent may be an aprotic solvent or a nonpolar solvent.
- Metal Metal magnesium (ALFA Aesar Co., Ltd.) (particle size: 150 ⁇ m or less) 0.5 g
- Solution Citric acid (Wako Pure Chemical Industries, Ltd.) in purified water treated by passing Fujisawa city tap water through an ion exchange column made by Organo 30 g of a solution prepared by dissolving 10% by weight) Test substance 4.
- Metal 0.5 g of magnesium hydride (ALFA Aesar)
- Solution 30 g of purified water treated by passing Fujisawa city tap water through an ion exchange column manufactured by Organo 4.
- Test substance Metal Magnesium hydride (ALFA Aesar) 0.5g, Solution: 10% by weight citric acid (Wako Pure Chemical Industries, Ltd.) in purified water treated with Fujisawa city tap water through an ion exchange column manufactured by Organo 30 g of solution dissolved to become 3.
- Test substance 1 peaks after about 10 minutes, 5 mL of hydrogen peak, test substance 2 peaks after approximately 10 minutes, and 280 mL of hydrogen peak, test substance 3 peaks after approximately 2.5 minutes 485 mL of hydrogen, Test Material 4 generated 0 mL of hydrogen, and Test Material 5 generated 840 mL of hydrogen peaking after approximately 12 minutes.
- the amount of hydrogen generated from 10 g of metal magnesium is calculated to be 830 mg.
- test substance 1 is 8.9 mg
- test substance 2 is 500 mg
- test substance 3 is 866 mg per 10 g of metal magnesium.
- the test substance 3 that is, 30 g of a 10% by weight citric acid solution is appropriate as a solution necessary for completely dissolving 0.5 g of metal magnesium.
- the solution necessary for completely dissolving 1 g of metal magnesium is 60 g of citric acid 10 wt% solution or 30 g of citric acid 20 wt% solution.
- the optimum amount / concentration balance between the metal and the acid can be calculated using the amount of metal, acid concentration, and amount of acid solution as variables. is there.
- a theoretical value of the amount of hydrogen that an appropriate amount of the metal or metal hydride can be generated at normal temperature and pressure is obtained from a chemical reaction formula of a metal or metal hydride and a protic solvent such as water.
- an appropriate acid such as citric acid
- the amount of the metal, the acid which can obtain a value that approximates the theoretical value.
- the amount of the acid solution solution in which the acid is dissolved in the protic solvent
- the remaining one variable is used for the external preparation.
- the amount of the metal or metal hydride used, the concentration of the acid, and the amount of the acid solution can be appropriately adjusted in consideration of the amount of hydrogen to be generated (concentration) and the blending balance of each component.
- the chemical reaction formula of magnesium hydride and water is: MgH2 + 2H2O ⁇ Mg (OH) 2 + 2H2 That is, 2 mol (4 g) of hydrogen is theoretically generated for 1 mol (26 g) of magnesium hydride. In other words, 76.923 mg of hydrogen is theoretically generated for 0.5 g of magnesium hydride.
- test substance 4 generated 0 mL of hydrogen and test substance 5 generated 840 mL of hydrogen.
- the composition of an external preparation considering the hydrogen amount (concentration) to generate
- an agent containing a metal or a metal hydride (first agent) and an agent containing a protic solvent (acid if necessary) (second agent) are mixed. It is desirable that about 0.0016 mg or more of hydrogen is generated per 1 g of the mixture (which is the amount of hydrogen contained in 1 g of saturated hydrogen water at 20 ° C. and 1 atm). This is because it is better to simply apply saturated hydrogen water below this concentration. In consideration of usability and safety, a hydrogen generation amount of about 1000 mg is desirable.
- the hydrogen generation amount for the mixture of the first agent and the second agent is 0.0016 mg / g to 1000 mg / g, preferably 0.016 to 100 mg / g, more preferably 0.16 to 10 mg / g. is there.
- the amount of hydrogen generated from the external preparation can be calculated from the metal or metal hydride, the above-mentioned method is performed with the amount of metal or metal hydride generating the desired hydrogen in mind. It is possible to adjust the amount of metal or metal hydride, the concentration of acid, and the amount of acid solution more appropriately.
- hydrogen molecules generated from the first agent in the container containing the first agent are 1 ppm to 100% by volume, preferably 100 ppm to 80%.
- Metal so as to fall within the range of volume%, more preferably 0.1 to 4 volume%, particularly preferably 1 to 4 volume% (with reference to the description described in the embodiment of the simple hydrogen generator described later) It is also desirable that the amount of metal hydride be adjusted.
- a metal such as magnesium or a metal hydride as the first agent
- a protic solvent such as water (including an acid if necessary) as the second agent
- the first and second agents are mixed there.
- a simple hydrogen generator for treatment or prevention comprising a container that generates active hydrogen or hydrogen molecules (preferably a gas poorly permeable container or a hydrogen gas hardly permeable container) can be configured. That is, at the time of use, the first agent and the second agent are charged and mixed in the container to generate hydrogen, and the user can use a tube or mask installed through the hydrogen outlet on the top of the container or at the outlet. Ingest gas or steam containing hydrogen through the like.
- Such a generator can be applied to devices such as humidifiers, gas cylinders, inhalers, and nebulizers that are intended to ingest gas or vapor, and the mechanisms of such devices can be used as appropriate.
- the metal or metal hydride in the first agent contains a dust explosion prevention agent, is subjected to corrosion prevention treatment, or is liquid (especially aprotic) It is desirable that an explosion prevention treatment such as being dispersed in a liquid containing a solvent or a nonpolar solvent) or being dispersed in an alkaline liquid.
- the concentration of hydrogen gas generated when the first agent and the second agent are mixed is 1 ppm to 100% by volume, preferably 100 ppm to 80% by volume, more preferably 0.8%.
- the particle size and amount of metal or metal hydride, the concentration of acid, the amount of solution used, etc. are appropriately adjusted so as to fall within the range of 1 to 4% by volume, particularly preferably 1 to 4% by volume. Is desirable.
- the method described in the above-mentioned [Measurement of hydrogen generation amount from metal magnesium and magnesium hydride by water displacement method] can be applied to the adjustment of the amount and concentration of such components.
- the hydrogen generated by the reaction between the first agent and the second agent must be 20 mL (about 1.8 mg).
- metallic magnesium is used as the first agent
- the amount of hydrogen generated from 10 g of metallic magnesium is calculated as described in [Measurement of hydrogen generation from metallic magnesium and magnesium hydride by water displacement method] above. Since it is 830 mg above, theoretically, about 21.7 mg of magnesium metal is required to generate 1.8 mg of hydrogen.
- a citric acid solution is used as the second agent, as described in [Measurement of hydrogen generation from metal magnesium and magnesium hydride by water displacement method]
- 0.5 g of metal magnesium is used.
- the “external preparation” is not particularly limited as long as it is applied to the skin and mucous membrane, and includes cosmetics, pharmaceuticals, quasi drugs and the like.
- the dosage form is also an aqueous system, solubilization system, emulsification system, oil liquid system, gel system, paste system, ointment system, aerosol system, gas phase system, water-oil two-layer system, water-oil-powder 3 Includes any dosage form, such as a layer. Further, it may be used by impregnating gauze, a film, a sheet, a non-woven fabric, etc. and sticking it on the skin.
- the use form is also arbitrary, for example, lotion, cosmetic oil, milky lotion, cream, pack, cosmetic liquid, sunscreen, makeup base, foundation, massage agent, cosmetic agent, nail cream, toothpaste, oral cleansing liquid, patch or It can be used in any form such as a spray.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Toxicology (AREA)
- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Emergency Medicine (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
2H(+)+2e(-)→H2 …(a)
H(+)+H(-)→H2 …(b)
すなわち、反応式(a)においては、電子供与体を含有する剤から供与される電子(e(-))が、プロトン供与体を含有する剤より供与されるプロトン(H(+))を還元することによって、水素分子(H2)を発生させる。
H2→2H・ …(c)
2H・→2H(+)+2e(-) …(d)
又は、
H2→H(+)+H(-) …(e)
H(-)→H(+)+2e(-) …(f)
活性水素という概念は、上述の(a)式におけるe(-)や(b)式におけるH(-)の他、反応式(c)で示されるような原子状水素(H・)と、反応式(e)で示されるような水素化物イオン(H(-))を共に含むとともに、水素分子イオンまたはプロトン化水素分子など、原理的にあり得る水素分子の活性化されたあらゆる態様を含む概念である。反応式(d)と(f)から示されるように、一つの水素分子を活性化することで、2個の電子が得られる。
《式3》
Mg+2H2O→Mg(OH)2+H2
となり、その反応機構としては、
《式4》
Mg→Mg(2+)+2e(-)
と、
《式5》
2H2O+2e(-)→2OH(-)+H2(水との反応の場合)
2H(+)+2e(-)→H2(水和プロトンとの反応の場合)
という素反応が考えられる。しかし、この想定は本発明を限定するものではない。
《式6》
CaH2+H2O→CaO+2H2となり、その反応は、基本的に次の反応式で表される。
H(+)+H(-)→H2
ここでH(-)は、水素化物イオンと呼ばれる物質である。水素化物イオンの直径は3オングストロームあり、Hの約3倍も大きい。その理由は、1s軌道に2個の電子が共存するため電子間の反発により電子雲が広がるためであると考えられている。電子雲が広いということは、電子が容易に取り去られることを意味する。
[実施例1]
第一剤:金属マグネシウム粉末(粒径:212~600μm、99.9%)(和光純薬工業株式会社製 試薬)を第一剤とした。
水素ガスを前記活性炭処理水にバブリングし、水素分子を飽和濃度(20℃、1気圧、1.6mg/L)まで溶存させた水素溶存水100mLに、田中貴金属製の白金コロイド4wt%溶液0.05gを添加した溶液(以下、抗酸化水)を作成し、プラスチック製容器に保管した。
実施例1 5秒
比較例1 消去せず
[DPPHラジカルの呈色変化による保存性評価試験]
[実施例2]
第一剤:金属マグネシウム粉末(粒径:212~600μm、99.9%)(和光純薬工業株式会社製 試薬)を第一剤とした。
抗酸化水を作成し、プラスチック製容器に保管した。
実施例2 60秒
比較例2 退色せず
[実施例の考察]
メチレンブルーは、酸化型にあるとき青色を呈しているが、還元され、還元型メチレンブルー(ロイコメチレンブルー)となるとき、青色が消失する。したがって、酸化型メチレンブルーに、任意の試薬を処理し、その後、青色が消失すれば、その試薬は、還元力を有すると見なすことができる。
1.試験手順
基本的な試験手順としては、まず各被験物質を1gずつ用意し、必要なものについては水素発生の操作を行い、そこに一定の濃度に調整されたメチレンブルー水溶液の滴下処理を施していく。それらの被験物質に還元力があれば、滴下された青色のメチレンブルーは還元されて無色になるが、メチレンブルー水溶液の投入量を徐々に増やしていき、被験物質内の還元剤が消費され尽くすと、メチレンブルーの青色から無色への呈色変化が観察できなくなる。各々の被験物質におけるこの時点までのメチレンブルー水溶液の合計滴下量から各々の物質がもつ還元力を評価する。
[実施例3]
Alfa Aesar(ALF)社製マグネシウムパウダー(-100+200 メッシュ、99.6%)50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈(白金コロイド濃度200mg/L、以下同様)し、そこにクエン酸を20%濃度(200g/L、以下同様)になるように加えたもの950mgを第二剤とした。
和光純薬工業株式会社製の亜鉛粉末(粒径:約6μm)50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈し、そこにクエン酸を20%濃度になるように加えたもの950mgを第二剤とする。
和光純薬工業株式会社製のカルシウム粒状50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈したもの950mgを第二剤とする。
Merck社製の水素化ホウ素ナトリウム50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈したもの950mgを第二剤とする。
和光純薬工業株式会社製の水素化カルシウム50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈したもの950mgを第二剤とする。他の例と同様に第一剤と第二剤を混合しメチレンブルーを滴下しようとしたが、第一剤と第二剤の反応があまりに激しく、第一剤第二剤が接触した瞬間に水素を発生させながら水が飛び散り瞬間的に反応が終了するため、測定できなかった。
Alfa Aesar(ALF)社製マグネシウムパウダー(-100+200 メッシュ、99.6%)50mgを第一剤、田中貴金属工業株式会社製のパラジウムコロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈し、そこにクエン酸を20%濃度になるように加えたもの950mgを第二剤とする。
Alfa Aesar(ALF)社製マグネシウムパウダー(-100+200 メッシュ、99.6%)50mgを第一剤、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にクエン酸を20%濃度になるように加えたもの950mgを第二剤とする。
藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水に水素ガスのバブリング処理を90分間行った飽和水素水に、田中貴金属工業株式会社製の白金コロイド4wt%溶液を200mg/Lの白金コロイド濃度になるように加えたもの1mLを被験物質とし、被験物質調整後、メチレンブルー水溶液を、被験物質の呈色変化を目視で観察しながら1mLずつピペットで滴下していった。呈色変化が確認できなくなるまでのメチレンブルー水溶液の滴下量は、50mg/L濃度のものが2mLであり、還元されたメチレンブルーの合計は、0.3μmolであった。
藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水に水素ガスのバブリング処理を90分間行った飽和水素水1mLを被験物質とし、被験物質調整後、メチレンブルー水溶液を、被験物質の呈色変化を目視で観察しながら1mLずつピペットで滴下していったところ、最も薄い濃度である50mg/L濃度のメチレンブルー水溶液を1mLも透明にすることができなかった。
田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈し、そこにクエン酸を20%濃度になるように加えたものを1mL被験物質とし、被験物質調整後、メチレンブルー水溶液を、被験物質の呈色変化を目視で観察しながら1mLずつピペットで滴下していったところ、最も薄い濃度である50mg/L濃度のメチレンブルー水溶液を1mLも透明にすることができなかった。
田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈したもの1mLを被験物質とし、被験物質調整後、メチレンブルー水溶液を、被験物質の呈色変化を目視で観察しながら1mLずつピペットで滴下していったところ、最も薄い濃度である50mg/L濃度のメチレンブルー水溶液を1mLも透明にすることができなかった。
以下、試験結果を表3に示すとともに図1にグラフを示す。
活性水素は、本来非常に不安定であると考えられるが、本治療または予防のための外用剤は、患部である抗酸化対象と接した状態で、活性水素を発生または水素分子を活性化するため、患部に活性水素を留めつつ(分散剤で剤に粘度を与えることが好ましい)、活性水素の還元力を患部に対して効率的に発揮することができる。
1.試験手順
上述のメチレンブルーの呈色変化による還元力評価試験の試験手順に準じて実施された。すなわち、セル内に1ccの被験物質と1ccのDPPH溶液を入れ、セル内のDPPH溶液が琥珀色に変化するかを目視で確認した。もしセル内のDPPHが紫色から琥珀色に変化すれば、被験物質が溶液中のDPPHラジカルを還元したということになる。
[実施例10]
Alfa Aesar(ALF)社製マグネシウムパウダー(-100+200 メッシュ、99.6%)50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈し、そこにクエン酸を20%濃度になるように加えたもの950mgを第二剤とした。
藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水に水素ガスのバブリング処理を90分間行った飽和水素水に、田中貴金属工業株式会社製の白金コロイド4wt%溶液を200mg/Lの白金コロイド濃度になるように加えたもの1mLを被験物質とし、被験物質調整後、DPPH溶液を濃度の低いものから順に呈色変化が確認できなくなるまでかわるがわる滴下していったところ、最終的に呈色変化を確認できたDPPH水溶液の濃度は、200mg/Lであった。
以上の試験結果を表4に示すとともに図2にグラフを示す。
本試験の方法では、実施例10が還元できたDPPH濃度は、溶解度限界である5000mg/Lとなったが、潜在的にははるかに濃い濃度のDPPHを還元することができるはずである。理論的には50mgのマグネシウムからは、4.17mgの水素が発生することになるが、これは、20℃、1気圧下における飽和水素水1gに含まれる水素量約0.0016mgのおよそ2600倍である。
本発明の治療又は予防のための外用剤を実際に作成しようとしたとき、その剤型は錠剤や貼付剤などいくつか考えられるが、ここでは、ジェル状の外用剤を作成する場合の組成例を挙げる。なお、本組成例は本発明を限定する趣旨ではない。
マグネシウム粉MG100(150μm以下)(株式会社関東金属)5.0wt%
メトローズ(メチルセルロース)SNB-30T(信越化学工業株式会社)2.0wt%
グリセリン(東豊薬品株式会社)10.0wt%
カルファ(グレープフルーツシード抽出エキス、防腐剤)(カルファケミカル株式会社)0.05wt%
精製水82.95wt%
第二剤:
白金コロイド4wt%溶液(田中貴金属工業株式会社)0.32wt%(白金コロイド自体の濃度は128mg/L)
クエン酸(和光純薬工業株式会社)10.0wt%
ヒドロキシプロピルセルロース(日本曹達株式会社)0.5wt%
グリセリン(東豊薬品株式会社)5.0wt%
カルファ(グレープフルーツシード抽出エキス、防腐剤)(カルファケミカル株式会社)0.05wt%
精製水84.13wt%
ここで、第一剤中のマグネシウム粉はジェルのなかに均等に分散されているが、この分散は水の粘性によって物理的に保持されているだけである。マグネシウムの比重のほうが大きいため、粘性が弱ければ次第にマグネシウムは沈んでいき、安定した製品にすることはできない。この意味においてマグネシウム粉の粒径は小さいほど良い。可能であれば本例で使用している150μm前後のものか、それ以下のものが望ましい。また増粘分散剤の種類および濃度には、そのマグネシウムを安定的にジェル中に保持できることが求められる。したがって必要に応じて、さらに酸化ポリエチレン、アマイドワックス、乾式シリカ等沈降防止剤を添加することは望ましいことである。
《式8》
Mg+2H2O→Mg(OH)2+H2
の反応が開始する。この反応によって混合直後は3程度であったpHはアルカリ性方向に引っ張られていくことになる(水酸化イオンの作用)。このとき、第二剤の酸が不十分であると、第一剤のマグネシウムが全て消費される前に、中性~アルカリ性環境になってしまい、その時点までに消費されていなかったマグネシウムは再び不動態被膜を形成し反応を止めてしまう。その結果、マグネシウム粉が残留することになり利便性の面からも望ましくない。なお本例においては、十分なクエン酸濃度になっており、マグネシウムが全て反応した後のpHは4程度の酸性である。
1.試験手順
1.1.アトピー性皮膚炎モデルの作製(初回惹起)
NC/Ngaマウスの背部,耳介部をバリカン,電気シェーバーで毛刈りした後,除毛剤(商品名:エピラット,カネボウ製)を適量塗布し除毛する。
必要に応じてシェーバーで除毛した後,4 %ドデシル硫酸ナトリウム水溶液150 μlをマイクロピペットで背部,耳介部に滴下しながらマイクロピペットのチップ裏部で均一に塗布する。
皮膚炎重症度が均一になるよう各群6匹づつに群分けを行い,1日1回、耳介部及び背部皮膚に100 mgを均一塗布する。
1.5の皮膚炎重症度スコア表に基づき,目視にてスコア付けを行う。スコアの確認は被験物質投与開始後0,3,6,9,12,15~日目に行う。
(a)発赤・出血
(背中の発赤および出血症状を観察する)
0 :無症状;背中に発赤および出血症状が認められない状態
1 :軽度;背中に発赤が局所的に認められ,連続的な擦傷に伴う出血が認められない状態
2 :中等度;背中に発赤が散在的に認められるか,連続的な擦傷に伴う出血が認められない状態
3 :重度;背中に発赤が全体的に認められるか,連続的な擦傷に伴う出血が認められる状態
(b)痂皮形成・乾燥
(背中の痂皮形成および乾燥症状を観察する)
0 :無症状;背中に痂皮形成および乾燥症状なし
1 :軽度;背中に局所的に認められ,皮膚がわずかに白色化し,角質の剥離がわずかに認められる状態
2 :中等度;背中に散在的に認められるか,明らかに角質の剥離が認められる状態
3 :重度;背中に痂皮が全体的に認められるか,明らかに角質の剥離が認められる状態
(c)浮腫
(耳介の浮腫を定性的に観察する)
0 :無症状;左右の耳介に厚みが認められない状態
1 :軽度;左右のどちらか1方にわずかに厚みが認められる状態
2 :中等度;いずれの耳介にも明らかな厚み,張りが認められる状態
3 :重度;いずれの耳介にも明らかな厚み,張りおよび反りが認められ,指で触れた時に硬さが感じられる状態
(d)擦傷・組織欠損
(耳介の擦傷および組織欠損症状を観察する)
0 :無症状;耳介に擦傷および組織欠損症状が認められない状態
1 :軽度;耳介に連続的でない擦傷が認められ,組織欠損は認められない状態
2 :中等度;耳介に小規模に連続的な擦傷が認められ,組織欠損は認められない状態
3 : 重度;耳介に連続的な擦傷が認められ,組織欠損が認められる状態
2.実施例、比較例、参考例の開示
[実施例11]
第一剤:株式会社関東金属製マグネシウム粉MG100(150μm以下)を5.0wt%、信越化学工業株式会社製メトローズ(メチルセルロース)SNB-30Tを2.0wt%、東豊薬品株式会社製グリセリン10.0wt%、カルファケミカル株式会社製カルファを0.05wt%、そして藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水82.95wt%から組成される組成物。
実施例11の第一剤と第二剤を混合し72時間以上放置することで水素が抜けてしまった反応生成物を、実施例11の基剤と見なし100mgを塗布した。
3.1.皮膚炎重症度の確認
実施例11の経皮投与試験における皮膚炎スコアの変化を全体(背部+耳介部),背部,耳介部に分けて示す。
1.試験手順
上述の試験手順に従った。
[実施例12]
Tangshan Weihao Magnesium Powder Co., Ltd.製Atomized magnesium powder(-400メッシュ)50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈し、そこにクエン酸を20%濃度になるように加えたもの950mgを第二剤とした。
Alfa Aesar(ALF)社製の水素化マグネシウム50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈したもの950mgを第二剤とする。
1.試験手順
基本的な試験手順としては、まず各被験物質を1gずつ用意し、必要なものについては水素発生の操作を行い、そこに一定の濃度に調整されたDPPHラジカル溶液の滴下処理を施していく。それらの被験物質に抗酸化力があれば、滴下された紫色のDPPHラジカル溶液は還元されて琥珀色になるが、DPPHラジカル溶液の投入量を徐々に増やしていき、被験物質内の抗酸化剤が消費され尽くすと、DPPHラジカル溶液の紫色から琥珀色への呈色変化が観察できなくなる。各々の被験物質におけるこの時点までのDPPHラジカル溶液の合計滴下量から各々の物質が有する抗酸化力を評価する。
0.1g/L(体積モル濃度:0.253mM)のものと、1g/L(体積モル濃度:2.53mM)のものと、5g/L(体積モル濃度:12.65mM)のものを用意する。ここで、濃度の異なる3種類のDPPHラジカル溶液を用意したのは、被験物質間での抗酸化力に差がありすぎるため、各被験物質の備える抗酸化力に応じて3種類の濃度のDPPHラジカル溶液を使い分けたほうが、より高い実験精度を期待できるからである。
[実施例14]
Alfa Aesar(ALF)社製マグネシウム パウダー(-100+200 メッシュ、99.6%)50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈し、そこにクエン酸を20%濃度になるように加えたもの950mgを第二剤とした。
和光純薬工業株式会社製の亜鉛粉末50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈し、そこにクエン酸を20%濃度になるように加えたもの950mgを第二剤とした。
和光純薬工業株式会社製のカルシウム粒状50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈したもの950mgを第二剤とした。
Merck社製の水素化ホウ素ナトリウム50mgを第一剤、田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈したもの950mgを第二剤とした。
Alfa Aesar(ALF)社製マグネシウム パウダー(-100+200 メッシュ、 99.6%)50mgを第一剤、田中貴金属工業株式会社製のパラジウムコロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈し、そこにクエン酸を20%濃度になるように加えたもの950mgを第二剤とした。
Alfa Aesar(ALF)社製マグネシウム パウダー(-100+200 メッシュ、 99.6%)50mgを第一剤、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にクエン酸を20%濃度になるように加えたもの950mgを第二剤とした。
藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水に水素ガスのバブリング処理を90分間行った飽和水素水に、田中貴金属工業株式会社製の白金コロイド4wt%溶液を200mg/Lの白金コロイド濃度になるように加えたもの1mlを被験物質とし、被験物質調整後、DPPHラジカル溶液を、被験物質の呈色変化を目視で観察しながら1mlずつピペットで滴下していった。呈色変化が確認できなくなるまでのDPPHラジカル溶液の滴下量は、0.1mg/L濃度のものが1mlであり、還元されたDPPHラジカルの合計は、0.25μmolであった。
藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水に、皇漢堂製薬社製日本薬局方アスコルビン酸を1000mg/Lになるように加えたもの1mlを被験物質とし、DPPHラジカル溶液を、被験物質の呈色変化を目視で観察しながら1mlずつピペットで滴下していった。呈色変化が確認できなくなるまでのDPPHラジカル溶液の滴下量は、5g/L濃度のものが1mlと1g/Lのものが1mlであり、還元されたDPPHラジカルの合計は、15.18μmolであった。
藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水に水素ガスのバブリング処理を90分間行った飽和水素水1mlを被験物質とし、被験物質調整後、DPPHラジカル溶液を、被験物質の呈色変化を目視で観察しながら1mlずつピペットで滴下していったところ、最も薄い濃度である0.1g/L濃度のDPPHラジカル溶液を1mlも透明にすることができなかった。
田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈し、そこにクエン酸を20%濃度になるように加えたものを1ml被験物質とし、被験物質調整後、DPPHラジカル溶液を、被験物質の呈色変化を目視で観察しながら1mlずつピペットで滴下していったところ、最も薄い濃度である0.1g/L濃度のDPPHラジカル溶液を1mlも透明にすることができなかった。
田中貴金属工業株式会社製の白金コロイド4wt%溶液を、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にて200倍に希釈したもの1mlを被験物質とし、被験物質調整後、DPPHラジカル溶液を、被験物質の呈色変化を目視で観察しながら1mlずつピペットで滴下していったところ、最も薄い濃度である0.1g/L濃度のDPPHラジカル溶液を1mlも透明にすることができなかった。
以下では、活性水素によるヒドロキシラジカルの消去を電子スピン共鳴法によって測定した。
OHラジカル発生系には、フェントン反応系と過酸化水素の光分解系がある。前者ではFe(II)と過酸化水素の反応よってOHラジカルとFe(III)が生成する。測定系に強力な還元剤が共存した場合、OHラジカル消去のほかに、Fe(III)の再還元を引き起こし、残っていた過酸化水素と反応してさらなるOHラジカルの生成を引き起こす危険性がある。
2-1 試薬について
過酸化水素は、原液30%(和光純薬工業株式会社製)を純水で希釈して、75 mMの水溶液を調製した。スピントラップ剤には5,5-ジメチル-1-ピロリン-N-オキシド(DMPO、ラボテック株式会社製)を使用し、純水を用いて1 M濃度の水溶液を調製した。クエン酸水溶液は、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にクエン酸を10wt%濃度になるように加えたものを使用した。マグネシウム(Mg)は、Alfa Aesar(ALF)社製のマグネシウムパウダー(-100+200 メッシュ、99.6%)を使用した。
ESRスペクトルの測定には、日本電子製JES-FR30 フリーラジカルモニターを使用した。測定の条件は次のとおりである。磁場:336 ± 5 mT、マイクロ波出力:4 mW、磁場変調:0.1 mT、増幅率:適宜調整。内部標準として、マンガンマーカーを使用して低磁場側から3本目と4本目を信号を前述の磁場の範囲内に記録するように調整した。紫外線および可視光線を照射するために、キセノンランプ(HAYASHI製、ルミナーエース、LA-100UV)を用い、10000 lxの照度で照射を行った。
OHラジカルを発生させて、DMPO-OHなどのアダクトを生成する方法は次の手順に従った。ガラス製試験管に、クエン酸160 mL、DMPO水溶液20 mL、過酸化水素水 20 mLを採り、キセノンランプで5 s間、光照射を行った。直ちに、ヘマトクリット管に溶液を採取して約30 s後に、ESRスペクトルの測定を開始した。発泡するMg系では、ガラス製試験管に該当する金属系粉末5 mgをとり、そこにあらかじめ混合しておいた上記のクエン酸160 mL、DMPO水溶液20 mL、過酸化水素水 20 mL(全量が200 mL)を加え、直ちに光照射を5 s間行った。発泡がやや落ち着いた後に、溶液をヘマトクリット管に移し、約30 s後にESRスペクトルの測定を行った。
3-1 OHラジカル発生系について
図7に示すように、クエン酸160 mL、DMPO水溶液20 mL、過酸化水素水 20 mLの各種溶液濃度、照射光強度、照射時間という条件では、比較的再現性のよいDMPO-OHのESR信号強度が得られた。その濃度は約0.1 mMであると推定される。なお、g値は、2.0055であった。
図9に示すように、DMPOアダクトのESRスペクトルが得られた。DMPO-OH、及び、水素ガス生成の初期段階における活性水素(発生期状態の水素)に由来するDMPO-Hの信号が生成していることを示している(参考:図10)。DMPO-Hの信号は全部で9本観測され、そのうち最も低磁場に現れるのが、マンガンマーカーのすぐ右側のものである。ノイズが重なっており解析が難しいが、DMPO-OHとDMPO-Hが確実に観測されている。
以下、これに限るものではないが、本発明を、触媒を含まない外用剤として構成した場合における組成例を挙げる。なお、上述のマグネシウム粉MG100を用いた組成例ともども本組成例においても、外用剤としての使い勝手や剤形バランス(デュアルディスペンサー容器から均等量で押し出すか、または、カプセル状の第一剤を溶液状の第二剤内で粉砕するかなど)等を考慮し、第一剤と第二剤は、第一剤を1としたとき、第二剤は重量比で0.001~10000、好ましくは0.01~1000、より好ましくは0.1から100、特に好ましくは0.5~50の割合で使用することを想定しているが、これに限るものではない。
Atomized magnesium powder(-400メッシュ)(Tangshan Weihao Magnesium Powder Co., Ltd.製)2.0wt%
ヒドロキシプロピルセルロース(日本曹達株式会社)2.0wt%
グリセリン(東豊薬品株式会社)10.0wt%
カルファ(グレープフルーツシード抽出エキス、防腐剤)(カルファケミカル株式会社)0.05wt%
AEROSIL200(日本アエロジル株式会社)2.0%
ジメチルスルホキシド(和光純薬工業株式会社)42.0wt%
精製水41.95wt%
あるいは、
第一剤:
水素化マグネシウム(Alfa Aesar)1.0wt%
メトローズ(メチルセルロース)SNB-30T(信越化学工業株式会社)2.0wt%
グリセリン(東豊薬品株式会社)10.0wt%
AEROSIL200(日本アエロジル株式会社、沈降防止剤)1.0%
カルファ(グレープフルーツシード抽出エキス、防腐剤)(カルファケミカル株式会社)0.05wt%
ジメチルスルホキシド(和光純薬工業株式会社、非プロトン性溶媒)83.95wt%
第二剤:
クエン酸(和光純薬工業株式会社)10.0wt%
ヒドロキシプロピルセルロース(日本曹達株式会社)0.5wt%
グリセリン(東豊薬品株式会社)5.0wt%
カルファ(グレープフルーツシード抽出エキス、防腐剤)(カルファケミカル株式会社)0.05wt%
精製水84.45wt%
本組成例のように粘度を持たせた外用剤を構成する場合、第一剤中の金属または金属の水素化物などの活性水素発生剤の含有量は、効果や粒子の分散性等を考慮し、0.001~100wt%、好ましくは0.01~50wt%、より好ましくは0.10~25wt%、特に好ましくは0.25~10wt%であるが、これに限るものではない。また、第二剤中に酸を含有させる場合、その含有量は、使用する金属または金属の水素化物の反応性や酸のプロトン供与性等を考慮し、0.01~99wt%、好ましくは0.25~90wt%、より好ましくは0.5~60wt%、特に好ましくは1~30wt%であるが、これに限るものではない。また、本組成例では含まれていないが、上述の組成例のように、第二剤中に触媒として白金などの貴金属微粒子を含有させる場合、その含有量は、反応速度や材料コスト等を考慮し、0.005~500000mg/L、好ましくは0.05~50000mg/L、より好ましくは0.5~5000mg/L、特に好ましくは5~500mg/Lであるが、これに限るものではない。また、第一剤中に沈降防止剤を含有させる場合、その含有量は、使用する金属または金属の水素化物の比重や使用量等を考慮し、0.01~50wt%、好ましくは0.25~25wt%、より好ましくは0.5~12.5wt%、特に好ましくは0.75~6.25wt%であるが、これに限るものではない。また、第一剤中に非プロトン性溶媒または無極性溶媒を含有させる場合、その含有量は、金属または金属の水素化物の使用量やプロトン性溶媒との反応性等を考慮し、1wt%以上、好ましくは25wt%以上、より好ましくは50wt%以上、特に好ましくは75wt%以上であるが、これに限るものではない。
また、
第一剤の粘度(剤温20℃、東機産業株式会社製TVB-10形粘度計にて測定)は、剤状やチクソ性などを考慮し、1~64000000mPA・s、好ましくは10~6400000mPA・s、より好ましくは100~640000mPA・s、特に好ましくは1000~64000mPA・sであるが、これに限るものではない。第二剤の粘度(剤温20℃、東機産業株式会社製TVB-10形粘度計にて測定)は、剤状やチクソ性などを考慮し、1~64000000mPA・s、好ましくは2~6400000mPA・s、より好ましくは3~640000mPA・s、特に好ましくは4~64000mPA・sであるが、これに限るものではない。また、第一剤と第二剤の混合物の粘度(剤温20℃、東機産業株式会社製TVB-10形粘度計にて第一剤と第二剤を混合し72時間以上放置した混合物を測定)は、皮膚や粘膜への滞留性や使用感を考慮し、1.25~256000mPA・s、好ましくは2.5~192000mPA・s、より好ましくは5~128000mPA・s、特に好ましくは10~64000mPA・sであるが、これに限るものではない。
水素化カルシウムなど著しい反応性を有する化合物を除けば、酸と反応し水素を発生する金属または金属の水素化物は、水道水など中性~アルカリ領域のpHを有するプロトン性溶媒とは非常に反応し難い。しかし一方で、こうした金属または金属の水素化物であっても、たとえば水中に分散しておけば僅かとはいえ水素を発生するため、経時的には、第一剤中の作用成分である金属または金属の水素化物は失われていくと言える。したがって、上述のような粒子表面への不動態被膜形成や、プロトン性溶媒の非プロトン性溶媒や無極性溶媒への一部置き換えが重要になってくるのだが、ここでは、第一剤中のプロトン性溶媒である水を、非プロトン性溶媒であるジメチルスルホキシド(DMSO)へ段階的に置き換えていった場合における容器ヘッドスペースの水素濃度を比較することによって、非プロトン性溶媒が金属または金属の水素化物の経時的減衰をどのように抑えるかを示す。なお、本実験の目的は上述のようなものであるため、本実験内で記述される水素量は、当該金属または金属の水素化物が発生させる実際の水素量とはあまり相関がないことを付言しておく。事実、本実験は、下記に記すようなハンドメイドな、緩い環境下で行われたが、容器ヘッドスペースの水素量を正確に測ることを目的とするのであれば、下述の水上置換法等を採用すべきであることは言うまでもない。
420cc容量のガラス容器に各試験物質を入れ、開口部をポリ塩化ビニリデン製ラップで覆った。さらにその上をアルミホイルで覆い、アルミホイル上から容器周囲を輪ゴムで堅く固定することで準密閉状態を作成した。約17時間後、慎重にラップとホイルに穴を開けホースを差込み、ガラス容器のヘッドスペース部に溜まった水素濃度を、東亜ディーケーケー株式会社製の溶存水素計『DHDI-1』で測定した。本来、溶存水素計は液相にある溶存水素を測定するための装置だが、試験物質に分散する水素化マグネシウムをポンプで吸い上げ機械を故障させることを避けるため、また、本実験の目的が正確な水素量測定にはないことを鑑みこのような方法を採った。
試験物質1:DMSO(和光純薬工業株式会社製)17.50g、水素化マグネシウム(Alfa Aesar社製)0.25g、藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水7.50g。
試験物質1を入れたガラス容器ヘッドスペースの水素濃度は、0.002ppmであった。試験物質2を入れたガラス容器ヘッドスペースの水素濃度は、0.007ppmであった。試験物質3を入れたガラス容器ヘッドスペースの水素濃度は、0.017ppmであった。試験物質4を入れたガラス容器ヘッドスペースの水素濃度は、0.058ppmであった。
1.試験方法
適宜な容量のフラスコを設置するとともに、ガラス管を、フラスコヘッドスペース部から、フラスコ脇の水の入ったビーカーに倒立して設置されたメスシリンダーまで延ばした。はじめに出てきた気体を捨てた後、フラスコ内に各試験物質を、金属、溶液の順に入れた。メスシリンダーヘッドスペース部に溜まった気体容積を、メスシリンダーの目盛りより測定した。
試験物質1.金属:金属マグネシウム(ALFA Aesar社)(粒径150μm以下)0.5g、溶液:藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水30g
試験物質2.金属:金属マグネシウム(ALFA Aesar社製)(粒径150μm以下)0.5g、溶液:藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にクエン酸(和光純薬工業株式会社製)を5重量%になるよう溶かした溶液30g
試験物質3.金属:金属マグネシウム(ALFA Aesar社製)(粒径150μm以下)0.5g、溶液:藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にクエン酸(和光純薬工業株式会社製)を10重量%になるよう溶かした溶液30g
試験物質4.金属:水素化マグネシウム(ALFA Aesar社)0.5g、溶液:藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水30g
試験物質5.金属:水素化マグネシウム(ALFA Aesar社)0.5g、溶液:藤沢市水道水をオルガノ社製イオン交換カラムに通して処理した精製水にクエン酸(和光純薬工業株式会社製)を10重量%になるよう溶かした溶液30g
3.結果及び考察
試験物質1は、およそ10分後をピークに5mLの水素を、試験物質2は、およそ10分後をピークに280mLの水素を、試験物質3は、およそ2.5分後をピークに485mLの水素を、試験物質4は0mLの水素を、試験物質5は、およそ12分後をピークに840mLの水素を発生させた。上述したように、金属マグネシウム10gより発生する水素量は計算上830mgであるが、同様に換算すると、金属マグネシウム10gあたり、試験物質1は8.9mg、試験物質2は500mg、試験物質3は866mgの水素を発生させたことになる。つまり、金属マグネシウム0.5gを溶かしきるのに必要な溶液としては、試験物質3、すなわちクエン酸10重量%溶液30gが妥当であることが想定される。さらにここから計算し、金属マグネシウム1gを溶かしきるのに必要な溶液としては、クエン酸10重量%溶液60g、あるいはクエン酸20重量%溶液30gなどであることが想定される。同様の仕方で、どのような金属、どのような酸を用いるのであれ、金属量、酸濃度、酸溶液量を変数として、該金属と該酸の大よその最適量/濃度バランスが算出可能である。すなわち、金属または金属の水素化物と水などのプロトン性溶媒との化学反応式から、該金属または金属の水素化物の適当量が常温・常圧下で発生させ得る水素量の理論値を得る。合わせて、水上置換法など水素量または体積測定方法を用いて、該金属をクエン酸など適宜な酸で反応させた際に前記理論値に近似する値を得られる、該金属の量、該酸の濃度、該酸の溶液(該酸を前記プロトン性溶媒に溶かした溶液)の量を変数とする関数を得る。該関数に基づき、該金属の量、該酸の濃度、該酸の溶液のいずれか2つの変数に適宜な数値を代入したときの、残りの1つの変数を計算する作業を通じて、外用剤に使用する金属または金属の水素化物の使用量、酸の濃度、及び酸の溶液の量を、発生させたい水素量(濃度)や各成分の配合バランスを考慮しながら、適宜調整することが可能である。たとえば、水素化マグネシウムと水の化学反応式は下記である:
MgH2+2H2O→Mg(OH)2+2H2
すなわち、水素化マグネシウム1mol(26g)に対し、水素2mol(4g)が理論上発生する。言い換えれば、水素化マグネシウム0.5gに対し、76.923mgの水素が理論上発生する。上述したように、本試験で、試験物質4は0mLの水素を、試験物質5は840mLの水素を発生させた。試験物質5における840mLの水素はとは重量にして75mgであるので、この値は理論値に近似する。つまり、水素化マグネシウム0.5gはクエン酸10重量%水溶液30gで理論値に近似する水素発生量を示した。ここから、例えば、水素化マグネシウムを1gに、クエン酸溶液を15g用いる場合は、クエン酸の濃度はほぼ40重量%が適切であることが想定される。あるいは例えば、クエン酸の濃度を5重量%にし、クエン酸溶液の量を10gにするならば、水素化マグネシウムの使用量はほぼ83mgが適切であることが想定される。このように、本方法を用いれば、発生させたい水素量(濃度)や各成分の配合バランスを考慮しながら、外用剤の組成を適宜調整することが可能である。なお、本発明における外用剤においては、金属または金属の水素化物を含有する剤(第一剤)と、プロトン性溶媒(必要に応じて酸)を含有する剤(第二剤)を混合したとき、該混合物1gにつき、少なくとも計算上、(20℃、1気圧における飽和水素水1gに含まれる水素量である)約0.0016mg以上の水素が発生することが望ましい。この濃度以下では、単に飽和水素水を塗布したほうが良いということになるからである。また、使い勝手や安全性を考慮すると、1000mg程度までの水素発生量が望ましい。すなわち、第一剤と第二剤を混合した混合物に対する水素発生量は、0.0016mg/g~1000mg/g、好ましくは0.016~100mg/g、より好ましくは0.16~10mg/gである。基本的に、外用剤よりの水素発生量は、金属または金属の水素化物より計算することができるので、望まれる水素を発生させる金属または金属の水素化物の量を念頭に置きつつ、上述の方法を使用することで、より適切に、金属または金属の水素化物の量と、酸の濃度と、酸の溶液の量を調整することが可能である。なお、その際、容器内での取り扱い上の安全性を考慮し、第一剤より計算上発生する水素分子が、第一剤を含む容器内において、1ppm~100容量%、好ましくは100ppm~80容量%、より好ましくは0.1~4容量%、特に好ましくは1~4容量%の範囲に収まるように(後述の簡易水素発生器の実施形態で記載される説明などを参考にして)金属または金属の水素化物の量が調整されていることは望ましいことである。
あり、例えば化粧水、化粧油、乳液、クリーム、パック、美容液、日焼け止め、化粧下地、ファンデーション、マッサージ剤、美容剤、爪クリーム、歯磨き粉、口腔清浄液、パッチ又は噴霧剤等任意の形態で使用できる。
Claims (18)
- 活性水素発生剤を含有する治療または予防のための外用剤であって、該活性水素が発生している過程のいずれかの時点で、皮膚または粘膜に接触させることを特徴とする外用剤。
- 請求項1に記載の外用剤において、
前記活性水素は、発生期状態の水素であることを特徴とする治療または予防のための外用剤。 - 請求項1~2のいずれか一項に記載の外用剤において、
前記活性水素発生剤は、水素分子を活性化する触媒を含むことを特徴とする外用剤。 - 請求項1~3のいずれか一項に記載の外用剤において、
前記活性水素発生剤は、少なくとも二つの物質を相互に接触させて前記活性水素を発生させることを特徴とする外用剤。 - 請求項1~4のいずれか一項に記載の外用剤において、
前記二つの物質の一方が、電子供与体または水素化物イオン供与体のうち少なくとも一方を含有する物質であり、前記二つの物質の他方が、プロトン供与体を含有する物質であることを特徴とする外用剤。 - 請求項1~5のいずれか一項に記載の外用剤において、
前記電子供与体または水素化物イオン供与体のうち少なくとも一方を含有する物質が、金属を含有する物質であることを特徴とする外用剤。 - 請求項1~6のいずれか一項に記載の外用剤において、
前記金属を含有する物質が、金属の水素化物または水素よりイオン化傾向が高い金属のうち少なくとも一方であることを特徴とする外用剤。 - 請求項1~7のいずれか一項記載の外用剤において、
前記金属がマグネシウムまたは水素化マグネシウムのうち少なくとも一方であることを特徴とする外用剤。 - 請求項1~8のいずれか一項記載の外用剤において、
前記電子供与体または水素化物イオン供与体のうち少なくとも一方が、非プロトン性溶媒または無極性溶媒の少なくとも一方を含む媒体に保持されていることを特徴とする外用剤。 - 請求項1~9のいずれか一項に記載の外用剤において、
前記プロトン供与体が水であることを特徴とする外用剤。 - 請求項1~10のいずれか一項に記載の外用剤において、
前記水は酸を含むことを特徴とする外用剤。 - 請求項1~11のいずれか一項に記載の外用剤において、
前記触媒が貴金属微粒子であることを特徴とする外用剤。 - 請求項1~12のいずれか一項に記載の外用剤において、
前記貴金属微粒子が、白金、パラジウム、ロジウム、イリジウム、ルテニウム、金、銀、レニウム、もしくはこれらの塩、合金化合物、錯体化合物、またはこれらの混合物のいずれかであることを特徴とする外用剤。 - 請求項1~13のいずれか一項に記載の外用剤において、
アトピー性皮膚炎の治療または予防のための外用剤であることを特徴とする外用剤。 - 請求項1~14のいずれか一項に記載の外用剤において、
前記外用剤が、化粧品であることを特徴とする外用剤。 - 請求項1~15のいずれか一項に記載の外用剤において、
前記活性水素発生剤が、水素含有リポソームを含むことを特徴とする外用剤。 - 金属の水素化物または水素よりイオン化傾向が高い金属のうち少なくとも一方と、貴金属微粒子である触媒とを含むことを特徴とする、胃粘膜の治療または予防のための外用剤。
- 第一剤として金属または金属の水素化物、第二剤としてプロトン性溶媒、及び第一剤と第二剤が混合しそこで活性水素または水素分子が発生する容器から成る治療または予防のための簡易水素発生器。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009548135A JPWO2009084743A1 (ja) | 2007-12-28 | 2009-01-05 | 治療または予防のための外用剤 |
US12/810,730 US20100272789A1 (en) | 2007-12-28 | 2009-01-05 | External medicine for treatment or prevention |
CN2009801015410A CN101951929A (zh) | 2007-12-28 | 2009-01-05 | 用于治疗或预防的外用剂 |
EP09700138A EP2236144A1 (en) | 2007-12-28 | 2009-01-05 | External preparation for preventive or therapeutic use |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007-340283 | 2007-12-28 | ||
JP2007340283 | 2007-12-28 | ||
JP2008-130957 | 2008-05-19 | ||
JP2008130957 | 2008-05-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009084743A1 true WO2009084743A1 (ja) | 2009-07-09 |
Family
ID=40824445
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2009/050010 WO2009084743A1 (ja) | 2007-12-28 | 2009-01-05 | 治療または予防のための外用剤 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20100272789A1 (ja) |
EP (1) | EP2236144A1 (ja) |
JP (1) | JPWO2009084743A1 (ja) |
CN (1) | CN101951929A (ja) |
WO (1) | WO2009084743A1 (ja) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012111834A1 (ja) * | 2011-02-17 | 2012-08-23 | バイオコーク技研株式会社 | 水素を発生する組成物 |
US8574503B2 (en) * | 2010-06-14 | 2013-11-05 | Miz Co., Ltd. | Instrument for nondestructively producing high-concentration hydrogen solution |
JP2014019689A (ja) * | 2012-07-23 | 2014-02-03 | Kracie Home Products Ltd | 水素発生用粉末 |
JP2014019635A (ja) * | 2012-07-23 | 2014-02-03 | Kracie Home Products Ltd | 水素発生用布および水素発生用紙ならびにそれらの製造方法 |
JP2014028714A (ja) * | 2012-07-31 | 2014-02-13 | Kracie Home Products Ltd | 水素発生用組成物 |
JP2015054073A (ja) * | 2013-09-11 | 2015-03-23 | 恵和株式会社 | 絆創膏 |
WO2015053225A1 (ja) * | 2013-10-09 | 2015-04-16 | 康弘 長岡 | 化粧料用キット及び毛髪処理剤用キット、並びに毛髪処理方法 |
WO2016010139A1 (ja) * | 2014-07-18 | 2016-01-21 | 株式会社ヴェルシーナ | 化粧用塗布剤、化粧用水素充填物の製造方法および化粧用水素充填物 |
JP2016132637A (ja) * | 2015-01-19 | 2016-07-25 | 康弘 長岡 | 肌質改善用化粧料キット及び髪質改善用毛髪処理剤キット並びに髪質改善方法 |
WO2017154514A1 (ja) * | 2016-03-11 | 2017-09-14 | バイオコーク技研株式会社 | 水素灸および水素灸の使用方法 |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9572880B2 (en) | 2010-08-27 | 2017-02-21 | Sienna Biopharmaceuticals, Inc. | Ultrasound delivery of nanoparticles |
TR201807153T4 (tr) | 2010-08-27 | 2018-06-21 | Sienna Biopharmaceuticals Inc | Hedefe yönelik termomodülasyon için bileşimler ve yöntemler. |
WO2012143041A1 (en) * | 2011-04-18 | 2012-10-26 | Sound Holding Ag | Composition, method for its manufacture and use thereof |
DE102012217387A1 (de) * | 2012-09-26 | 2014-04-17 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Therapeutische Nutzung von Wasserstoffmolekülen |
MX2015004524A (es) | 2012-10-11 | 2015-09-25 | Nanocomposix Inc | Metodos y composiciones de nanoplacas de plata. |
SI3086793T1 (sl) | 2013-12-24 | 2022-10-28 | Virginia Commonwealth University | Uporaba oksigeniranih holesterol sulfatov (OCS) za zdravljenje ledvične disfunkcije |
CN105456288B (zh) * | 2015-12-15 | 2020-07-14 | 上海交通大学 | 一种补镁兼具抗氧化作用的保健药品制剂及其制备方法 |
JP6704050B2 (ja) * | 2016-07-13 | 2020-06-03 | 株式会社マイトス | 水素を有効成分として含む軽度認知障害又は認知症の予防又は治療用組成物 |
JP7061354B2 (ja) * | 2018-02-01 | 2022-04-28 | 株式会社 ナチュラル | 化粧用組成物 |
US11904124B2 (en) * | 2018-04-06 | 2024-02-20 | H2 Universe, Llc. | Systems and methods for topical application of molecular hydrogen |
KR102194089B1 (ko) * | 2019-03-18 | 2020-12-22 | 랩앤피플주식회사 | 항산화 활성 및 미백 효과를 갖는 플렉시블 금속 패치 및 그 사용방법 |
CN113616671B (zh) * | 2020-05-09 | 2022-06-28 | 上海交通大学 | 微纳米MgH2化合物颗粒在制备抑制利什曼原虫感染及治疗利什曼病药物中的应用 |
CN112168786B (zh) * | 2020-09-04 | 2021-08-13 | 西安交通大学 | 一种储氢纳米钯光热效应靶向释放脂质体功能团及其制备方法和应用 |
CN112057468A (zh) * | 2020-09-23 | 2020-12-11 | 上海交通大学 | 一种氢化镁在制备防治慢性牙周炎的组合物中的应用及氢化镁牙膏 |
KR102668299B1 (ko) | 2021-07-30 | 2024-05-30 | 김형준 | 대사질환, 피부질환의 예방 또는 치료용 약제학적 조성물 |
KR102621276B1 (ko) * | 2021-07-30 | 2024-01-04 | 서울대학교산학협력단 | 항산화성 조성물 및 그 제조 방법 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003002466A1 (fr) | 2001-06-29 | 2003-01-09 | Miz Co., Ltd. | Procede d'antioxydation et eau a fonction antioxydante |
JP2003010865A (ja) | 2001-07-02 | 2003-01-14 | Hikari Berukomu:Kk | 酸性還元水製造装置 |
WO2004039735A1 (ja) * | 2002-04-26 | 2004-05-13 | Miz Co., Ltd. | 抗酸化方法、抗酸化機能水およびその用途 |
JP2004330146A (ja) * | 2003-05-09 | 2004-11-25 | Nippon Torimu:Kk | 活性水素溶存水の製造方法、その製造方法により得られる活性水素溶存水および発癌抑制剤 |
JP2004330028A (ja) * | 2003-05-02 | 2004-11-25 | San Waaku:Kk | 活性水素含有水の製法 |
JP2005126384A (ja) * | 2003-10-24 | 2005-05-19 | Mizu Kk | 薬理機能水、およびその用途 |
JP2006199866A (ja) | 2005-01-21 | 2006-08-03 | Nippon Torimu:Kk | 水素発生還元石鹸およびその製造方法 |
JP2006255613A (ja) * | 2005-03-17 | 2006-09-28 | Seiki Shiga | 活性水素溶存水の生成方法、生成器および生成用の石こう供給部材、並びに活性水素の生成性物質とその製造方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI260344B (en) * | 2001-01-12 | 2006-08-21 | Safe Hydrogen Llc | A method of operating a hydrogen-fueled device |
-
2009
- 2009-01-05 CN CN2009801015410A patent/CN101951929A/zh active Pending
- 2009-01-05 WO PCT/JP2009/050010 patent/WO2009084743A1/ja active Application Filing
- 2009-01-05 JP JP2009548135A patent/JPWO2009084743A1/ja active Pending
- 2009-01-05 EP EP09700138A patent/EP2236144A1/en not_active Withdrawn
- 2009-01-05 US US12/810,730 patent/US20100272789A1/en not_active Abandoned
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003002466A1 (fr) | 2001-06-29 | 2003-01-09 | Miz Co., Ltd. | Procede d'antioxydation et eau a fonction antioxydante |
JP2003010865A (ja) | 2001-07-02 | 2003-01-14 | Hikari Berukomu:Kk | 酸性還元水製造装置 |
WO2004039735A1 (ja) * | 2002-04-26 | 2004-05-13 | Miz Co., Ltd. | 抗酸化方法、抗酸化機能水およびその用途 |
JP2004330028A (ja) * | 2003-05-02 | 2004-11-25 | San Waaku:Kk | 活性水素含有水の製法 |
JP2004330146A (ja) * | 2003-05-09 | 2004-11-25 | Nippon Torimu:Kk | 活性水素溶存水の製造方法、その製造方法により得られる活性水素溶存水および発癌抑制剤 |
JP2005126384A (ja) * | 2003-10-24 | 2005-05-19 | Mizu Kk | 薬理機能水、およびその用途 |
JP2006199866A (ja) | 2005-01-21 | 2006-08-03 | Nippon Torimu:Kk | 水素発生還元石鹸およびその製造方法 |
JP2006255613A (ja) * | 2005-03-17 | 2006-09-28 | Seiki Shiga | 活性水素溶存水の生成方法、生成器および生成用の石こう供給部材、並びに活性水素の生成性物質とその製造方法 |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8574503B2 (en) * | 2010-06-14 | 2013-11-05 | Miz Co., Ltd. | Instrument for nondestructively producing high-concentration hydrogen solution |
JP6076092B2 (ja) * | 2011-02-17 | 2017-02-08 | バイオコーク技研株式会社 | 皮膚外用組成物 |
JPWO2012111834A1 (ja) * | 2011-02-17 | 2014-07-07 | バイオコーク技研株式会社 | 水素を発生する組成物 |
WO2012111834A1 (ja) * | 2011-02-17 | 2012-08-23 | バイオコーク技研株式会社 | 水素を発生する組成物 |
JP2014019689A (ja) * | 2012-07-23 | 2014-02-03 | Kracie Home Products Ltd | 水素発生用粉末 |
JP2014019635A (ja) * | 2012-07-23 | 2014-02-03 | Kracie Home Products Ltd | 水素発生用布および水素発生用紙ならびにそれらの製造方法 |
JP2014028714A (ja) * | 2012-07-31 | 2014-02-13 | Kracie Home Products Ltd | 水素発生用組成物 |
JP2015054073A (ja) * | 2013-09-11 | 2015-03-23 | 恵和株式会社 | 絆創膏 |
WO2015053225A1 (ja) * | 2013-10-09 | 2015-04-16 | 康弘 長岡 | 化粧料用キット及び毛髪処理剤用キット、並びに毛髪処理方法 |
JPWO2015053225A1 (ja) * | 2013-10-09 | 2017-03-09 | 康弘 長岡 | 化粧料用キット及び毛髪処理剤用キット、並びに毛髪処理方法 |
WO2016010139A1 (ja) * | 2014-07-18 | 2016-01-21 | 株式会社ヴェルシーナ | 化粧用塗布剤、化粧用水素充填物の製造方法および化粧用水素充填物 |
JPWO2016010139A1 (ja) * | 2014-07-18 | 2017-04-27 | 株式会社ヴェルシーナ | 化粧用塗布剤、化粧用水素充填物の製造方法および化粧用水素充填物 |
JP2016132637A (ja) * | 2015-01-19 | 2016-07-25 | 康弘 長岡 | 肌質改善用化粧料キット及び髪質改善用毛髪処理剤キット並びに髪質改善方法 |
WO2017154514A1 (ja) * | 2016-03-11 | 2017-09-14 | バイオコーク技研株式会社 | 水素灸および水素灸の使用方法 |
Also Published As
Publication number | Publication date |
---|---|
EP2236144A1 (en) | 2010-10-06 |
JPWO2009084743A1 (ja) | 2011-05-19 |
CN101951929A (zh) | 2011-01-19 |
US20100272789A1 (en) | 2010-10-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2009084743A1 (ja) | 治療または予防のための外用剤 | |
EP2200619B1 (en) | Electricity-generating particulates and the use thereof | |
Lim et al. | Comprehensive evaluation of carboxylated nanodiamond as a topical drug delivery system | |
US5756107A (en) | Formulations and methods for reducing skin irritation | |
US5958436A (en) | Formulations and methods for reducing skin irritation | |
US20030147937A1 (en) | Use of compatible solutes as substances having free radical scavenging properties | |
WO2007092085A2 (en) | Fragranced therapeutic delivery system | |
WO2007117352A2 (en) | Topical therapeutic delivery system | |
AU2007254653A1 (en) | Skin rejuvenation cream | |
JPWO2019211960A1 (ja) | 水素発生用複合組成物の製造方法及び水素製造方法 | |
JP2012514004A (ja) | 色素過剰を治療するための組成物及び方法 | |
JPH10511360A (ja) | 皮膚刺激を軽減するための製剤および方法 | |
WO2016061284A1 (en) | Compositions and methods comprising extracts of zingiberaceae | |
CN116035980A (zh) | 一种皮肤美白和祛斑功效的纳米脂质体组合物及其制备方法和应用 | |
Bajgai et al. | Role of molecular hydrogen in skin diseases and its impact in beauty | |
JP2007526218A (ja) | 新規な皮膚科学的組成物関連応用 | |
JP2008063295A (ja) | 白金/銀コロイドを含有する皮膚外用剤 | |
CN112137954A (zh) | 纳米银在制备预防和去除狐臭味的化妆品或药物中的应用以及一种液剂及其制备方法 | |
Mahitha et al. | Bacopa monniera stabilized silver nanoparticles attenuates oxidative stress induced by aluminum in albino mice | |
HRP20010696A2 (en) | Resorcinol composition | |
Chou et al. | Selective accumulation of ionic nanocrystal H2 storage system as an in situ H2/boric acid nanogenerator fights against ethanol-induced gastric ulcers | |
WO2020227367A1 (en) | Nitric oxide compositions and topical uses thereof | |
Ferrara et al. | Combined exposure to UV and PM affect skin oxinflammatory responses and it is prevented by antioxidant mix topical application: Evidences from clinical study | |
KR102591389B1 (ko) | 오르토 수소수가 첨가된 백금 및 은 나노 콜로이드 용액, 이를 포함하는 화장료 조성물 및 그 제조 방법 | |
TW202139966A (zh) | 美白用化妝料組合物、色素沉著症治療用藥學組合物及色素沉著症治療用皮膚外用劑組合物,美白方法及色素沉著症治療方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980101541.0 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09700138 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009548135 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12810730 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009700138 Country of ref document: EP |