JP2005246013A - Photochemical therapy - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a photochemical therapy which can destruct a lesion of tissue highly effective without any adverse effect, and can regenerate tissue to be used for curing a disease, cosmetic treatment and antiaging. <P>SOLUTION: In this photochemical therapy with less adverse effect, more than one kind of substances selected from photosensitive substances and antioxidants, and photolyase are applied on an affected part and light with an output of 10-300 mW/cm including 100-11,000 nm wavelength range is radiated thereto. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to photochemotherapy in which a therapeutic effect is enhanced and side effects are reduced by applying phototherapy to a tissue coated with one or more substances selected from a photosensitive substance and an antioxidant and photolyase.

Photochemotherapy is a chemotherapy that performs treatment and beauty treatment by administration of a photosensitive substance excited by light irradiation. In this method, by irradiating light to a tissue part of a living body where the pre-administered photosensitizer is accumulated, or to the blood inside the body containing the photosensitizer or to the bloodstream obtained by circulating the blood extracorporeally, It excites a photosensitive substance to exert its therapeutic action.

Michael J.M. Manya, J .; Clin. Oncology, 6,380, (1988)
According to these documents, most of the porphyrin compounds that have been studied and clinically applied as photochemotherapeutic agents so far are currently sold in Japan under the trade name Photofrin. ing. For photochemotherapy using these porphyrin compounds, drugs are administered to cancer patients (in principle, skin cancer and other cancers in the vicinity of the body surface unless surgical techniques are used), and normal cells are obtained after several days. In this case, the drug is largely metabolized, while the drug taken up by the cancer cell remains in the cancer cell as it is. At this time, the difference in the residual amount is several to several tens of times. Next, when the cancer cells are irradiated with light of 600 to 700 nm, only the cancer cells in which the drug remains are specifically killed.
The reason why these drugs remain only in cancer cells is not clear enough, but is thought to be due to differences in blood flow between cancer cells and normal cells, or differences in the activity of immune systems such as lymphocytes. Yes.

In these conventional phototherapy, the energy transfer from a drug activated by light irradiation causes the side oxygen to change to highly cytotoxic singlet oxygen or hydroxy radical, causing side effects that cause cell membrane damage or DNA damage. It was. Active oxygen, such as singlet oxygen and hydroxy radicals, is highly reactive, polymerizes cellular DNA, dimerizes it, inhibits normal reading of genetic information, suppresses cell growth, destroys collagen, It is known to exhibit cytotoxicity such as inhibition of enzyme activity, and these cell membrane damage and DNA damage have caused problems such as inflammation, necrosis and pigmentation in tissues.

Of the damaged DNA, it has been found that there is a phenomenon that it recovers by irradiating light of 300 to 500 nm. This disorder is a DNA damage of skin cells, and it has been known that photolyase recovers this. This photolyase has not yet been identified in humans, but it exists in most organisms from bacteria to animals to plants. DNA damage occurs in skin DNA irradiated with light having a high energy level used a plurality of times, such as aging cells, ultraviolet rays, and beauty. One of them is base dimerization. Photolyase specifically recognizes and binds to this base dimer to form a complex. The complex reacts with light of 300 to 500 nm, and photolyase uses the energy to convert the dimer into a monomer to repair DNA damage in the skin. If this base dimer is not repaired, damaged skin replication and gene expression are inhibited, causing protein synthesis inhibition and mutation, which may cause inflammation, disease and side effects.

The present invention has been studied to reduce the side effects of these conventional phototherapy, and as a result, one or more substances selected from a photosensitive substance and an antioxidant and a photolyase are applied to the affected area, and a wavelength region of 100 to 11000 nm. It was possible to complete photochemotherapy with high effects and few side effects by irradiating light with an output of 10 to 3000 mw / cm.
The photolyase used in the present invention is a known substance registered under the enzyme classification number EC4.11.99.3. DNA repair by photolyase is described in D.C. Yarosh and E.M. Klein in Trends in Photochemistry & Photobiology 3,175-181,1994. And U.S. Pat. No. 20030223982.

Ultraviolet rays and high-energy visible light used for photochemotherapy cause side effects such as burns and inflammation on tissues. These side effects induce tissue necrosis, sores, erythema, pigmentation and the like. Moreover, a photochemical reaction is caused by being absorbed by DNA in the cell nucleus, and a 6,4 photoadduct and a cyclobutane-type pyrimidine dimer (a dimer of DNA bases) are generated. It is also known that these lights sometimes generate active oxygen, resulting in oxidation of the DNA and damage. Our living body has a mechanism for automatically repairing such DNA damage, and in many cases, damaged DNA is repaired in a short time to become normal DNA. However, if many DNAs are damaged by being exposed to a large amount of ultraviolet rays at a time or being exposed to ultraviolet rays for a long time, the DNA cannot be recovered in time, and erroneous repair is performed. This incorrect repair causes mutations and causes skin cancer. In addition, DNA damage may affect collagen and elastin synthesis, causing wrinkles and tarmi, and may affect melanin metabolism in melanocytes, resulting in pigmentation.

Traditionally, photolyases, also called deoxyribodipyrimidine photolyases or DNA photolyases, have been found in eukaryotic organisms (eg yeast). Photolyase is activated by light having a wavelength of 350-500 nm. Activated photolyase specifically binds to and repairs the DNA mutation cyclobutane dipyridine.
A particularly efficient photolyase is extracted from the cyanobacteria Anacystis nidulans (marine microorganisms). This A. Nidulans-derived photolyase can be produced by fermentation using Escherichia coli or the like, and such a product can also be used in the present invention.
The light used for the photochemotherapy of the present invention is preferably 100 to 11000 nm, preferably 300 to 500 nm, more preferably 10 to 3000 mw / cm including a wavelength range of 370 to 430 nm because the effect can be expressed in a short time. .

These lights can excite fullerene photochemically to generate active oxygen and destroy old skin tissue. The light used in the photochemotherapy of the present invention may or may not be laser light, and may be pulsed light, but laser light is desirable because the irradiation range and intensity of light can be specified precisely, and Pulsed light is also desirable for maximizing effects with minimal energy and reducing pain and side effects. The combination of the dose of the administered compound and the number of times of light irradiation may be sufficient to develop the photocatalytic activity of fullerene. In the case of pulsed light, it is desirable that one pulse width is 1 ns (nanosecond) or more and 1 second or less, 30 mJ / square centimeter or more per pulse, and the number of shots is 1 to 10,000.

The light source that can be used in the present invention is not particularly limited as long as photocatalytic activity can be expressed in fullerene, and sunlight or a general visible light lamp can also be used. An incandescent lamp, a fluorescent lamp, a black lamp, a halogen lamp, A metal halide lamp, a xenon lamp, an ultraviolet fluorescent lamp, a light emitting diode, a chemical light, or the like can be used, which is extremely simple.
The light used in the present invention may be laser light, and suitable laser light is not particularly limited, but semiconductor lasers such as pulsed dye laser, Alexandrite laser, Ti: sapphire laser and Ga: As diode laser, CO2 laser, Er : YAG laser, Ho: YAG laser, ruby laser, Nd: YAG laser light may be used. In the present invention, the laser beam can be used when it is desired to exhibit high photocatalytic activity and completely destroy the tissue or to limit the photocatalytic activity to a local part of the skin, such as for hair removal.
More specifically, lasers that can be used in the present invention include, for example, a pulsed dye laser (585 nm), a ruby laser (694 nm), and a double Nd: YAG laser (532 nm) in the visible light spectrum region. Lasers emitting in the infrared spectral region include CO2 (10.6 μm), Er: YAG (2.94 μm), Hc: YAG (2.12 μm), Nd: YAG (1.06 μm) lasers, etc. It is not limited to.

Examples of optical devices that can actually be used in the present invention include products having the following specifications.
Photo Revive Blue, light source: semiconductor lamp, color: Blue, wavelength: 415 + 3 nm, light source LED, power supply: 500VA, input power supply: 90V-250V, frequency: 50 / 60Hz ± 5%, standard: 315mm x 280mm, output: 80mW / cm2
Luminous clear light, light source: metal halide gas lamp, treatment area: 30 x 30 cm2, wavelength: about 400-420 nm (UV-Free), output: maximum 200 mW / cm2, operation mode: CW (continuous)
ACULite Accu light, light source: Lamp, Power: 100 to 240Vlts AC, ^Frequency: 50 - 60 Hz, power: 360VA, wavelength: 400-500 nm, output: 1.370W / cm2
The photochemotherapy of the present invention may be any form of external preparation, and can be in any dosage form such as a dispersant, a fluidity agent, and a solid powder.

The photosensitizer of the present invention includes porphyrin, derivatives and complexes thereof, compounds and salts thereof, porfimer sodium (Photofurin (registered trademark)), hematoporphyrin, metalloporphyrin, tetraphenylporphyrin sulfate, protoporphyrin, uroporphyrin , Coproporphyrin, dihematoporphyrin ether (DHE), benzoporphyrin (BPS), ATX-70 (gallium-profylline complex), ATX-S10 (four-formyloxymethylidene-3-hydroxy-2-deuterio porphynyl (I) -6-7-bispartic acid), titanium oxide, zinc oxide, iron oxide, tungsten oxide, lead oxide, iron titanate, strontium titanate, Nickel titanate, gallium phosphide, silicon carbide, acridine, rose bengal, acridine orange, berberine sulfate, fluorescein, tetracycline, eosin Y, NTS, psoralen, bonerin, pheoformimide, chlorin e6, mesotetra (hydroxyphenyl) chlorin, phthalocyanine, It may be one or more substances selected from purpurin, 5-aminolevulinic acid (ALA), and HAT-DO1 (magnesium chlorine-chlorine dimer).

The following photosensitizers can also be used for the photosensitive material of the present invention. For example, in addition to various porphyrin derivatives, acridine, rose bengal, acridine orange, berberine sulfate, fluorescein, tetracycline, eosin Y, NTS, psoralen, bonerin, pheoformimide, chlorin e6, which are conventionally used as photosensitizers, Various photosensitizers such as mesotetra (hydroxyphenyl) chlorine, phthalocyanine, purpurin, 5-aminolevulinic acid (ALA), HAT-DO1 (magnesium chlorine-chlorine dimer) can be used.

In addition, porphyrin derivatives can also be used as the photosensitive substance of the present invention, porfimer sodium (Photofurin (registered trademark)), hematoporphyrin, metalloporphyrin, tetraphenylporphyrin sulfate, protoporphyrin, uroporphyrin, coproporphyrin, Dihematoporphyrin ether (DHE), benzoporphyrin (BPS), ATX-70 (gallium-profylline complex), ATX-S10 (four-formyloxymethylidene-3-hydroxy-2-deuterio porphynyl (IX) -6-7 -Bispartic acid). Among various porphyrin derivatives, porfimer sodium can be particularly preferably used.

Antioxidants of the present invention include ascorbic acid (hereinafter referred to as AsA), α-tocopherol (hereinafter abbreviated as TOC. TOC may be any of dl, d, and l), carotenoid (carotenoid is β-carotene) , Α-carotene, astaxanthin, retinol, retinoic acid, tretinoin, lycopene, lutein, cryptoxanthine and other carotenoids and optical isomers thereof), epigallocatechin gallate, epicatechin, proanthocyanidins, catechins, chopped acid , Phenol, polyphenols, glutathione, superoxydimastase, metal thionene, kojic acid, cysteine, cystine, dipotassium glycyrrhizinate, catalase, plant seed extract, grape seed extract, licorice extract. One or more antioxidants selected from the above may be used.

The above-mentioned photosensitive substance and antioxidant substance may be organic acid esters, sugar esters, fatty acid ester derivatives or the like or salts thereof and capsules thereof.
The organic acid constituting the organic acid ester may be phosphoric acid, acetic acid, sulfuric acid, α-hydroxy acid, amino acid, etc., and the sugar constituting the sugar ester may be natural simple substances such as glucose, fructose, sialic acid, etc. Any sugar or natural polysaccharide may be used. The amino acid constituting the amino acid ester may be an amino acid selected from essential amino acids such as glycine, alanine, lysine, cysteine, cystine and arginine.
The salt may be a highly safe salt such as an alkali metal, alkaline earth metal, or amine salt. Specific examples thereof include sodium (hereinafter abbreviated as Na), potassium (hereinafter abbreviated as K), calcium, Aluminum, magnesium (hereinafter abbreviated as Mg), zinc, iron, bismuth, triethanolamine salt, and the like may be used.

As examples of the photosensitive substance and the antioxidant substance that can be used in the present invention, the following mixtures and structures may be used. Liposome capsule, 1,3 butylene glycol (hereinafter abbreviated as BG) dispersion, propylene glycol (hereinafter abbreviated as PG) dispersion, ethanol and cetanol dispersion, polyhydric alcohol dispersion, alcohol dispersion, glycerin dispersion, natural Oil coating, room temperature hydrogenated oil coating, vegetable oil dispersion, liposome capsule, microcapsule, nanocapsule. Those coated with a coating agent such as gelatin and fats and oils, those encapsulated with liposomes or dextrin, and those intercalated with diatomaceous earth can also be used.

A gene repair enzyme other than photorease can also be added to the photorease of the present invention. For example, as an example, T4 endonuclease 5 (hereinafter referred to as T4N5) may be used in combination with the photorease of the present invention. This T4N5 is a type of phosphodiesterase that is produced by the denV genetic factor of bacteriophage T4 and hydrolyzes nucleic acids with (5'-3 ') linkages. It recognizes the DNA part damaged by pyrimidine dimers induced by ultraviolet light or high energy light, and has the function of excising it. The new correct base is taken up by the polymerizing enzyme using the complementary strand as a matrix and ligated to the first DNA strand by ligase. This gene excision repair mechanism is a reaction that does not require photoactivation. T4N5 is a prokaryotic enzyme, but is known to act on human cells.

The dosage of the photosensitizer, antioxidant, and photorease of the present invention varies depending on age, body weight, disease state, therapeutic effect, administration method, administration time, administration days, administration period, but is usually 0.01 mg at one photochemotherapy. Although -100 mg is apply | coated to 1 square cm of skin of an affected part, it is not limited to this.

Specific diseases effective for the photochemotherapy of the present invention include malignant tumors, benign tumors, pigmentation, acne, moles, hair loss, warts, oily skin, dry skin, seborrhea, thickening of the epidermis, wrinkles, tarmi , Athlete's foot, infection, hyperkeratosis, skin hyperproliferation, psoriatic plaque, actinic keratosis, keloid, aging, streaks, warts, atrophied scars, enlarged scars, scars, non-aesthetic It can also be used as a cosmetic method of a characteristic characteristic or as a supplement method thereof.

In the present invention, the photosensitizer, antioxidant, and photolyase are used by dispersing the photolyase in a base material such as highly transparent glycerin or oil in the range of 0.001% to 90% by weight. Or it can also apply | coat to one part.

After application, it can also be diffused and penetrated by a sonic or optical unit, preferably operating at 0.01-10 w / cm2. Specifically, Sonic Nanocare from Nanocare or Model 3325A pulse generator and Model A5525 parameter converter from Hewlett-Packard may be used. By performing a sound wave or light penetration treatment with these instruments, a large amount of photolyase easily penetrates into the skin.

Furthermore, it makes it possible to increase the penetration of cosmetics or pharmaceuticals, in particular dermatological active agents. In this case, a cosmetic or pharmaceutical composition containing one or more active agents can be applied after irradiation and before complete formation of the new skin. Examples of active agents include active agents used transdermally as pharmaceuticals intended for local and / or systemic administration, in particular retinoic acid, acid inclusions (retinoids), benzoyl peroxide, antibiotics, Corticosteroids, antibacterial agents, vitamins D3, D2 and their inclusions.

Additives that can be added to normal cosmetics, quasi-drugs, and pharmaceuticals are added to the photosensitizers, antioxidants, and photoreases used in the skin photochemotherapy of the present invention to improve dispersibility, feeling of use, stability, etc. The physical properties can be improved satisfactorily. For example, as a secondary agent of photolyase that can be used in the present invention, for example, water, physiological saline, 5% glucose or mannitol solution, water-soluble organic solvent, glycerin, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, butylene glycol , Polyethylene glycol, cremophor and the like and a mixture thereof, and a mixture of water and the water-soluble organic solvent.

The photosensitizer, antioxidant, and photorease used in the skin photochemotherapy of the present invention are prepared by blending the above-mentioned components with various forms of bases known as normal skin photochemotherapy according to conventional methods. can do. For example, basic cosmetics such as milky lotion, cream, lotion, cosmetic liquid, pack, oil, nail care product, lip balm, hair restorer, hair nourishing agent, bathing agent, antiperspirant, facial cleanser such as shampoo, rinse, and whole body cleanser , Foundation, white powder, makeup cosmetics such as makeup base, ointments, dispersions, etc., liquid, multilayer, emulsion, paste, gel, solid, powder, granule Various forms such as a shape can be selected.

Moreover, in the photosensitizer used for the photochemotherapy of the skin of the present invention, the antioxidant, and the photorease, in addition to the above-mentioned components, usually within the range not impairing the effects of the present invention, cosmetics and quasi drugs, Ingredients used in pharmaceutical preparations such as topical medicine, ie water (purified water, hot spring water, deep water, etc.), oil agent, surfactant, metal soap, gelling agent, powder, alcohol, water-soluble polymer, film Forming agents, resins, clathrate compounds, moisturizers, antibacterial agents, fragrances, deodorants, salts, pH adjusters, fresheners, animal / microbe derived extracts, plant extracts, vitamins, amino acids, nucleic acids, hormones More preferably, one kind or two or more kinds of cells, cell activators, blood circulation promoters, astringents, antiseborrheic agents, active oxygen scavengers, keratolytic agents, enzymes, etc. in the range of 0.001 to 90% by weight. Add in the range of 0.01 to 50% weight It can be.

As an oil agent, as long as it is used for normal cosmetics, it is a natural oil, a synthetic oil, or a solid, semi-solid, liquid, etc. , Waxes, fatty acids, higher alcohols, ester oils, silicone oils, fluorinated oils, and the like can be used. For example, hydrocarbons such as ozokerite, squalane, squalene, ceresin, paraffin, paraffin wax, liquid paraffin, pristane, polyisobutylene, microcrystalline wax, petroleum jelly, waxes such as beeswax, carnauba wax, candelilla wax, whale wax, beef fat , Beef leg fat, beef bone fat, hardened beef fat, hardened oil, turtle oil, pork fat, horse fat, mink oil, liver oil, egg yolk oil and other animal oils, lanolin, liquid lanolin, reduced lanolin, lanolin alcohol, hard lanolin, acetic acid Lanolin inclusions such as lanolin, lanolin fatty acid isopropyl, phospholipid, phosphadylcholine, POE lanolin alcohol ether, POE lanolin alcohol acetate, lanolin fatty acid polyethylene glycol, POE hydrogenated lanolin alcohol ether, lauric Fatty acids such as acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, oleic acid, linoleic acid, arachidonic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), isostearic acid, 12-hydroxystearic acid Lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, behenyl alcohol, hexadecyl alcohol, oleyl alcohol, isostearyl alcohol, hexyl decanol, octyldodecanol, cetostearyl alcohol-2-decyltetradecinol, cholesterol, phytosterol , Sitosterol, lanosterol, POE cholesterol ether, monostearyl glycerol ether (batyl alcohol), etc. Coal, diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, N-alkyl glycol monoisostearate, isocetyl isostearate, trimethylolpropane triisostearate, ethylene di-2-ethylhexanoate Glycol-2-ethylhexanoate cetyl, tri-2-ethylhexanoate trimethylolpropane, tetra-2-ethylhexanoate pentaerythritol, cetyl octoate, octyldodecyl gum ester, oleic oleate, octyldodecyl oleate, oleic acid Decyl, neopentyl glycol dicaprate, triethyl citrate, 2-ethylhexyl succinate, amyl acetate, ethyl acetate, butyl acetate, isocetyl stearate, butyl stearate, Diisopropyl sebacate, di-2-ethylhexyl sebacate, cetyl lactate, myristyl lactate, isopropyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptylundecyl palmitate, cholesteryl 12-hydroxystearylate, Dipentaerythritol fatty acid ester, isopropyl myristate, octyldodecyl myristate, 2-hexyldecyl myristate, myristyl myristate, hexyldecyl dimethyloctanoate, ethyl laurate, hexyl laurate, 2-octyl N-lauroyl-L-glutamate Ester oil such as dodecyl ester, diisostearyl malate, acetoglyceride, triisooctanoic acid glyceride, triisostearic acid glyceride, Glyceride oil such as glyceride of lysopalmitic acid, glyceride of tri-2-ethylhexanoic acid, glyceride of monostearic acid, glyceride of di-2-heptylundecanoic acid, glyceride of trimyristic acid, dimethylpolysiloxane, methylphenylpolysiloxane, methylhydrogen Higher alkoxy-modified silicones such as polysiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, tetramethyltetrahydrogencyclotetrasiloxane, stearoxysilicone, higher fatty acid-modified silicone, silicone resin, silicone rubber , Silicone oil such as silicone resin, perfluoropolyether, perfluorodecalin, perfluorooctane, etc. Motokei oil and the like.

As the surfactant, there are anionic, cationic, nonionic and amphoteric active agents. In the present invention, nonionic surfactants can be used.
However, when the (A component) storage stabilizer defined in claim 1 of the present invention or an organic acid having a chelating effect or a salt thereof is blended, the anionic, cationic, and amphoteric activators are reduced to 0. It can be used in the range of 0.01 to 10%. Examples of the anionic surfactant that can be used at this time include fatty acid soaps such as sodium stearate and triethanolamine palmitate, alkyl ether carboxylic acids and salts thereof, carboxylates such as condensation of amino acids and fatty acids, alkyl sulfonic acids, and alkenes. Sulfonate, sulfonate of fatty acid ester, sulfonate of fatty acid amide, sulfonate of alkyl sulfonate and its formalin condensate, alkyl sulfate, secondary higher alcohol sulfate, alkyl and allyl ether Sulfate ester, sulfate ester of fatty acid ester, sulfate ester salt of fatty acid alkylol amide, sulfate ester salt such as funnel oil, alkyl phosphate, ether phosphate, alkyl allyl ether phosphate, amide phosphate, N -Acylamino Cationic surfactants include alkylamine salts, amine salts such as polyamines and amino alcohol fatty acid inclusions, alkyl quaternary ammonium salts, aromatic quaternary ammonium salts, pyridium salts, imidazolium salts and the like; Nonionic surfactants include sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyethylene glycol fatty acid ester, sucrose fatty acid ester, polyoxyethylene alkyl ether, polyoxypropylene alkyl ether, poly Oxyethylene alkyl phenyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxy Tylene glycerin fatty acid ester, polyoxyethylene propylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene phytostanol ether, polyoxyethylene phytosterol ether, polyoxyethylene cholestanol ether, polyoxyethylene cholesteryl Ethers, polyoxyalkylene-modified organopolysiloxanes, polyoxyalkylene / alkyl co-modified organopolysiloxanes, alkanolamides, sugar ethers, sugar amides, etc .; amphoteric surfactants include betaines, aminocarboxylates, imidazoline inclusions, etc. Examples include, but are not limited to:

As the metal soap, 12-hydroxy aluminum stearate, zinc stearate, aluminum stearate, calcium stearate, magnesium stearate, zinc myristate, magnesium myristate, zinc cetyl phosphate, calcium cetyl phosphate, zinc sodium cetyl phosphate, zinc laurate And zinc undecylenate.

Examples of gelling agents include amino acid inclusions such as N-lauroyl-L-glutamic acid, α, γ-di-n-butylamine, dextrin palmitate, dextrin stearate, dextrin 2-ethylhexanoate palmitate, etc. Dextrin fatty acid ester, sucrose palmitate ester, sucrose fatty acid ester such as sucrose stearate ester, benzylidene inclusion body of sorbitol such as monobenzylidene sorbitol, dibenzylidene sorbitol, dimethylbenzyl dodecyl ammonium montmorillonite clay, dimethyl dioctadecyl ammonium montmorillonite clay Organic modified clay minerals such as

If the powder is used in ordinary cosmetics, its shape (spherical, needle-like, plate-like, etc.), particle size (smoke-like, fine particles, pigment grade, etc.), particle structure (porous) Any inorganic powder can be used, for example, magnesium oxide, barium sulfate, calcium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, talc, synthetic mica. , Mica, kaolin, sericite, muscovite, synthetic mica, phlogopite, saucite, biotite, lithia mica, silicic acid, anhydrous silicic acid, aluminum silicate, magnesium silicate, aluminum magnesium silicate, calcium silicate, Barium silicate, strontium silicate, metal tungstate, hydroxyapatite, vermiculite, hydrite, montmorillonite, z Light, ceramic powder, dicalcium phosphate, alumina, aluminum hydroxide, boron nitride, boron nitride, etc .; organic powders include polyamide powder, polyester powder, polyethylene powder, polypropylene powder, polystyrene powder, polyurethane, benzoguanamine powder, polymethyl Benzoguanamine powder, tetrafluoroethylene powder, polymethyl methacrylate powder, cellulose, silk powder, nylon powder, 12 nylon, 6 nylon, styrene / acrylic acid copolymer, divinylbenzene / styrene copolymer, vinyl resin, urea resin, phenol Resin, fluororesin, silicon resin, acrylic resin, melamine resin, epoxy resin, polycarbonate resin, microcrystalline fiber powder, Lauro Luridine, etc .; Colored pigments include inorganic red pigments such as iron oxide, iron hydroxide and iron titanate, inorganic brown pigments such as γ-iron oxide, yellow inorganic oxides such as yellow iron oxide and loess, black iron oxide, Inorganic black pigments such as carbon black, inorganic purple pigments such as manganese violet and cobalt violet, inorganic green pigments such as chromium hydroxide, chromium oxide, cobalt oxide and cobalt titanate, inorganic blue pigments such as bitumen and ultramarine, tar Dye raked, natural dye raked, composite powder made by combining these powders, etc .; pearl pigments include titanium oxide-coated mica, titanium oxide-coated mica, bismuth oxychloride, titanium oxide Coated bismuth oxychloride, titanium oxide coated talc, fish scale foil, titanium oxide coated colored mica, etc .; -Powder, stainless steel powder, etc. As tar pigments, Red No. 3, Red No. 104, Red No. 106, Red No. 201, Red No. 202, Red No. 204, Red No. 205, Red No. 220, Red No. 226, Red No. 227 , Red 228, Red 230, Red 401, Red 505, Yellow 4, Yellow 5, Yellow 202, Yellow 203, Yellow 204, Yellow 401, Blue 1, Blue 2, Blue No. 201, Blue No. 404, Green No. 3, Green No. 201, Green No. 204, Green No. 205, Orange No. 201, Orange No. 203, Orange No. 204, Orange No. 206, Orange No. 207, etc .; A powder selected from acids, laccaic acid, calsamine, bradylin, crocin, etc., and these powders are compounded or surface treated with oils, silicones, or fluorine compounds It may be carried out powder.

Examples of alcohols include lower alcohols such as ethanol and isopropanol, glycerin, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, sorbitol, erythritol, maltitol, maltose, Examples include xylitol, xylose, trehalose, inositol, glucose, mannitol, polyhydric alcohols such as polyethylene glycol.

Examples of water-soluble polymers include chondroitin sulfate, hyaluronic acid, mucin, dermatan sulfate, mucopolysaccharides selected from heparin and keratan sulfate and salts thereof, gum arabic, tragacanth, galactan, carob gum, guar gum, caraya gum, carrageenan, pectin, agar , Quince seeds, algae colloids, plant gums such as Trang gum, locust bean gum, galactomannan, microbial polymers such as xanthan gum, dextran, succinoglucan, pullulan, animal systems such as collagen, casein, albumin, gelatin Molecule, starch polymer such as starch, carboxymethyl starch, methylhydroxypropyl starch, methylcellulose, ethylcellulose, methylhydroxypropylcellulose, carboxymethylcell Cellulose, hydroxymethylcellulose, hydroxypropylcellulose, nitrocellulose, sodium cellulose sulfate, sodium carboxymethylcellulose, crystalline cellulose, cellulose polymer of cellulose powder, sodium alginate, propylene glycol ester of alginic acid, polyvinyl methyl ether, Acrylic polymers such as vinyl polymers such as carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer, polyoxyethylene polymers, polyoxyethylene polyoxypropylene copolymer polymers, sodium polyacrylate, polyethyl acrylate and polyacrylamide Inorganic water-soluble polymers such as polymer, polyethyleneimine, cationic polymer, bentonite, laponite, hectorite, etc. That. Also included are film forming agents such as polyvinyl alcohol and polyvinyl pyrrolidone.

Antibacterial agents include benzoic acid, sodium benzoate, salicylic acid, coalic acid, sorbic acid, potassium sorbate, paraoxybenzoic acid ester, parachlorometacresol, hexachlorophene, benzalkonium chloride, chlorhexidine chloride, trichlorocarbanilide, photosensitive And silicon, bis (2-pyridylthio-1-oxide) zinc, pentadiol, iturin, surfactin, polyglycine, ethanol, phenoxyethanol, isopropylmethylphenol, and the like.

Examples of the pH adjusting agent include lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, malic acid, potassium carbonate, sodium hydrogen carbonate, ammonium hydrogen carbonate, and the like, and examples of the refreshing agent include L-menthol and camphor.

Examples of animal-derived and microorganism-derived extracts include blood extracts such as pigs and cows, serum deproteinized extracts, spleen extracts, avian egg components, chicken crown extracts, fish meat extracts, squid, chitin, chitosan Shellfish extract, shellfish extract, royal jelly, silk protein and its degradation products or inclusions thereof, hemoglobin or degradation product thereof, milk, casein and inclusions or degradation products thereof, lactoferrin or degradation product thereof, collagen And inclusion bodies thereof or hydrolysates thereof, elastin and inclusion bodies or hydrolysis products thereof, keratin and inclusion bodies or decomposition products thereof, mammals, birds, fish, molluscs, crustaceans, shellfish, Extracts from animals such as insects; extraction from microorganisms such as yeast metabolites, fermentation metabolites, yeast extracts, lactic acid bacteria extracts, bifidobacteria extracts Thing, and the like.

Examples of natural extracts that can be added to the external preparation of the present invention include glabrizine, glabrene, liquiritin, isoliquiritin, licorice extract containing these, placenta extract, carotenoids, and animal and plant extracts containing these, neo agarobiose , Agarose oligosaccharide, Asparagus extract, Ibukitorano extract, Pea extract, Ages extract, Ogon extract, Ononis extract, Seaweed extract, Raspberry extract, Kujin extract, Caiquet extract, Gokahi extract , Linoleic acid-containing vegetable oil, saicin extract, hawthorn extract, sunpens extract, shirayuri extract, peonies extract, sempukuka extract, sopakuhi extract, soybean extract, tea extract, toki extract, molasses Extract, sandalwood extract, beech extract, bud Seed extract, Flow demanita extract, Hop extract, Mikaika extract, Mokka extract, Yukinosita extract, Yokuinin extract and Rakan fruit extract, Asparagus, Akane, Red grape, Akamegashiwa, Akebobi, Asa, Asagao, Azuki , Asenyaku, Achacha, Achacharu, Japanese knotweed, Fig, Ginkgo biloba, Ylang-ylang, Moray eel, Ume, Uwaurushi, Satsuma mandarin, Ezoukogi, Ebisu rush, Enju, Pea, Psyllium, Okra, Oguruma, Onigurumi, Ominaeshi, Cattle strawberry, Cattle Cashew, cashew, valerian, crow cricket, karin, guarana, pygmy, chrysanthemum, catalpa, burrowing, gymnema sylvestre, goldfish, guava, wolfberry, kudzu, camphor, chestnut, caquette, gage , Keihi, Gosho Strawberry, Pepper, Coffee, Prunus, Colombo, Sasanqua, Salamander, Saffron, Sakura, Pomegranate, Sandscon, Sunpens, Zion, Shobu, Watermelon, Stevia, Plum, Kizota, Pear, Psyllium, Prunus Wasabi, Sekisho, Seri, Senega, Senna, Daiou, Daidai, Tamarind, Taranoki, Dandelion, Chicory, Clove, Datura, Chorei, Tsukimiso, Tsukubusa, Tsuyusa, Tsuruna, Teuchigurumi, Tougan, Tochu, Torooien, Tuna , Oysters, yarrow, pineapple, hibiscus, papaya, basil, lotus, hadakamugi, higi, peanuts, toukikoshi, bean, pistachio, hiba, himematsu Bamboo, peony, loquat, dandelion, fushinoki, fujibakamama, blueberry, boufuu, physalis, honoki, bokeh, maikai, maou, mango, mannentake, shimashima psycho, misohagi, honeybee, mimosa, merirot, momorino, momoro Examples include coconut palm, yakchi, yakso, cornflower, palm, yashajitsu, mistletoe, willow, pokeweed, bayberry, quail, wormwood, rye, orchid, longan, apple, litchi and forsythia.

As vitamins, vitamin Fs such as linolenic acid and its inclusions; vitamin Ks such as phytonadione, menaquinone, menadione, menadiol; vitamins P such as eriocitrin, hesperidin; and other biotin, carcinin, ferulic acid, etc. Can be mentioned.

As amino acids, glycine, alanine, valine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, cystine, methionine, phenylalanine, tyrosine, proline, hydroxyproline, ortinin, citrulline, Examples include amino acids such as theanine and their inclusions and salts thereof, amino acid inclusions such as pyrrolidonecarboxylic acid, and inclusions thereof. Examples of nucleic acid-related substances include deoxyribonucleic acid and salts thereof, adenylate inclusion bodies selected from adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate and salts thereof, ribonucleic acid and salts thereof, cyclic AMP, cyclic Examples of GMP, flavin adenine nucleotide, guanine, adenine, cytosine, thymine, xanthine and their inclusions caffeine, theophylline, and salts and hormones thereof include estradiol, etenyl estradiol, and the like. Examples of the enzyme include lipase and papain.

Examples of the blood circulation promoter include nonyl acid wallenylamide, capsaicin, gingerone, cantalis tincture, ictamol, α-borneol, inositol hexanicotinate, cyclandrate, cinnarizine, trazoline, acetylcholine, verapamil, cephalanthin, γ-oryzanol, etc. Examples of the agent include tannic acid and the like, and examples of the antiseborrheic agent include sulfur and thianthol.

The photochemotherapy of the present invention is a highly effective method of destroying tissue lesions without causing side effects by irradiating a composition such as a photosensitizer, antioxidant, and photolyase applied to the surface of the tissue such as skin. The new tissue can be regenerated and used for disease treatment, beauty, and anti-aging.

Although the composition of the photolyase used for the photochemotherapy of this invention and the effect are demonstrated concretely below, the photochemotherapy of this invention is not limited by this.
Example 1
1 g of photolyase (trade name: Photosome) manufactured by Nikko Chemical Co., Ltd. and 1 g of tetrahexyl decanoic acid ascorbic acid (trade name: VC-IP) manufactured by Nikko Chemical Co. are well dispersed in 99 g of glycerin, and 0.01 g / Skin pigmentation, acne, mole, wart, oily skin, dry skin, seborrhea, thickening of the epidermis, wrinkle worried 20 to 50-year-old women and 10 men did. Thereafter, the skin surface of the affected area to which the photolyase was applied was irradiated with light under the following optical device and light irradiation conditions for a total of 3 times once every 5 days.
Photo Revive Blue, light source: semiconductor lamp, color: Blue, wavelength: 415 + 3 nm, light source LED, power supply: 500VA, input power supply: 90V-250V, frequency: 50 / 60Hz ± 5%, standard: 315mm x 280mm, output: 80mW / cm2
After 30 days, whether or not those symptoms were improved was confirmed by photographs taken before and after treatment with a digital camera. The photographs after 50 days compared to before treatment clearly showed skin pigmentation, acne, moles, warts and oily skin. , Dry skin, seborrhea, thickening of the epidermis, wrinkles were improved. None of the patients had significant side effects.

Example 2
1 g of photolyase of Example 1 and 5 g of aluminum oxide powder having an average particle diameter of 300 nm were well dispersed in 94 g of glycerin, and this was applied to 10 women aged 20 to 51 who suffered from skin pigmentation, acne, wrinkles and spots. Apply in half while rubbing well on the skin surface to 0.001 g / square cm.
Thereafter, the skin surface of the affected area to which the photolyase was applied was irradiated with light under the following optical device and light irradiation conditions three times in total once every seven days.
Photo Revive Blue, light source: semiconductor lamp, color: Blue, wavelength: 415 + 3 nm, light source LED, power supply: 500VA, input power supply: 90V-250V, frequency: 50 / 60Hz ± 5%, standard: 315mm x 280mm, output = 80mW / cm2
After 30 days, whether or not those symptoms had improved was confirmed by photographs taken before and after treatment with a digital camera, the skin pigmentation, acne, wrinkles and spots were clearly improved in the photograph after 30 months compared to before the treatment. Was. In addition, the left half where photolyase was applied was clearly improved compared to the right half which was not applied. None of the patients had significant side effects.

Example 3
1 g of the photolyase of Example 1, 4% Na of ascorbic acid-2-phosphate, 1% of Mg ascorbic acid-2-phosphate, 5 g of aluminum oxide powder having an average particle size of 300 nm were well dispersed in 94 g of glycerin. Apply to 10 23- to 39-year-old women suffering from skin pigmentation, acne, wrinkles and blemishes while rubbing well on the left half of the face so that the skin surface is 0.001 g / square cm.
Thereafter, the skin surface of the affected area to which photolyase was applied was irradiated with light under the following optical device and light irradiation conditions three times in total once every 8 days.
Photo Revive Blue, light source: semiconductor lamp, color: Blue, wavelength: 415 + 3 nm, light source LED, power supply: 500VA, input power supply: 90V-250V, frequency: 50 / 60Hz ± 5%, standard: 315mm x 280mm, output: 80mW / cm2
After 30 days, whether or not those symptoms had improved was confirmed by photographs taken before and after treatment with a digital camera, the skin pigmentation, acne, wrinkles and spots were clearly improved in the photograph after 30 months compared to before the treatment. Was. In addition, the left half where photolyase was applied was clearly improved compared to the right half which was not applied. None of the patients had significant side effects.

Gel containing the photolyase of Production Example 2 was applied to skin pigmentation, acne, moles, warts, oily skin, dry skin, seborrhea, epidermal thickening, wrinkles, athlete's foot, infection, hyperkeratosis, skin Each of 77 women aged 18-55 with one or more of hyperproliferation, psoriasis plaques, actinic keratosis, keloid, aging, streaks, warts, atrophic scars and / or enlarged scars each And uniformly applied to a concentration of 0.1 g / square cm.
Thereafter, the skin surface of the affected area to which the photolyase was applied was irradiated with light under the following optical device and light irradiation conditions for a total of 4 times once every 10 days.
Photo Revive Blue, light source: semiconductor lamp, color: Blue, wavelength: 415 + 3 nm, light source LED, power source: 500VA, input power source: 90V-250V, frequency: 50 / 60Hz ± 5%, standard: 315mm x 280mm, output: 80mW / cm2
Skin pigmentation, acne, mole, warts, oily skin, dry skin, seborrhea, thickening of the epidermis, wrinkles, athlete's foot, infection, hyperkeratosis, skin hyperproliferation, psoriasis plaques, actinic keratosis, Of 98 women aged 10 to 67 who have one or more of keloid, aging, streaks, warts, atrophic scars and / or enlarged scars, 88 after 30 days, each skin is caused by scar formation Regenerated, skin pigmentation, acne, mole, warts, oily skin, dry skin, seborrhea, epidermis thickening, wrinkles, athlete's foot, infection, hyperkeratosis, skin hyperproliferation, psoriatic plaques, photohorn Chlorosis, keloid, aging, streaks, warts, atrophic scars and / or enlarged scars were clearly improved by visual observation by a third party before irradiation. None of the patients had significant side effects.

Comparative Example 1
1 g of tetrahexyl decanoic acid ascorbic acid (trade name: VC-IP) manufactured by Nikko Chemical Co., Ltd. is well dispersed in 99 g of glycerin, and the pigmentation of skin, acne, moles is 0.01 g / square cm on the skin surface. It was applied to 20 women, 20 to 50 years old, 10 men who suffered from wrinkles, oily skin, dry skin, seborrhea, thickening of the epidermis, wrinkles. Thereafter, the skin surface of the affected area to which the photolyase was applied was irradiated with light under the following optical device and light irradiation conditions for a total of 3 times once every 5 days.
Photo Revive Blue, light source: semiconductor lamp, color: Blue, wavelength: 415 + 3 nm, light source LED, power supply: 500VA, input power supply: 90V-250V, frequency: 50 / 60Hz ± 5%, standard: 315mm x 280mm, output: 80mW / cm2
After 30 days, whether or not those symptoms had improved was confirmed by photographs taken before and after treatment with a digital camera. In the photographs after 50 days compared to before treatment, skin pigmentation, acne, moles, warts, oily skin, dryness Although skin, seborrhea, thickening of the epidermis, and wrinkles were improved, 3 patients had side effects such as pigmentation.

Claims (14)

There are few side effects by applying photolyase to the affected area and irradiating the affected area with light having an output of 10 to 3000 mw / cm including a wavelength range of 100 to 11000 nm, preferably 300 to 500 nm, more preferably 370 to 430 nm. Photochemotherapy. One or more substances selected from a photosensitive substance and an antioxidant and a photolyase are applied to the affected area, and an output of 10 to 3000 mw / cm including a wavelength range of 100 to 11000 nm, preferably 300 to 500 nm, more preferably 370 to 430 nm. Photochemotherapy with fewer side effects by irradiating the affected area with light devices. The photolyase of claims 1 and 2 is a photolyase derived from a eukaryotic organism, preferably a photolyase derived from the genus Cyanobacteria, more preferably a photolyase derived from a eukaryotic organism, Preferably, it is a photolyase derived from plankton of the genus Cyanobacteria, more preferably a deoxyribodipyrimidine photolyase or DNA photolyase or photolyase derived from anacystis nidulans, more preferably an enzyme classification Photochemotherapy using the photolyase number EC 4.11.99.3. Skin photochemotherapy using photolyase, wherein the photolyase of claim 1 or 2 is produced by fermentation using yeast or bacteria. The photochemotherapy according to claim 1, wherein the microcapsules according to claim 1 and 2 are microcapsules having an average particle diameter of 1 µm or less, preferably 500 nm or less, and more preferably 100 to 1 nm. The photochemotherapy according to claim 1, wherein the light according to claims 1 and 2 is a laser beam. . The photochemotherapy according to claim 1, wherein the light according to claims 1 and 2 is pulsed light. 3. An optical device according to claim 1 or 2 is an incandescent lamp, a liquid crystal lamp, a light emitting diode made of a gallium nitride compound semiconductor, or a light emitting diode and laser diode other than a laser diode, a semiconductor lamp, a black lamp, a metal halide lamp, a metal halide lamp. , Xenon lamp, chemical light, pulsed dye laser, alexandrite laser, semiconductor laser such as Ti: sapphire laser and Ga: As diode laser, CO2 laser, Er: YAG laser, Ho: YAG laser, ruby laser, Nd: YAG The photochemotherapy of claim 1, wherein the photochemotherapy is one or more devices selected from lasers, dual Nd: YAG lasers. The method for preventing and improving skin pigmentation, wrinkles, tarmi and acne according to claim 1, wherein the photosensitive substance according to claims 1 and 2 comprises at least one substance selected from photolyase alone. Photochemotherapy, wherein the photochemotherapy of claims 1 and 2 is a method for preventing and improving skin pigmentation, wrinkles, tarmi, and acne. The photosensitive substance is porphyrin and its derivatives and complexes and compounds and salts thereof, porfimer sodium (Photofurin (registered trademark)), hematoporphyrin, metalloporphyrin, tetraphenylporphyrin sulfate, protoporphyrin, uroporphyrin, coproporphyrin, Dihematoporphyrin ether (DHE), benzoporphyrin (BPS), ATX-70 (gallium-profylline complex), ATX-S10 (four-formyloxymethylidene-3-hydroxy-2-deuterio porphyryl (IX) -6-7 -Bispartic acid), titanium oxide, zinc oxide, iron oxide, tungsten oxide, lead oxide, iron titanate, strontium titanate, titanium Nickel, gallium phosphide, silicon carbide, acridine, rose bengal, acridine orange, berberine sulfate, fluorescein, tetracycline, eosin Y, NTS, psoralen, bonerin, pheoformimide, chlorin e6, mesotetra (hydroxyphenyl) chlorin, phthalocyanine, purpurin, 3. The photochemotherapy according to claim 2, which is one or more substances selected from 5-aminolevulinic acid (ALA) and HAT-DO1 (magnesium chlorine-chlorine dimer). The photochemotherapy according to claim 2, wherein the antioxidant agent is one or more substances selected from antioxidant vitamins, antioxidant phenols, antioxidant amino acids, antioxidant peptides, and antioxidant proteins. The target diseases of photochemotherapy are malignant tumor, benign tumor, pigmentation, acne, mole, wart, oily skin, dry skin, seborrhea, thickening of epidermis, wrinkles, tarmi, athlete's foot, infection, hyperkeratosis, The photochemotherapy according to claim 1 or 2, which is skin hyperproliferation, psoriatic plaque, actinic keratosis, keloid, aging, streaks, warts, atrophic scars, enlarged scars, scars. 14. The photochemotherapy according to claim 1, wherein the optical device is an optical device other than a phosphor and a light emitting diode other than a light emitting diode made of a gallium nitride compound semiconductor, or a laser diode.