WO2016031875A1 - 光線力学療法用組成物、殺菌方法、殺菌システムおよび殺菌システムの作動方法 - Google Patents
光線力学療法用組成物、殺菌方法、殺菌システムおよび殺菌システムの作動方法 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01M—CATCHING, TRAPPING OR SCARING OF ANIMALS; APPARATUS FOR THE DESTRUCTION OF NOXIOUS ANIMALS OR NOXIOUS PLANTS
- A01M31/00—Hunting appliances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- 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
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
Definitions
- the present invention relates to a composition for photodynamic therapy, a sterilization method, a sterilization system, or a method for operating a sterilization system.
- photosensitizers photosensitive substances
- pathogenic microorganisms present in lesions of mucocutaneous infections
- light with a wavelength corresponding to the photosensitizer is irradiated.
- active oxygen is generated from a photosensitizer and pathogenic microorganisms are sterilized to treat mucocutaneous infection.
- Non-Patent Document 1 Photodynamic therapy is a promising alternative because there is no problem of increased resistance of pathogenic bacteria to antibiotics used in therapies that use antibiotics, such as tetracycline and ⁇ -lactam antibiotics.
- Cationic chlorin derivatives have been reported as photosensitizers effective against both gram-negative and gram-positive bacteria (Patent Document 1). However, the use of cationic chlorin derivatives is limited because the safety to the human body is unknown.
- Patent Document 2 discloses the use of methylene blue as an antibacterial agent in the dental field by utilizing cell death induced by singlet oxygen generated by light absorption. The overall mechanism of methylene blue cell killing is not clear, but the rigid and flat molecular structure intercalates into the DNA double helix structure and directly damages the DNA. It is described in Non-Patent Document 2 and Non-Patent Document 3.
- Patent Document 2 also suggests that the antibacterial activity of methylene blue is insufficient.
- a method by derivative synthesis has been studied for the purpose of enhancing the antibacterial activity of methylene blue (Patent Document 3).
- Non-Patent Document 4 reports that a hydrophobic derivative of methylene blue showed a stronger killing effect than MRA against MRSA (methicillin-resistant Staphylococcus aureus) and VRSA (vancomycin-resistant Staphylococcus aureus). Yes.
- derivatization of the safe methylene blue used in the medical field does not ensure the safety to the living body, and clinical trials that require cost and time are required.
- JP 2012-092024 A Japanese Patent No. 4564596 Special table 2007-512297 gazette
- the present invention provides a photodynamic therapy having high safety and a better bactericidal effect for treating H. pylori infection and other mucocutaneous infections by photodynamic therapy using methylene blue as a photosensitizer. It is an object of the present invention to provide a composition for sterilization, a method for sterilizing pathogenic microorganisms of Helicobacter pylori and other mucocutaneous infections, or a sterilization system for lesions caused by Helicobacter pylori infection or mucocutaneous infection and an operation method of the sterilization system .
- the present inventors can accept at least one pharmaceutically acceptable selected from the group consisting of methylene blue, osmolyte, a reducing agent, urea, and a proton donor.
- H. pylori infection by combining with an additive and mucocutaneous infection by combining methylene blue with at least one pharmaceutically acceptable additive selected from the group consisting of osmolyte and a reducing agent. It was learned that the disease can be treated by photodynamic therapy with an effect superior to that of methylene blue alone and with safety equivalent to that of methylene blue alone.
- a composition for photodynamic therapy for use in photodynamic therapy for treating H. pylori infection by contacting H. pylori present at the lesion site of H. pylori infection and irradiating H. pylori with light A photodynamic therapy composition comprising methylene blue and at least one pharmaceutically acceptable additive selected from the group consisting of osmolite, a reducing agent, urea and a proton donor.
- composition for photodynamic therapy according to (1) or (2) above wherein the light is white light, LED light having a wavelength of 660 ⁇ 10 nm, or laser light.
- a photodynamic therapy composition comprising methylene blue and at least one pharmaceutically acceptable additive selected from the group consisting of osmolite and a reducing agent.
- composition for photodynamic therapy according to (5) above wherein the osmolyte is mannitol and the reducing agent is ascorbic acid.
- the composition for photodynamic therapy according to (5) or (6) above, wherein the light is white light, LED light having a wavelength of 660 ⁇ 10 nm or laser light.
- a method for sterilizing Helicobacter pylori (10) The method for sterilizing H. pylori as described in (9) above, wherein the light projection amount of white light, LED light or laser light is 1 to 200 J / cm 2 .
- (11) A step of bringing the composition for photodynamic therapy according to any one of (5) to (8) above into contact with a pathogenic microorganism of a mucocutaneous infection, and causing the pathogenic microorganism to have white light or a wavelength of 660 ⁇ 10 nm.
- a method for sterilizing pathogenic microorganisms of skin mucosal infections comprising a step of irradiating LED light or laser light.
- Imaging means for sterilizing a pathogenic microorganism of a dermal mucosal infection as described in (11) above, wherein the light projection amount of white light, LED light or laser light is 1 to 200 J / cm 2 .
- Imaging means for controlling the imaging direction of the imaging means, irradiation direction control means for controlling the light irradiation direction of the light irradiation means, and composition
- An ejection direction control unit that controls the ejection direction of the ejection unit, an imaging unit, a light irradiation unit, a composition ejection unit, an imaging direction control unit, an irradiation direction control unit, and a calculation / control unit that controls the ejection direction control unit.
- a sterilization system for lesions caused by Helicobacter pylori infection or mucocutaneous infection (a) The imaging direction control means and the irradiation direction control means operate based on the control signal from the calculation / control unit so that the light irradiation means illuminates the observation area of the imaging means, (b) Based on the control signal from the calculation / control unit, the imaging means images the skin / mucous membrane and transmits a video signal to the calculation / control unit.
- the calculation / control unit receives the video signal transmitted from the imaging means, performs video processing so as to emphasize the color difference between the normal region and the abnormal region of the mucous membrane, and Identify and locate the lesion,
- the injection direction control means operates to match the injection direction of the composition injection means with the lesion based on the control signal from the calculation / control section,
- the composition ejecting means ejects the composition for photodynamic therapy according to any one of (1) to (8) based on a control signal from the calculation / control unit,
- the irradiation direction control means operates to match the irradiation direction of the light irradiation means with the lesioned part based on the control signal from the calculation / control unit, and
- the light irradiation means emits white light or LED light or laser light having a wavelength of 660 ⁇ 10 nm based on a control signal from the calculation / control unit.
- Imaging means for lesions caused by Helicobacter pylori infection or mucocutaneous infection.
- Imaging means for controlling the imaging direction of the imaging means, irradiation direction control means for controlling the light irradiation direction of the light irradiation means, and composition
- An ejection direction control unit that controls the ejection direction of the ejection unit, an imaging unit, a light irradiation unit, a composition ejection unit, an imaging direction control unit, an irradiation direction control unit, and a calculation / control unit that controls the ejection direction control unit.
- a method of operating a sterilization system for lesions caused by Helicobacter pylori infection or mucocutaneous infection (a) a step of operating the imaging direction control unit and the irradiation direction control unit based on a control signal from the calculation / control unit so that the light irradiation unit illuminates the observation region of the imaging unit; (b) a step in which the imaging means images the skin / mucous membrane based on a control signal from the calculation / control unit and transmits a video signal to the calculation / control unit; (c) The calculation / control unit receives the video signal transmitted from the imaging means, performs video processing so as to emphasize the color difference between the normal region and the abnormal region of the mucous membrane, and Identifying and identifying the location of the lesion, (d) a step of operating the injection direction control means based on a control signal from the calculation / control unit so as to match the injection direction of the composition injection means with the lesioned part, (e) a step of injecting the composition for photo
- photodynamic therapy having high safety and better bactericidal effect for treating H. pylori infection and other skin mucosal infections by photodynamic therapy Composition, a method for sterilizing pathogenic microorganisms of Helicobacter pylori and other mucocutaneous infections, or a system for sterilizing lesions caused by Helicobacter pylori infection or skin mucosal infection, and a method for operating the sterilization system can be provided.
- the composition for photodynamic therapy for using in the photodynamic therapy which contacts the Helicobacter pylori which exists in the lesion site of a Helicobacter pylori infection, and irradiates light to Helicobacter pylori, and treats the Helicobacter pylori infection.
- Mucosal infections by contacting the pathogenic microorganisms with light and irradiating the pathogenic microorganisms with a photodynamic therapy composition for treating H. pylori infection and pathogenic microorganisms present at the lesion site of cutaneous mucosal infections
- compositions and the composition for photodynamic therapy for treating mucocutaneous infection are collectively referred to as “the composition for photodynamic therapy of the present invention”, the method for killing H. pylori and the disease of mucocutaneous infection. They are collectively referred to as sterilization method of microorganisms may be referred to as "sterilization method of the present invention”.
- composition for photodynamic therapy is used in photodynamic therapy for treating H. pylori infection by contacting H. pylori present on the lesion site of H. pylori infection and irradiating H. pylori with light.
- a photodynamic therapy composition comprising: methylene blue; and at least one pharmaceutically acceptable additive selected from the group consisting of osmolite, a reducing agent, urea, and a proton donor.
- Composition for photodynamic therapy for treating skin mucosal infection by contacting with pathogenic microorganisms present at lesion site of skin mucosal infection and irradiating light to pathogenic microorganisms A methylene blue and at least one pharmaceutically acceptable additive selected from the group consisting of osmolyte and a reducing agent It is a line photodynamic therapy composition.
- Helicobacter pylori infection is an infection of the mucous membrane caused by Helicobacter pylori, and particularly refers to an infection of the gastric mucosa caused by Helicobacter pylori.
- a mucocutaneous infection is an infection of the skin or mucous membrane caused by pathogenic microorganisms.
- the skin is not particularly limited.
- the mucosa is not particularly limited, and includes oral mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, nostril, lips, ears, genital organs, anus and the like.
- the pathogenic microorganisms for dermal mucosal infections include Escherichia coli, Pseudomonas aeruginosa, Helicobacter pylori, Staphylococcus aureus, Streptococcus sp., Mycobacterium Pathogenic bacteria such as Mycobacterium sp. And Treponema sp. Parasites such as Candida sp., Cryptococcus sp. And Malassezia sp. Examples include insects, amoeba such as Acanthamoeba, and viruses having an envelope such as herpes simplex virus.
- Methylene blue [3,7-bis (dimethylamino) phenothiazinium chloride] is not particularly limited.
- it may be an anhydride or a hydrate.
- the hydrate include, but are not limited to, dihydrate, trihydrate, tetrahydrate and the like.
- methylene blue may be sold as a pharmaceutical or may be sold as a reagent.
- the reagent is preferably of a high purity, for example, those specified in JIS K 8897: 2012.
- concentration of about 5.0 w / v% is also preferable.
- W / v% means “weight / volume%” and represents the mass (g) of a drug or the like (solute) dissolved in 100 mL of the solution.
- Methylene blue is safe for the human body to be used for staining during chromoendoscopy of the gastrointestinal tract, intravenously or orally administered in the treatment of drug-induced methemoglobinemia, treatment of ifosfamide encephalopathy It has been established because it is used by intravenous injection.
- methylene blue can be used at any concentration.
- concentration at the time of contacting methylene blue with H. pylori or other pathogenic microorganisms of skin mucosal infection is not particularly limited, but is preferably 0.001 w / v% or more, more preferably 0.005 w / v%. More preferably, it is 0.01 w / v% or more, more preferably 0.03 w / v% or more, and still more preferably 0.05 w / v% or more.
- the upper limit of the concentration of methylene blue at the time of use is not particularly limited, but it is difficult to make a significant difference in the bactericidal effect in a high concentration range, so that it is preferably 5.0 w / v% or less, more preferably 3.0 w / v%.
- it is more preferably 1.0 w / v% or less, and still more preferably 0.5 w / v% or less.
- the in-use concentration range of methylene blue is preferably 0.001 w / v% to 5.0 w / v%, more preferably 0.005 w / v% to 5.0 w / v%, still more preferably 0.
- the upper limit of the in-use concentration range of methylene blue may be 1.0 w / v%, 0.5 w / v%, or 0.1 w / v% instead of 5.0 w / v%.
- the photodynamic therapy composition for treating H. pylori infection comprises at least one pharmaceutically acceptable additive selected from the group consisting of osmolytes, reducing agents, urea and proton donors. Any one of osmolyte, reducing agent, urea and proton donor may be used, or two or more of them may be used.
- the composition for photodynamic therapy for treating mucocutaneous infection also contains at least one pharmaceutically acceptable additive selected from the group consisting of osmolite and a reducing agent. Any one or two of osmolite and reducing agent may be used.
- Osmolyte is an osmotic pressure regulator for changing the osmotic pressure around the pathogenic microorganisms of H. pylori or mucocutaneous disease. It promotes the uptake of methylene blue into the inside of H. pylori or pathogenic microorganisms by changing the surrounding osmotic pressure.
- Osmolite is not particularly limited as long as it can change the osmotic pressure around H. pylori or pathogenic microorganisms of skin mucosal diseases. Moreover, osmolite can be used individually by 1 type or in combination of 2 or more types.
- osmolite examples include inorganic ions such as potassium ion (K + ) and chloride ion (Cl ⁇ ), monosaccharides such as glycerol, mannitol, trehalose, glucose, sucrose, sorbitol, and inositol.
- K + potassium ion
- Cl ⁇ chloride ion
- monosaccharides such as glycerol, mannitol, trehalose, glucose, sucrose, sorbitol, and inositol.
- Amino acids such as disaccharides and polyhydric alcohols, alanine, ⁇ -alanine, glycine, glutamic acid, proline, GABA ( ⁇ -aminobutyric acid), ectoine; aminosulfonic acids such as taurine; trimethylamine-N-oxide (TMAO), Examples thereof include methylammonium and sulfonium such as glycine betaine (such as trimethylglycine), proline betaine, glycerophosphocholine (GPC), and dimethylsulfoniopropinate (DMSP).
- glycine betaine such as trimethylglycine
- proline betaine such as trimethylglycine
- GPC glycerophosphocholine
- DMSP dimethylsulfoniopropinate
- monosaccharides / disaccharides / polyhydric alcohols such as glycerol, mannitol, trehalose, glucose, sucrose, sorbitol, and inositol are preferable, and they have abundant experience in clinical practice. Mannitol is most preferred because of its safety.
- osmolyte can be used in any concentration.
- concentration of mannitol when used is not particularly limited, but is preferably 0.01 w / v% or more, more preferably 0.03 w / v% or more, and even more preferably 0.05 w / v. % Or more, more preferably 0.10 w / v% or more.
- the upper limit of the concentration of mannitol when used is not particularly limited, but since the bactericidal effect reaches a plateau, it is preferably 10 w / v% or less, more preferably 5.0 w / v% or less, and even more preferably 3.0 w / v. % Or less. More specifically, the concentration range of mannitol in use is preferably 0.01 w / v% to 10 w / v%, more preferably 0.03 w / v% to 10 w / v%, and still more preferably 0.05 w / v. % To 10 w / v%, more preferably 0.10 to 10 w / v%. The upper limit of the concentration range during use may be 5.0 w / v%, 3.0 w / v%, or 1.0 w / v% instead of 10 w / v%.
- the reducing agent reduces methylene blue to convert it into reduced leuco methylene blue, and enhances the bactericidal effect by inhibiting the ATP synthesis pathway of H. pylori or pathogenic microorganisms with its reducing power.
- Leucomethylene blue is easily reduced to colorless leucomethylene blue by being reduced by intracellular NAD.
- Leucomethylene blue has a strong reducing power and can be expected to increase the killing power by acting on the ATP production cycle of H. pylori or pathogenic microorganisms.
- the reducing agent is not particularly limited as long as it can reduce methylene blue to leucomethylene blue. Moreover, a reducing agent can be used individually by 1 type or in combination of 2 or more types.
- methylene blue can be quickly converted to leucomethylene blue, so low molecular weight reductions such as glutathione, N-acetylcysteine, ascorbic acid, ⁇ -tocopherol, butylhydroxyanisole, catechin, quercetin, uric acid, bilirubin, glucose, flavonoids, etc.
- Ascorbic acid is most preferred because it is preferable, has a proven track record in clinical practice, and is biologically safe when administered to the body.
- These compounds may be metal salts such as sodium salts or hydrates.
- the reducing agent can be used at any concentration.
- concentration of sodium ascorbate when used is not particularly limited, but is preferably 0.01 w / v% or more, more preferably 0.04 w / v% or more, and still more preferably 0.8. 07 w / v% or more, more preferably 0.10 w / v% or more.
- the upper limit of the concentration of sodium ascorbate at the time of use is not particularly limited, but since the bactericidal effect reaches a plateau, it is preferably 10 w / v% or less, more preferably 5.0 w / v% or less, and even more preferably 2.0 w. / V% or less, more preferably 1.0 w / v% or less, and even more preferably 0.50 w / v% or less. More specifically, the concentration range of sodium ascorbate in use is preferably 0.01 w / v% to 10 w / v%, more preferably 0.04 w / v% to 10 w / v%, and still more preferably 0.07 w.
- the upper limit of the concentration range of sodium ascorbate when used may be 5.0 w / v%, 3.0 w / v%, 1.0 w / v%, or 0.50 w / v% instead of 10 w / v% Good.
- Urea is a substrate for urease and enhances the bactericidal effect of Helicobacter pylori by changing the inside or the periphery of Helicobacter pylori to basic by ammonia produced by hydrolysis by urease of H. pylori.
- Helicobacter pylori expresses urease with two optimum pH in neutral and acidic regions, hydrolyzes urea in the stomach to produce ammonia, and locally neutralizes gastric acid, Enables colonization and growth in the stomach.
- urea is excessively supplied from outside the cells, it becomes more basic than the optimum pH 6.1 for survival of H. pylori, and it can be expected that the sterilization efficiency is supplementarily increased.
- urea can be used at any concentration.
- concentration of urea in use is not particularly limited, but is preferably 0.01 w / v% or more, more preferably 0.05 w / v% or more, still more preferably 0.10 w / v% or more, and still more preferably 0.15 w. / V% or more, more preferably 0.20 w / v% or more.
- the upper limit of the use concentration of urea is not particularly limited, but since the bactericidal effect reaches a plateau, it is preferably 10 w / v% or less, more preferably 5.0 w / v% or less, and even more preferably 2.0 w / v. % Or less, more preferably 1.0 w / v% or less, and even more preferably 0.50 w / v% or less. More specifically, the concentration range of urea when used is preferably 0.01 w / v% to 10 w / v%, more preferably 0.05 w / v% to 10 w / v%, still more preferably 0.10 to 10 w.
- the upper limit of the concentration range of urea when used may be 5.0 w / v%, 22.0 w / v%, 1.0 w / v%, or 0.50 w / v% instead of 10 w / v%.
- the proton donor changes the cell membrane and enzyme activity of H. pylori.
- the cell membrane of H. pylori has a proton-sensitive urea channel that closes at a neutral pH and opens at an acidic pH, and maintains the spatial periplasm between the cell membrane (inner membrane) and the outer membrane at pH 6.1, which is the optimum pH.
- the periplasm contains metabolic enzymes necessary for life support of Helicobacter pylori. In an acidic environment, the channel opens, and protons and urea flow into it, making it easier to contact urease.
- H. pylori which is a polyhydric alcohol having an effect of increasing the acid dissociation degree (pKa) of a weak acid, coexists, it can be expected that the function of the proton donor is further enhanced.
- the proton donor is not particularly limited as long as it can release hydrogen ions (H + ) and open the proton-sensitive urea channel of the Helicobacter pylori cell membrane. Moreover, a proton donor can be used individually by 1 type or in combination of 2 or more types.
- lysine, arginine, histidine, and tryptophan are preferable because they are proton-releasing basic amino acids, and histidine is the most preferable because it has an imidazole group and is thought to change cell membranes and enzyme activities. preferable.
- these basic amino acids salts such as hydrochloride, hydrates, and enantiomers may be used.
- the proton donor can be used in any concentration.
- the concentration of histidine when used is not particularly limited, but is preferably 0.50 mM or more, more preferably 0.75 mM or more, still more preferably 1.0 mM or more, and still more preferably 2. It is 0 mM or more, more preferably 3.5 mM or more.
- the upper limit of the concentration of histidine when used is not particularly limited, but is preferably 200 mM or less, more preferably 100 mM or less, still more preferably 75 mM or less, and even more preferably 50 mM or less because the bactericidal effect reaches a plateau. More specifically, the concentration range of histidine in use is preferably 0.50 mM to 200 mM, more preferably 0.75 mM to 200 mM, still more preferably 1.0 to 200 mM, more preferably 2.0 to 200 mM, and even more. Preferably, it is 3.5 to 200 mM. The upper limit of the concentration range of histidine in use may be 100 mM or less, 75 mM or less, or 50 mM or less, instead of 200 mM. “MM” represents 10 ⁇ 3 M (10 ⁇ 3 mol / L).
- the photodynamic therapy composition of the present invention may contain one or more pharmaceutically acceptable carriers, diluents or excipients.
- the photodynamic therapy composition of the present invention may further comprise liposomes, nanoparticles, colloidal suspensions, micelles, microemulsions, vesicles and nanospheres.
- the photodynamic therapy composition of the present invention may also contain additional ingredients such as conventional delivery vehicles and excipients, which may be a solvent such as an alcohol (eg ethanol, polyethylene glycol, glycerol or n-butanol). ), Dimethyl sulfoxide, water, saline, solubilizer, pH adjuster, gelling agent, thickener, buffer and combinations thereof.
- Suitable pH typically includes 15 to 65 ° C.
- Suitable pH typically includes pH 3-9, preferably physiologically relevant pH, such as pH 6.5-7.5.
- the photodynamic therapy composition provided by the present invention may be a dry composition that can be reconstituted before use, or may be in the form of a prefill that is pre-sterilized and sealed.
- methylene blue and an additive may be aseptically dissolved in pure water or physiological saline and aseptically filled into a syringe having a tube at the tip.
- composition for photodynamic therapy of the present invention can also be used as an antibacterial agent, antifungal agent and antiviral agent.
- the composition for photodynamic therapy of the present invention can be used not only for humans but also for animals other than humans.
- non-human animals include, without limitation, non-human mammals including monkeys, cats, pigs, dogs and the like.
- animals other than humans include, but are not limited to, vertebrates other than mammals such as birds, reptiles, amphibians, and fish.
- non-human animals include domestic animals such as dogs, cats, cows, horses, pigs, sheep, goats, donkeys, camels, etc., dogs, cats, foxes, raccoons, monkeys, donkeys, horses, etc.
- pets include, but are not limited to.
- the composition for photodynamic therapy of the present invention can be used not only in vivo but also in vitro.
- photodynamic therapy compositions of the present invention include use as antimicrobial and antifungal treatments for skin and wound infections such as burns; use for parasitic infections, stomach infections, malaria, leprosy; bacteria And use for fungal spore inactivation; use for the treatment of prion and viral infections such as HIV; ear, nose and throat infection, use for tuberculosis; sexually transmitted disease (STD), for herpes Use; eg for the treatment of Candida local infections of the hair, nails and epidermis, eg foot and body tinea and vulvar candidiasis; and infection preventives eg surgical wound disinfection, skin disinfection, stem cell disinfection, transplantation Use as a one-to-host rejection disease; skin diseases such as psoriasis, acne, vitiligo and eczema and other skin conditions such as hirsutism and sunburn damage, Use for benign conditions such as endometriosis and menorrhagia; bacterios
- composition for photodynamic therapy can be administered intravenously, orally, transdermally, transmucosally, intramuscularly, etc., but is preferably administered locally.
- administration by direct spraying through the endoscope to the lesion site of the upper digestive tract or the lower digestive tract specifically, methylene blue and additives are dissolved in pure water or physiological saline, and a tube is provided at the tip. It is preferable to fill the syringe, insert a tube into the forceps opening of the endoscope, and push the syringe to spray the drug on the stomach wall or the like.
- the composition When administered topically, the composition is delivered via various means, for example via sprays, lotions, suspensions, emulsions, gels, ointments, salves, sticks, soaps, liquid aerosols, powder aerosols, drops or pastes. can do.
- the sterilization method using the composition for photodynamic therapy of the present invention comprises a step of bringing the composition for photodynamic therapy of the present invention into contact with H. pylori or pathogenic microorganisms of skin mucosal infection, and irradiating H. pylori or pathogenic microorganisms with light. And a step of performing.
- the method for bringing the composition for photodynamic therapy of the present invention into contact with Helicobacter pylori or a pathogenic microorganism of mucocutaneous infection is not particularly limited.
- the composition for photodynamic therapy of the present invention can be used according to the above dosage form and administration method. Examples thereof include a method of administering to a subject and a method of contacting the composition for photodynamic therapy of the present invention in a solid or solution state in vitro.
- the sterilization method using the composition for photodynamic therapy of the present invention can be applied to humans as well as animals other than humans.
- non-human animals include, without limitation, non-human mammals including monkeys, cats, pigs, dogs and the like.
- animals other than humans include, but are not limited to, vertebrates other than mammals such as birds, reptiles, amphibians, and fish.
- non-human animals include domestic animals such as dogs, cats, cows, horses, pigs, sheep, goats, donkeys, camels, etc., dogs, cats, foxes, raccoons, monkeys, donkeys, horses, etc.
- pets include, but are not limited to.
- the sterilization method using the composition for photodynamic therapy of the present invention can be used in vivo or in vitro.
- the activation of the composition for photodynamic therapy of the present invention by light is by light containing an appropriate wavelength, usually white light, or red light in the range of 600 nm to 800 nm.
- the wavelength of light is preferably 630 nm to 700 nm, particularly preferably 660 ⁇ 10 nm.
- the light source is not particularly limited as long as it can emit light having the above wavelength, and may be a coherent light source or an incoherent light source.
- the coherent light source include a laser and a laser diode, and an AlGaInP (aluminum gallium indium phosphide) quantum well structure laser diode or an aluminum gallium arsenide laser having a wavelength of 660 nm is particularly preferable.
- the incoherent light source include an LED (light emitting diode), an incandescent lamp, a fluorescent lamp, and the like, and a red LED that emits red light having a wavelength of 660 nm is particularly preferable.
- the white light may also be white light obtained by combining blue laser light having a wavelength of 445 nm and fluorescence excited and emitted from the phosphor by the blue laser light.
- the phosphors are a plurality of kinds of phosphors that absorb a part of blue laser light and emit light with excitation from green to yellow (for example, YAG (yttrium, aluminum, garnet) phosphors, BAM (barium / aluminum)). It is preferable to use a material including an oxide (phosphor such as BaMgAl 10 O 17 : Eu 2+ ).
- the amount of light to be projected is preferably 1 J / cm 2 to 200 J / cm 2 , more preferably 5 J / cm 2 to 100 J / cm 2 , and even more preferably 10 to 30 J / cm 2 . Within this range, a safer and higher sterilizing effect can be expected.
- the present invention uses a composition for photodynamic therapy of the present invention to sterilize a lesion due to Helicobacter pylori infection or mucocutaneous infection (hereinafter sometimes simply referred to as “sterilization system of the present invention”). And an operating method thereof (hereinafter, simply referred to as “an operating method of the sterilization system of the present invention”).
- the sterilization system 100 includes a calculation / control unit 101, an imaging unit 102, an imaging direction control unit 103, a light irradiation unit 102, an irradiation direction control unit 103, and a composition injection unit 104.
- the injection direction control means 105 and the transmission paths 108 to 113 are provided.
- the imaging unit 102 includes an imaging optical system 102a including an imaging device (not shown) that images the observation region, a signal processing unit that performs analog / digital conversion processing of an image signal from the imaging device, and an arithmetic / control unit 101. With an interface.
- the imaging unit 102 is controlled based on a control signal from the calculation / control unit 101. Communication is performed between the imaging unit 102 and the calculation / control unit 101 via the transmission path 108.
- the image sensor is a color image sensor, which captures a reflected image of a subject and outputs an image signal.
- the imaging device is preferably a CCD (Charge Coupled Device) image sensor or a CMOS (Complementary Metal-Oxide Semiconductor) image sensor.
- the imaging direction control means 103 includes a drive mechanism for changing the imaging direction of the imaging means 102 and an interface with the calculation / control unit 101.
- the imaging direction control means 103 is controlled based on a control signal from the calculation / control unit 101. Communication is performed between the imaging direction control unit 103 and the calculation / control unit 101 via the transmission path 109.
- the light irradiation unit 104 includes an illumination optical system 104a that emits illumination light and / or excitation light, a light source unit that supplies light to the illumination optical system 104a, and an interface with the calculation / control unit 101.
- the light irradiation unit 104 is controlled based on a control signal from the calculation / control unit 101. Communication is performed between the light irradiation unit 104 and the calculation / control unit 101 via the transmission path 110.
- the light irradiation means 104 may be an integrated type in which the illumination optical system 104a and the light source unit are built in the same housing, or a separate type in which the illumination optical system 104a and the light source unit are built in separate housings. It may be.
- the illumination light and / or excitation light emitted by the light irradiation means 104 can be appropriately selected depending on the application.
- white light, daylight white light, daylight color light, light bulb color light, or the like is usually used as light for illuminating the observation region.
- white light is preferable because a natural color tone of the observation region can be obtained.
- light that emphasizes the color difference is used. It is preferable.
- the excitation light for the composition for photodynamic therapy of the present invention it is preferable to irradiate white light, LED light having a wavelength of 660 ⁇ 10 nm, or laser light because methylene blue can be efficiently excited, and the wavelength is 660 ⁇ . It is more preferable to irradiate 10 nm LED light or laser light.
- the irradiation direction control unit 105 includes a drive mechanism for changing the irradiation direction of the light irradiation unit 106 and an interface with the calculation / control unit 101.
- the irradiation direction control means 105 is controlled based on a control signal from the calculation / control unit 101. Communication is performed between the irradiation direction control unit 105 and the calculation / control unit 101 via the transmission path 110.
- the composition injection means 106 has an injection part 106 a having an opening for injecting the composition for photodynamic therapy of the present invention (sometimes simply referred to as “the composition of the present invention”), and the composition of the present invention is stored therein.
- the composition injection unit 106 is controlled based on a control signal from the calculation unit 101. Communication is performed between the composition injection unit 106 and the calculation / control unit 101 via the transmission path 112.
- the composition injection means 106 may be an integrated type in which the injection unit 106a, the liquid supply tank, and the liquid supply pump are built in the same housing, or only the liquid supply tank may be disposed outside.
- the liquid feeding tank and the liquid feeding pump may be arranged outside, and the liquid feeding tank and the liquid feeding pump may be separated.
- the opening of the injection unit 106a may be a simple hole or a nozzle capable of spraying the composition of the present invention in a spray form.
- the injection direction control unit 107 includes a drive mechanism for changing the injection direction of the injection direction control unit 107 and an interface with the calculation / control unit 101.
- the injection direction control means 107 is controlled based on a control signal from the calculation / control unit 101. Communication is performed between the ejection direction control means 107 and the calculation / control unit 101 via the transmission path 113.
- the transmission paths 108 to 113 may be wired or wireless. In the case of a wired connection, either a metal cable or an optical cable may be used.
- the imaging direction control unit 103 When the imaging unit 102, the light irradiation unit 104, and the composition ejecting unit 106 move together, the imaging direction control unit 103, the irradiation direction control unit 105, and the ejection direction control unit 107 are integrated into one direction control unit. It may be.
- the imaging direction control unit 103 and the irradiation direction control unit 105 are operated based on a control signal from the calculation / control unit 101 so that the light irradiation unit 104 illuminates the observation region of the imaging unit 102.
- the imaging unit 102 images the skin / mucous membrane 200 based on the control signal from the calculation / control unit 101 and transmits a video signal to the calculation / control unit 101.
- the calculation / control unit 101 receives the video signal transmitted from the imaging unit 102, performs video processing so as to emphasize the color difference between the normal region and the abnormal region of the mucous membrane, and the normal unit 201 and the lesion
- the part 202 is identified, and the position of the lesioned part 202 is specified.
- the injection direction control means 107 is operated based on a control signal from the calculation / control section 101 so that the injection direction of the composition injection means 106 matches the lesioned portion 202.
- the composition ejecting means 106 ejects the composition for photodynamic therapy of the present invention based on the control signal from the calculation / control unit 101.
- the irradiation direction control unit 105 is operated based on a control signal from the calculation / control unit 101 so that the irradiation direction of the light irradiation unit 104 is aligned with the lesioned part 202.
- the light irradiation means 104 emits white light, LED light having a wavelength of 660 ⁇ 10 nm or laser light based on a control signal from the calculation / control unit 101.
- the light irradiation to the composition for photodynamic therapy may be performed as follows.
- the imaging direction control unit 103 and the irradiation direction control unit 105 are operated based on a control signal from the calculation / control unit 101 so that the light irradiation unit 104 illuminates the observation region of the imaging unit 102.
- the imaging unit 102 images the skin / mucous membrane 200 based on a control signal from the calculation / control unit 101 and transmits a video signal to the calculation / control unit 101.
- the calculation / control unit 101 receives the video signal transmitted from the imaging means 102, identifies the normal region and the abnormal region of the mucous membrane, and identifies the presence or absence of adhesion of the photodynamic therapy composition of the present invention. Image processing is performed so as to be able to be performed, and the position of the region where the lesioned part 202 and the attachment part 203 of the composition for photodynamic therapy overlap is specified. (f4) Irradiation direction control means based on a control signal from the calculation / control unit 101 so that the irradiation direction of the light irradiation means 104 matches the region where the lesioned part 202 and the photodynamic therapy composition attachment part 203 overlap. 105 is activated. (g1) The light irradiation unit 104 emits white light, LED light having a wavelength of 660 ⁇ 10 nm, or laser light based on a control signal from the calculation / control unit 101.
- the sterilization system 10 shown in FIG. 2 includes an endoscope 11, an arithmetic control device 12, a light source device 13, an air / water supply device 14, and a liquid supply device 15.
- the air / water supply device 14 is built in the light source device 13 and is provided outside the light source device 13 and a known air supply pump 14a that generates a delivery pressure of fluid such as air and cleaning water, and stores cleaning water.
- the cleaning water tank 14b is constituted.
- the liquid delivery device 15 can deliver the composition for photodynamic therapy of the present invention to the endoscope 11, and has an image processing unit that identifies the position of the abnormal site.
- a point that can be discharged from the WJ outlet 24 (see FIGS. 3A and 3B) provided at the distal end portion 16a toward the lesioned portion of the mucous membrane, and illumination windows 22a and 22b provided at the distal end portion 16a of the endoscope 11 (FIG. 3A, see FIG. 3B) to the point where mucosal lesions or areas where the composition for photodynamic therapy of the present invention is attached can be irradiated with white light or LED light or laser light having a wavelength of 660 ⁇ 10 nm. That.
- the endoscope 11 shown in FIG. 2 includes an insertion unit 16 to be inserted into a subject, an operation unit 17 connected to a proximal end (rear end) portion of the insertion unit 16, an arithmetic / control device 12, And a universal cord 18 connected to the light source device 13.
- the insertion portion 16 shown in FIG. 2 is provided at the distal end thereof, and is connected to a distal end portion 16a in which an imaging element (not shown) for in-subject imaging is incorporated, and a proximal end of the distal end portion 16a.
- the portion 16a is rotatably supported and includes a bendable bendable portion 16b and a flexible flexible tube portion 16c that is connected to the base end of the bendable portion 16b.
- a tip cap 20 shown in FIGS. 3A and 3B is attached to the tip of the tip portion 16a shown in FIG.
- the tip cap 20 is provided with an observation window 21, illumination windows 22a and 22b, and a forceps outlet 23 from which the tip of the forceps protrudes.
- the tip cap 20 has a liquid such as a composition for photodynamic therapy of the present invention, washing water, a chemical solution, or the like toward a portion to be observed in the subject (hereinafter sometimes referred to as “observed site”).
- observation site a portion to be observed in the subject
- WJ outlet water jet outlet
- injection nozzle 25 for injecting air or cleaning water toward the observation window 21.
- the observation window 21 is formed in front of the image sensor and allows photographing light incident on the image sensor to pass therethrough.
- Two illumination windows 22a and 22b are arranged at symmetrical positions with respect to the observation window 21, and irradiate the observation site in the subject with illumination light from the light source device 13.
- the forceps outlet 23 shown in FIGS. 3A and 3B communicates with a forceps inlet 26 provided in the operation unit 17 shown in FIG.
- Various kinds of treatment tools having an injection needle, a high-frequency knife or the like arranged at the tip are inserted into the forceps inlet 26.
- an air / water button 30 for feeding cleaning water may be provided.
- the air / water supply button 30 is operated so as to supply air
- the air supplied from the air supply pump 14 a is sent to the endoscope 11.
- the air / water supply button 30 is operated so as to perform water supply, the air supplied from the air supply pump 14a is sent to the wash water tank 14b, and the wash water is supplied from the wash water tank 14b by this air pressure. And sent to the endoscope 11.
- the operation portion 17 receives a control signal from the arithmetic / control device 12, and drives the bending portion up / down bending mechanism and / or the bending portion left / right bending mechanism built in the endoscope 11. Then, the bending portion 16b is bent up and down / left and right.
- the air supply pump 14a receives a control signal from the arithmetic / control device 12, and the air supply pump 14a operates to supply air to the endoscope 11.
- the supplied air is sent to the endoscope 11.
- the air supply pump 14a receives a control signal from the arithmetic / control device 12, operates so that the air supply pump 14a supplies air to the cleaning water tank 14b, and supplies air from the air supply pump 14a.
- the air that has been aired is sent to the washing water tank 14 b, and the washing water is sent from the washing water tank 14 b by this air pressure and sent to the endoscope 11.
- the operation unit 17 may be provided with a mode switch 27 and a zoom operation unit 31 in addition.
- the mode changeover switch 27 is used for a switching operation between two types of modes, a normal observation mode and a special observation mode.
- the normal observation mode is a mode in which white light is used for illumination of the observation area.
- the special observation mode is a mode that uses bluish light to illuminate the area to be observed, and emphasizes changes in the color of the mucous membrane and blood see-through to distinguish between normal and abnormal areas of the mucosa (lesioned areas). This mode makes it easy to distinguish.
- the zoom operation unit 31 is used for a zoom operation for driving the zooming mechanism in the endoscope 11 to enlarge or reduce the observation image. In the normal observation mode, daylight white light, daylight color light, light bulb color light, or the like may be used instead of white light, and in the special observation mode, white light may be used instead of the special light.
- a connector 32 is attached to one end of the universal cord 18 shown in FIG.
- the connector 32 is a composite type connector and is connected to the calculation / control device 12, the light source device 13, and the liquid feeding device 15, respectively.
- the arithmetic / control device 12 shown in FIG. 2 performs various image processing on the imaging signal input from the imaging element via the universal cord 18 and the connector 32, and generates an endoscopic image.
- the endoscopic image generated by the arithmetic / control device 12 is displayed on a monitor 33 connected to the arithmetic / control device 12 by a cable.
- the arithmetic / control device 12 is connected to the light source device 13 via a communication cable, and communicates various control information with the light source device 13.
- the liquid delivery device 15 shown in FIG. 2 includes a composition for photodynamic therapy according to the present invention, washing water or washing liquid for washing the inside of a subject, or a liquid feeding tank 35 in which a chemical solution is stored, a motor and a control circuit. And a liquid feed pump 37 disposed on the front surface of the apparatus main body 36 for sending out the cleaning liquid stored in the liquid feed tank 35.
- the liquid feeding device 15 includes a liquid feeding pipe 39 that connects the liquid feeding pump 37 and the connector 32, and a connecting pipe 40 that connects the liquid feeding tank 35 and the liquid feeding pump.
- the liquid feeding device 15 may include a foot switch 38 for operating the liquid feeding pump 37 to perform a liquid feeding operation. Instead of the foot switch 38, a manually operable switch or a remote controller may be used.
- the liquid delivery device 15 normally operates based on a control signal from the arithmetic / control device.
- the light guides 41 a and 41 b have one end fixed to the tip cap 20 and the other end connected to the light source device 13 via the universal cord 18 and the connector 32.
- An illumination optical system (not shown) including an illumination lens (not shown) is incorporated behind the illumination windows 22a and 22b.
- the light guides 41a and 41b have their emission ends facing illumination lenses disposed behind the illumination windows 22a and 22b, and guide the light from the light source device 13 to the illumination windows 22a and 22b.
- One end of the forceps tube 42 is fixed to the tip cap 20 and connected to the forceps outlet 23, and the other end is connected to the forceps inlet 26 through the inside of the bending portion 16 b, the flexible tube portion 16 c, the operation portion 17, and the like.
- the forceps outlet 23 and the forceps inlet 26 communicate with each other.
- One end of the air / water supply tube 43 is connected to the injection nozzle 25, and the other end is connected to the air / water supply device 14 via the universal cord 18 and the connector 32.
- the air / water supply tube 43 sends the air and the wash water supplied from the air / water supply device 14 to the injection nozzle 25.
- the injection nozzle 25 injects air and cleaning water supplied from the air / water supply device 14 toward the observation window 21 to wipe away dirt adhering to the observation window 21.
- the multi-core cable 44 electrically connects the arithmetic / control device 12 and the image sensor.
- the multi-core cable 44 includes a plurality of signal cables 44a, and the plurality of signal cables 44a are covered with an outer cover 44b that functions as an electric shield layer.
- the flexible tube portion 16c includes a screw tube 51 called a flex that protects the inside while maintaining flexibility in order from the inside, and a net 52 called a blade that covers the screw tube 51 and prevents the screw tube 51 from extending. And a flexible rubber 53 covered on the net 52.
- the outer layer of the curved portion 16 b is also composed of rubber 53.
- the WJ tube 45 includes a soft rubber WJ soft tube (not shown) that passes through the curved portion 16b and the flexible tube portion 16c, and a hard metal WJ that passes through the tip portion 16a. It consists of a hard tube (not shown), and the photodynamic therapy composition, cleaning solution or chemical solution of the present invention fed by the solution feeding device 15 is sent to the WJ outlet 24.
- One end of the WJ soft tube passes through the operation unit 17 and is connected to the liquid feeding device 15 via the universal cord 18, the connector 32, and the liquid feeding pipe 39. The other end of the WJ soft tube is connected to the WJ hard tube.
- the WJ hard tube (not shown) extends in the photographic optical axis direction, and its distal end is bent in a direction substantially perpendicular to the photographic optical axis direction, and an image sensor (not shown) is formed in the radial direction of the distal end portion 16a.
- a first WJ path (not shown) extending in the photographic optical axis direction at a position away from the optical axis), one end communicating with the WJ outlet 24, and the other end extending in a direction substantially perpendicular to the photographic optical axis direction.
- a second WJ path 47b in communication.
- the first WJ path is connected to a WJ soft tube (not shown).
- the second WJ path is linearly formed on an orthogonal plane orthogonal to the photographing optical axis, but may be bent or curved as long as it is on the orthogonal plane. .
- the tip end portion 16a is made of a metal cylindrical tip portion main body (not shown) and a metal tip pipe (not shown) covering the tip portion main body.
- the WJ hard tube (not shown) is fixed to the tip body with the tip inserted into the tip body.
- the light guides 41a and 41b, the forceps tube 42, and the air / water supply tube 43 are also fixed to the distal end portion main body in a state where the distal end portions are inserted into the distal end portion main body.
- the distal end pipe has an outer peripheral surface covered with rubber 53, and a distal end cap 20 is attached to the distal end portion.
- an imaging optical system including an imaging lens (not shown) and an imaging element (not shown) is arranged.
- the imaging optical system is fixed to a tip body (not shown).
- the imaging device is preferably a CCD (Charge Coupled Device) image sensor or a CMOS (Complementary Metal-Oxide Semiconductor) image sensor.
- the imaging optical system makes the image light of the observation region incident from the observation window 21 enter the imaging lens, and the imaging lens forms an image on the imaging surface of the imaging element.
- the calculation / control device 12 and the light source device 13 are turned on, and the insertion portion 16 of the endoscope 11 is inserted into the subject.
- the light from the light source device 13 is irradiated to the observation site in the subject through the light guides 41a and 41b, the illumination optical system (not shown), and the illumination windows 22a and 22b.
- the light may be white light, but bluish light may be used in order to emphasize the color difference between the normal area and the abnormal area (lesioned area) of the mucous membrane.
- An imaging element (not shown) built in the distal end portion 16a of the insertion portion 16 images the inside of the subject and outputs an imaging signal.
- This imaging signal is input to the arithmetic / control device 12 via the universal cord 18 and the connector 32.
- the arithmetic / control device 12 performs image processing that emphasizes the color difference between the normal area and abnormal area (lesion) of the mucous membrane, and identifies the position of the abnormal area (lesion area) of the mucosa based on the color difference. To do.
- the arithmetic / control device 12 can perform various image processing on the input imaging signal to generate an image in the subject, and display the image in the subject on the monitor 33.
- the calculation / control device 12 When observing the inside of the subject, the calculation / control device 12 outputs a control signal to the operation unit 17 so as to bend the bending portion 16b in the vertical direction and the horizontal direction.
- This control signal is input to the operation unit 17 via the universal cord 18 and the connector 32, and the operation unit 17 operates the bending portion up-and-down bending mechanism and the bending portion right and left bending mechanism built in the endoscope 11, so that the distal end The direction of the part 16a is changed, and different places of the mucous membrane in the subject are observed.
- the calculation / control device 12 Instead of transmitting a control signal to the operation unit 17 to operate the bending unit up-down direction bending mechanism and the bending unit left-right bending mechanism, the calculation / control device 12 gives an instruction to the operator, and each angle of the operation unit 17 is set.
- the knobs 28 and 29 may be operated to bend the bending portion 16b in the vertical direction and the horizontal direction.
- the calculation / control device 12 When the calculation / control device 12 specifies the position of the abnormal region (lesion) in the mucous membrane of the subject, the calculation / control device 12 transmits a control signal to the operation unit 17 to bend the bending portion 16b. The jet direction of the WJ outlet 24 is adjusted to the abnormal region (lesioned portion). Then, a control signal is transmitted to the liquid delivery device 15, the liquid delivery pump 37 is operated, and the composition for photodynamic therapy of the present invention stored in the liquid delivery tank 35 is connected to the connecting tube 40, the liquid delivery pump 37, It is sent to the WJ tube via the liquid feed pipe 39 and the connector 32.
- composition for photodynamic therapy of the present invention sent to the WJ tube is ejected from the WJ outlet 24 through the WJ soft tube and the WJ hard tube, and includes at least a part of an abnormal region (lesion) of the mucous membrane. Adhere to.
- the arithmetic / control device 12 transmits a control signal to the light source device 13, and the light from the light source device 13 passes through the light guides 41a and 41b, the illumination optical system (not shown), and the illumination windows 22a and 22b. Then, irradiation is performed toward the region of the mucous membrane of the subject to which the composition for photodynamic therapy of the present invention is attached.
- the irradiated light is white light, LED light having a wavelength of 660 ⁇ 10 nm, or laser light.
- the position of the part of the abnormal region (lesion) of the mucous membrane to which the composition for photodynamic therapy of the present invention is attached may be specified. This is preferable because the risk of light irradiation other than the part to which the composition for photodynamic therapy of the present invention is attached in the abnormal region (lesion) of the mucous membrane is reduced.
- the light source device 13 is activated, emits white light or bluish light from the illumination windows 22a and 22b, and irradiates the observation site in the subject.
- a video signal from the imaging device is input to the arithmetic / control device 12, and the arithmetic / control device 12 is a portion of the abnormal region (lesion) of the mucous membrane of the subject to which the composition for photodynamic therapy of the present invention is attached. Specify the position of.
- the arithmetic / control device 12 transmits a control signal to the light source device 13, and the light from the light source device 13 passes through the illumination windows 22a and 22b, and the composition for photodynamic therapy of the present invention on the mucous membrane of the subject.
- the irradiated light is white light, LED light having a wavelength of 660 ⁇ 10 nm, or laser light. This light excites methylene blue contained in the composition for photodynamic therapy of the present invention to sterilize abnormal areas (lesions) of the mucosa.
- H. pylori suspension (bacterial solution) JCM 12093 strain was purchased, and the bacterial species was identified and confirmed using the Apihelico culture identification kit (manufactured by Sysmex Biomelieu). A culture was used. The cultured H. pylori was suspended in sterile physiological saline, and the number of bacteria was adjusted to 2.0 ⁇ 10 8 cells / mL.
- urea aqueous solution having a concentration of 0 w / v% was prepared using sterilized purified water.
- a urea aqueous solution having a concentration of 2.0 w / v% was prepared using urea and sterilized purified water.
- D-histidine aqueous solution A sterilized purified water was used to prepare a 0-M D-histidine aqueous solution. Using D-histidine and sterilized purified water, D-histidine aqueous solutions having concentrations of 0.01M, 0.03M and 0.05M were prepared.
- Antibacterial activity test ⁇ Example 1> When osmolyte (D-mannitol) was added as an additive Bacterial fluid (20 ⁇ L), methylene blue solution (100 ⁇ L) with each concentration shown in Table 1, and D- with each concentration shown in Table 1 Prepare microbial / reagent mixture (130 ⁇ L) by mixing mannitol aqueous solution (10 ⁇ L), immediately add the whole amount (130 ⁇ L) to Helicobacter agar medium (Nissui Pharmaceutical Co., Ltd.) And left in the dark for 5 minutes. After standing for 5 minutes, the cells were cultured in an incubator at 37 ° C.
- Group with light irradiation (No. 1 to 20) >> The group containing no methylene blue (No. 1, 6, 11, 16; group to which a methylene blue solution having a concentration of 0 w / v% was added) had an antibacterial activity evaluation of “ ⁇ ”, and no antibacterial activity was observed.
- the group containing methylene blue (No. 2 to 5, 7 to 10, 12 to 15, 17 to 20; a group to which a methylene blue solution having a concentration of 0.01 to 0.10 w / v% was added) had an antibacterial activity evaluation of “ 3+ "to" 5+ "and antibacterial activity was observed.
- the D-mannitol concentration was compared with the group containing no D-mannitol (group to which a D-mannitol aqueous solution having a concentration of 0 w / v% was added; No. 2 to 5).
- the group containing mannitol (the group to which a D-mannitol aqueous solution having a concentration of 0.5 to 2.0 w / v% was added; No. 7 to 10, 12 to 14, and 17 to 20) had a high evaluation of antibacterial activity. Enhancement of antibacterial activity by addition of mannitol was observed (No. 7, 12, 17, etc. with respect to No. 2).
- Example 2 When a reducing agent (sodium ascorbate) is added as an additive Bacterial fluid (20 ⁇ L), methylene blue solution (100 ⁇ L) with each concentration shown in Table 2, and aqueous sodium ascorbate solution with each concentration shown in Table 2 ( 10 ⁇ L) to prepare a bacteria / reagent mixed solution (130 ⁇ L), immediately add the entire amount (130 ⁇ L) to Helicobacter agar medium (manufactured by Nissui Pharmaceutical Co., Ltd.), Left in the dark for 5 minutes. After standing for 5 minutes, the cells were cultured in an incubator at 37 ° C.
- a reducing agent sodium ascorbate
- Group with light irradiation (No. 1-6) >> The groups not containing methylene blue (No. 1, 4; group to which a methylene blue solution having a concentration of 0 w / v% was added) had an antibacterial activity evaluation of “ ⁇ ” and no antibacterial activity was observed.
- the group containing methylene blue (No. 2, 3, 5, 6; group to which a methylene blue solution having a concentration of 0.05 to 0.10 w / v% was added) had an antibacterial activity evaluation of “4+” or “5+” Antibacterial activity was observed.
- Example 3 When urea is added as an additive Bacterial solution (20 ⁇ L), methylene blue solution (100 ⁇ L) of each concentration shown in Table 3 and urea aqueous solution (10 ⁇ L) of each concentration shown in Table 3 A reagent mixture (130 ⁇ L) was prepared, and immediately the entire amount (130 ⁇ L) was added to a Helicobacter agar medium (manufactured by Nissui Pharmaceutical Co., Ltd.), and evenly applied to the medium with a conage bar, and left in the dark for 5 minutes. After standing for 5 minutes, the cells were cultured in an incubator at 37 ° C.
- the group containing urea (groups containing urea aqueous solution having a concentration of 0 w / v%; No. 2 to 4) compared to the group not containing urea (No. 2 to 4)
- Example 4 When a proton donor (D-histidine) is added as an additive Bacterial solution (20 ⁇ L), methylene blue solution (100 ⁇ L) having various concentrations shown in Table 4, and D-histidine aqueous solution having various concentrations shown in Table 4 (10 ⁇ L) is mixed to prepare a bacteria / reagent mixed solution (130 ⁇ L), and immediately after adding the entire amount (130 ⁇ L) to Helicobacter agar medium (Nissui Pharmaceutical Co., Ltd.) Left in the dark for 5 minutes. After standing for 5 minutes, the cells were cultured in an incubator at 37 ° C.
- Group with light irradiation (No. 1-12) >> The group containing no methylene blue (No. 1, 4, 7, 10; group to which a methylene blue solution having a concentration of 0 w / v% was added) had an antibacterial activity evaluation of “ ⁇ ” and no antibacterial activity was observed.
- the group containing methylene blue (No. 2, 3, 5, 6, 8, 9, 11, 12; a group to which a methylene blue solution having a concentration of 0.05 to 0.10 w / v% was added) had an antibacterial activity evaluation of “ 4+ "or" 5+ "and antibacterial activity was observed.
- the methylene blue concentration is the same in the group containing methylene blue, it contains D-histidine as compared to the group not containing D-histidine (groups to which a 0-M concentration of D-histidine aqueous solution was added; No. 2, 3). (No. 5, 6, 8, 9, 11, 12) has a high antibacterial activity evaluation, and the antibacterial activity by addition of D-histidine (No. 5 with respect to No. 2 etc.) was observed.
- Example 5 When a proton donor (L-histidine) is added as an additive Bacterial solution (20 ⁇ L), methylene blue solution (100 ⁇ L) with each concentration shown in Table 5, and D-histidine aqueous solution with each concentration shown in Table 5 (10 ⁇ L) is mixed to prepare a bacteria / reagent mixed solution (130 ⁇ L), and immediately after adding the entire amount (130 ⁇ L) to Helicobacter agar medium (Nissui Pharmaceutical Co., Ltd.) Left in the dark for 5 minutes. After standing for 5 minutes, the cells were cultured in an incubator at 37 ° C. for 4 days with or without irradiation with LED light (wavelength 660 nm, projection amount 15 J / m 2 ) for 4 minutes. After incubation for 4 days, the number of surviving colonies in each medium (No. 1 to 8) was counted, compared with the blank (No. 5), and antibacterial activity was evaluated according to the above “standard for antibacterial activity evaluation”.
- Group with light irradiation (No. 1 to 4)
- the group containing no methylene blue (No. 1, 3; group to which a methylene blue solution having a concentration of 0 w / v% was added) had an antibacterial activity evaluation of “ ⁇ ” and no antibacterial activity was observed.
- the group containing methylene blue (No. 2, 4; group to which a methylene blue solution having a concentration of 0.10 w / v% was added) had an antibacterial activity evaluation of “4+” or “5+”, and antibacterial activity was recognized.
- the group containing L-histidine (the concentration of 0.01-M L-L) was compared with the group containing no L-histidine (the group to which an L-histidine aqueous solution having a concentration of 0 M was added; No. 2).
- the group to which the histidine aqueous solution was added; No. 4 had a high evaluation of antibacterial activity, and the enhancement of the antibacterial activity by adding D-histidine was recognized.
- methylene blue alone has a bactericidal activity, but that the bactericidal activity is further improved by adding an additive.
- all the additives are pharmaceutically acceptable and have safety equivalent to or higher than that of methylene blue alone.
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Abstract
Description
(1)ピロリ菌感染症の病変部位に存在するピロリ菌に接触させ、ピロリ菌に光を照射することによりピロリ菌感染症を治療する光線力学療法において使用するための光線力学療法用組成物であって、メチレンブルーと、オスモライト、還元剤、尿素およびプロトン供与剤からなる群から選択される少なくとも1つの製薬学的に許容しうる添加剤とを含む光線力学療法用組成物。
(2)オスモライトがマンニトールであり、還元剤がアスコルビン酸であり、かつ、プロトン供与剤がヒスチジンである、上記(1)に記載の光線力学療法用組成物。
(3)光が白色光または波長660±10nmのLED光もしくはレーザー光である、上記(1)または(2)に記載の光線力学療法用組成物。
(4)光の光線投射量が1~200J/cm2である、上記(1)~(3)のいずれか1つに記載の光線力学療法用組成物。
(5)皮膚粘膜感染症の病変部位に存在する病原微生物に接触させ、病原微生物に光を照射することにより皮膚粘膜感染症を治療する光線力学療法において使用するための光線力学療法用組成物であって、メチレンブルーと、オスモライトおよび還元剤からなる群から選択される少なくとも1つの製薬学的に許容しうる添加剤とを含む光線力学療法用組成物。
(6)オスモライトがマンニトールであり、かつ、還元剤がアスコルビン酸である、上記(5)に記載の光線力学療法用組成物。
(7)光が白色光または波長660±10nmのLED光もしくはレーザー光である、上記(5)または(6)に記載の光線力学療法用組成物。
(8)光の光線投射量が1~200J/cm2である、上記(5)~(7)のいずれか1つに記載の光線力学療法用組成物。
(9)上記(1)~(4)のいずれか1つに記載の光線力学療法用組成物をピロリ菌に接触させる工程と、ピロリ菌に白色光または波長660±10nmのLED光もしくはレーザー光を照射する工程とを備えるピロリ菌の殺菌方法。
(10)白色光またはLED光もしくはレーザー光の光線投射量が1~200J/cm2である、上記(9)に記載のピロリ菌の殺菌方法。
(11)上記(5)~(8)のいずれか1つに記載の光線力学療法用組成物を皮膚粘膜感染症の病原微生物に接触させる工程と、病原微生物に白色光または波長660±10nmのLED光もしくはレーザー光を照射する工程とを備える皮膚粘膜感染症の病原微生物の殺菌方法。
(12)白色光またはLED光もしくはレーザー光の光線投射量が1~200J/cm2である、上記(11)に記載の皮膚粘膜感染症の病原微生物の殺菌方法。
(13)撮像手段と、光照射手段と、組成物噴射手段と、撮像手段の撮像方向を制御する撮像方向制御手段と、光照射手段の光照射方向を制御する照射方向制御手段と、組成物噴射手段の噴射方向を制御する噴射方向制御手段と、撮像手段、光照射手段、組成物噴射手段、撮像方向制御手段、照射方向制御手段および噴射方向制御手段を制御する演算・制御部とを備える、ピロリ菌感染症または皮膚粘膜感染症による病変部の殺菌システムであって、
(a)撮像方向制御手段および照射方向制御手段は、演算・制御部からの制御信号に基づいて、撮像手段の被観察領域を光照射手段が照明するように作動し、
(b)撮像手段は、演算・制御部からの制御信号に基づいて、皮膚・粘膜を撮像し、映像信号を演算・制御部に送信し、
(c)演算・制御部は、撮像手段から送信された映像信号を受信し、粘膜の正常領域と異常領域との色の差を強調するように映像処理を行い、正常部と病変部とを識別し、病変部の位置を特定し、
(d)噴射方向制御手段は、演算・制御部からの制御信号に基づいて、組成物噴射手段の噴射方向を病変部に合わせるように作動し、
(e)組成物噴射手段は、演算・制御部からの制御信号に基づいて、(1)~(8)のいずれか1つに記載の光線力学療法用組成物を噴射し、
(f)照射方向制御手段は、演算・制御部からの制御信号に基づいて、光照射手段の照射方向を病変部に合わせるように作動し、および
(g)光照射手段は、演算・制御部からの制御信号に基づいて、白色光または波長660±10nmのLED光もしくはレーザー光を発射する、
ピロリ菌感染症または皮膚粘膜感染症による病変部の殺菌システム。
(14)撮像手段と、光照射手段と、組成物噴射手段と、撮像手段の撮像方向を制御する撮像方向制御手段と、光照射手段の光照射方向を制御する照射方向制御手段と、組成物噴射手段の噴射方向を制御する噴射方向制御手段と、撮像手段、光照射手段、組成物噴射手段、撮像方向制御手段、照射方向制御手段および噴射方向制御手段を制御する演算・制御部とを備える、ピロリ菌感染症または皮膚粘膜感染症による病変部の殺菌システムの作動方法であって、
(a)撮像手段の被観察領域を光照射手段が照明するように、演算・制御部からの制御信号に基づいて、撮像方向制御手段および照射方向制御手段を作動させる工程、
(b)撮像手段が、演算・制御部からの制御信号に基づいて、皮膚・粘膜を撮像し、映像信号を演算・制御部に送信する工程、
(c)演算・制御部が、撮像手段から送信された映像信号を受信し、粘膜の正常領域と異常領域との色の差を強調するように映像処理を行い、正常部と病変部とを識別し、病変部の位置を特定する工程、
(d)組成物噴射手段の噴射方向を病変部に合わせるように、演算・制御部からの制御信号に基づいて、噴射方向制御手段を作動させる工程、
(e)組成物噴射手段が、演算・制御部からの制御信号に基づいて、(1)~(8)のいずれか1つに記載の光線力学療法用組成物を噴射する工程、
(f)光照射手段の照射方向を病変部に合わせるように、演算・制御部からの制御信号に基づいて、照射方向制御手段を作動させる工程、および
(g)光照射手段が、演算・制御部からの制御信号に基づいて、白色光または波長660±10nmのLED光もしくはレーザー光を発射する工程
を含む、ピロリ菌感染症または皮膚粘膜感染症による病変部の殺菌システムの作動方法。
本発明の光線力学療法用組成物は、ピロリ菌感染症の病変部位に存在するピロリ菌に接触させ、ピロリ菌に光を照射することによりピロリ菌感染症を治療する光線力学療法において使用するための光線力学療法用組成物であって、メチレンブルーと、オスモライト、還元剤、尿素およびプロトン供与剤からなる群から選択される少なくとも1つの製薬学的に許容しうる添加剤とを含む光線力学療法用組成物、または皮膚粘膜感染症の病変部位に存在する病原微生物に接触させ、病原微生物に光を照射することにより皮膚粘膜感染症を治療する光線力学療法において使用するための光線力学療法用組成物であって、メチレンブルーと、オスモライトおよび還元剤からなる群から選択される少なくとも1つの製薬学的に許容しうる添加剤とを含む光線力学療法用組成物である。
ピロリ菌感染症はピロリ菌(ヘリコバクター・ピロリ(Helicobacter pylori))による粘膜の感染症であり、特にはピロリ菌による胃粘膜の感染症をいう。皮膚粘膜感染症は病原微生物による皮膚または粘膜の感染症である。
皮膚は特に限定されない。粘膜も特に限定されず、口腔粘膜、食道粘膜、胃粘膜、腸粘膜、鼻孔、唇、耳、生殖器、肛門等を含む。
皮膚粘膜感染症の病原微生物としては、大腸菌(Escherichia coli)、緑膿菌(Pseudomonas aeruginosa)、ピロリ菌(Helicobacter pylori)、黄色ブドウ球菌(Staphylococcus aureus)、連鎖球菌(Streptococcus sp.)、マイコバクテリウム(Mycobacterium sp.)、トレポネマ(Treponema sp.)等の病原性細菌、カンジダ(Candida sp.)、クリプトコッカス(Cryptococcus sp.)、マラセチア(Malassezia sp.)等の病原性真菌、線条虫等の寄生虫、アカントアメーバ等のアメーバ、単純ヘルペスウイルス等のエンベロープを有するウイルスなどが挙げられる。
メチレンブルー〔3,7-ビス(ジメチルアミノ)フェノチアジニウムクロリド〕は特に限定されない。例えば、無水物であってもよいし、水和物であってもよい。水和物としては、二水和物、三水和物、四水和物等が挙げられるが、これらに限定されるものではない。また、メチレンブルーは、医薬品として販売されているものであってもよいし、試薬として販売されているものでもよい。試薬は高純度のもの、例えば、JIS K 8897:2012に規定するものが好ましい。また、メチレンブルーを溶媒(エタノール等)に溶解し、濃度5.0w/v%程度の溶液としたものも好ましい。
なお、「w/v%」は「weight/volume%」のことであり、溶液100mL中に溶けている薬剤等(溶質)の質量(g)を表す。
ピロリ菌感染症を治療するための光線力学療法用組成物は、オスモライト、還元剤、尿素およびプロトン供与剤からなる群から選択される少なくとも1つの製薬学的に許容しうる添加剤を含む。オスモライト、還元剤、尿素およびプロトン供与剤は、いずれか1つを用いてもよいし、これらのうち2つ以上を用いてもよい。
また、皮膚粘膜感染症を治療するための光線力学療法用組成物は、オスモライトおよび還元剤からなる群から選択される少なくとも1つの製薬学的に許容しうる添加剤を含む。オスモライトおよび還元剤は、いずれか1つを用いてもよいし、これら2つを用いてもよい。
オスモライトはピロリ菌または皮膚粘膜疾患の病原微生物の周囲の浸透圧を変化させるための浸透圧調節剤である。周囲の浸透圧を変化させることにより、ピロリ菌または病原微生物の内部へのメチレンブルーの取込みを促進する。
オスモライトとしてマンニトールを使用する場合、マンニトールの使用時濃度は、特に限定されないが、好ましくは0.01w/v%以上、より好ましくは0.03w/v%以上、さらに好ましくは0.05w/v%以上、いっそう好ましくは0.10w/v%以上である。マンニトールの使用時濃度の上限は、特に限定されないが、殺菌効果がプラトーに達することから、好ましくは10w/v%以下、より好ましくは5.0w/v%以下、さらに好ましくは3.0w/v%以下である。より詳細には、マンニトールの使用時濃度範囲は、好ましくは0.01w/v%~10w/v%、より好ましくは0.03w/v%~10w/v%、さらに好ましくは0.05w/v%~10w/v%、いっそう好ましくは0.10~10w/v%である。使用時濃度範囲の上限は、10w/v%に代えて、5.0w/v%、3.0w/v%、または1.0w/v%としてもよい。
還元剤はメチレンブルーを還元して還元型のロイコメチレンブルーに変換し、その還元力でピロリ菌または病原微生物のATP合成経路を阻害することによって、殺菌効果を高める。
還元剤としてアスコルビン酸ナトリウムを使用する場合、アスコルビン酸ナトリウムの使用時濃度は、特に限定されないが、好ましく0.01w/v%以上、より好ましくは0.04w/v%以上、さらに好ましくは0.07w/v%以上、いっそう好ましくは0.10w/v%以上である。アスコルビン酸ナトリウムの使用時濃度の上限は、特に限定されないが、殺菌効果がプラトーに達することから、好ましくは10w/v%以下、より好ましくは5.0w/v%以下、さらに好ましくは2.0w/v%以下、いっそう好ましくは1.0w/v%以下、よりいっそう好ましくは0.50w/v%以下である。より詳細には、アスコルビン酸ナトリウムの使用時濃度範囲は、好ましくは0.01w/v%~10w/v%、より好ましくは0.04w/v%~10w/v%、さらに好ましくは0.07w/v%~10w/v%、いっそう好ましくは0.10w/v%~10w/v%である。アスコルビン酸ナトリウムの使用時濃度範囲の上限は、10w/v%に代えて、5.0w/v%、3.0w/v%、1.0w/v%、または0.50w/v%としてもよい。
尿素は、ウレアーゼの基質であり、ピロリ菌のウレアーゼにより加水分解されて生じるアンモニアにより、ピロリ菌の細胞内または周辺を塩基性に変化させることでピロリ菌の殺菌効果を高める。
プロトン供与剤は、ピロリ菌の細胞膜や酵素活性を変化させる。
ピロリ菌細胞膜には中性pHで閉じ、酸性pHで開くプロトン感受性尿素チャネルがあり、細胞膜(内膜)と外膜の間にある空間ペリプラズムを至適pHであるpH6.1に保っている。
ペリプラズムにはピロリ菌の生命維持に必要な代謝酵素が存在する。酸性環境になるとチャネルが開き、プロトンと尿素が流入しウレアーゼと接触しやすくなる。プロトンを放出する添加剤があると開いたチャネルからプロトンと尿素が過剰に流入するが、ピロリ菌はウレアーゼによるアンモニア産生を増加させてpHを塩基性側に変化させて至適pHを維持しようとする。もしチャネルが閉じても過剰に流入した尿素が分解されpH上昇が起こればピロリ菌細胞質とペリプラズムに生存に不適当な環境が形成されることになる(非特許文献5)。また、弱酸の酸解離度(pKa)を増大させる効果もある多価アルコールであるマンニトールが共存すると、プロトン供与剤の機能がより増強されることが期待できる。
プロトン供与剤としてヒスチジンを使用する場合、ヒスチジンの使用時濃度は、特に限定されないが、好ましくは0.50mM以上、より好ましくは0.75mM以上、さらに好ましくは1.0mM以上、いっそう好ましくは2.0mM以上、よりいっそう好ましくは3.5mM以上である。ヒスチジンの使用時濃度の上限は、特に限定されないが、殺菌効果がプラトーに達することから、好ましくは200mM以下、より好ましくは100mM以下、さらに好ましくは75mM以下、いっそう好ましくは50mM以下である。より詳細には、ヒスチジンの使用時濃度範囲は、好ましくは0.50mM~200mM、より好ましくは0.75mM~200mM、さらに好ましくは1.0~200mM、いっそう好ましくは2.0~200mM、よりいっそう好ましくは3.5~200mMである。ヒスチジンの使用時濃度範囲の上限は、200mMに代えて、100mM以下、75mM以下、または50mM以下としてもよい。
なお、「mM」は10-3M(10-3mol/L)を表す。
さらに、本発明の光線力学療法用組成物は、in vivoで用いることができるほか、in vitroで用いることもできる。
本発明の光線力学療法用組成物を用いる殺菌方法は、本発明の光線力学療法用組成物をピロリ菌または皮膚粘膜感染症の病原微生物に接触させる工程と、ピロリ菌または病原微生物に光を照射する工程とを備える。
さらに、本発明の光線力学療法用組成物を用いる殺菌方法は、in vivoで用いることができるほか、in vitroで用いることもできる。
また、本発明は、本発明の光線力学療法用組成物を用いる、ピロリ菌感染症または皮膚粘膜感染症による病変部の殺菌システム(以下、単に「本発明の殺菌システム」という場合がある。)およびその作動方法(以下、単に「本発明の殺菌システムの作動方法」という場合がある。)を提供する。
(a)撮像手段102の被観察領域を光照射手段104が照明するように、演算・制御部101からの制御信号に基づいて、撮像方向制御手段103および照射方向制御手段105を作動させる。
(b)撮像手段102が、演算・制御部101からの制御信号に基づいて、皮膚・粘膜200を撮像し、映像信号を演算・制御部101に送信する。
(c)演算・制御部101が、撮像手段102から送信された映像信号を受信し、粘膜の正常領域と異常領域との色の差を強調するように映像処理を行い、正常部201と病変部202とを識別し、病変部202の位置を特定する。
(d)組成物噴射手段106の噴射方向を病変部202に合わせるように、演算・制御部101からの制御信号に基づいて、噴射方向制御手段107を作動させる。
(e)組成物噴射手段106が、演算・制御部101からの制御信号に基づいて、本発明の光線力学療法用組成物を噴射する。
(f)光照射手段104の照射方向を病変部202に合わせるように、演算・制御部101からの制御信号に基づいて、照射方向制御手段105を作動させる。
(g)光照射手段104が、演算・制御部101からの制御信号に基づいて、白色光または波長660±10nmのLED光もしくはレーザー光を発射する。
(f1)撮像手段102の被観察領域を光照射手段104が照明するように、演算・制御部101からの制御信号に基づいて、撮像方向制御手段103および照射方向制御手段105を作動させる。
(f2)撮像手段102が、演算・制御部101からの制御信号に基づいて、皮膚・粘膜200を撮像し、映像信号を演算・制御部101に送信する。
(f3)演算・制御部101が、撮像手段102から送信された映像信号を受信し、粘膜の正常領域と異常領域との識別および本発明の光線力学療法用組成物の付着の有無の識別を行えるように映像処理を行い、病変部202と光線力学療法用組成物の付着部203が重なる領域の位置を特定する。
(f4)光照射手段104の照射方向を病変部202と光線力学療法用組成物の付着部203が重なる領域に合わせるように、演算・制御部101からの制御信号に基づいて、照射方向制御手段105を作動させる。
(g1)光照射手段104が、演算・制御部101からの制御信号に基づいて、白色光または波長660±10nmのLED光もしくはレーザー光を発射する。
本発明の殺菌システムおよびその作動方法について、電子内視鏡システムを利用する場合を具体的に説明する。
送気を行うように、送気・送水ボタン30が操作されると、送気ポンプ14aから送気された空気が内視鏡11に送られる。送水を行うように、送気・送水ボタン30が操作されると、送気ポンプ14aから送気された空気が洗浄水タンク14bに送られ、この空気圧により、洗浄水タンク14bから洗浄水が送水されて、内視鏡11に送られる。
湾曲部16bを湾曲させるには、演算・制御装置12からの制御信号を操作部17が受信し、内視鏡11に内蔵されている湾曲部上下湾曲機構および/または湾曲部左右湾曲機構を駆動して、湾曲部16bを上下/左右に湾曲させる。
送気を行わせるには、演算・制御装置12からの制御信号を送気ポンプ14aが受信して、送気ポンプ14aが内視鏡11に送気するように作動し、送気ポンプ14aから送気された空気が内視鏡11に送られる。送水を行わせるには、演算・制御装置12からの制御信号を送気ポンプ14aが受信して、送気ポンプ14aが洗浄水タンク14bに送気するように作動し、送気ポンプ14aから送気された空気が洗浄水タンク14bに送られ、この空気圧により、洗浄水タンク14bから洗浄水が送水されて、内視鏡11に送られる。
モード切替スイッチ27は、通常観察モードと、特殊観察モードの2種類のモード間の切替え操作に用いられる。通常観察モードは、被観察領域の照明に白色光を用いるモードである。特殊観察モードは、被観察領域の照明に青味を帯びた光を用いるモードであり、粘膜の色の変化や血管の透見を強調して粘膜の正常領域と異常領域(病変部)とを見分けやすくするモードである。ズーム操作部31は、内視鏡11内のズーミング機構を駆動させて、観察画像を拡大縮小させるズーム操作に用いられる。なお、通常観察モードでは、白色光に代えて、昼白色光、昼光色光、電球色光などを用いてもよく、特殊観察モードでは、特殊光に代えて、白色光を用いてもよい。
なお、上記実施形態では、第2WJ路を、撮影光軸に直交する直交面上において直線状に形成しているが、上記直交面上であれば、折り曲げたり、曲線状に形成してもよい。
演算・制御装置12および光源装置13の電源をオンにして、内視鏡11の挿入部16を被験体内に挿入する。
また、演算・制御装置12は、入力された撮像信号に各種画像処理を施して、被検体内の画像を生成し、この被検体内の画像をモニタ33に表示することができる。
次いで、演算・制御装置12は、光源装置13に制御信号を送信して、光源装置13からの光が、照明窓22a,22bを通って、被検体の粘膜の本発明の光線力学療法用組成物が付着している領域に向けて照射される。照射される光は、白色光または波長660±10nmのLED光もしくはレーザー光である。
この光により、本発明の光線力学療法用組成物に含まれるメチレンブルーが励起させられ、粘膜の異常領域(病変部)の殺菌が行われる。
1.材料
(1)ヘリコバクター・ピロリ(Helicobacter pylori) JCM 12093株
(2)メチレンブルー(メチレンブルー原液、5.0w/v%、キシダ化学株式会社製)
(3)D-マンニトール(日本薬局方 D-マンニトール注射液、20w/v%;日本製薬株式会社製)
(4)アスコルビン酸(L(+)-アスコルビン酸ナトリウム、和光純薬工業株式会社製、和光特級)
(5)尿素(和光純薬工業株式会社製、試薬特級)
(6)D-ヒスチジン(D-ヒスチジン塩酸塩一水和物、和光純薬工業株式会社製、和光特級)
(7)L-ヒスチジン(L-ヒスチジン塩酸塩一水和物、東京化成工業株式会社製)
(8)滅菌精製水(日本薬局方 滅菌精製水)
(9)生理食塩水(日本薬局方 生理食塩液)
(10)エタノール(エタノール(99.5)、和光純薬工業株式会社製、試薬特級)
(1)ピロリ菌懸濁液(菌液)の調製
JCM 12093株を購入し、アピ ヘリコ培養同定キット(シスメックス・ビオメリュー株式会社製)を用いて菌種を同定・確認した培養株を使用した。
培養したピロリ菌を、滅菌生理食塩水に懸濁し、菌数を2.0×108個/mLに調整した。
生理食塩水5mLをとり、これをMB濃度0.0w/v%のMB溶液とした。
5w/v%メチレンブルー原液を、10μL、30μL、50μL、100μLとり、それぞれ、生理食塩水で5mLにフィルアップして、MB濃度0.01w/v%、0.03w/v%、0.05w/v%、0.1w/v%のMB溶液を、5mLずつ調製した。
滅菌精製水を用いて、濃度0w/v%のD-マンニトール水溶液を調製した。
D-マンニトールと滅菌精製水とを用いて、濃度0.5w/v%、1.0w/v%、2.0w/v%のD-マンニトール水溶液を調製した。
滅菌精製水を用いて、濃度0w/v%のアスコルビン酸水溶液を調製した。
アスコルビン酸と滅菌精製水とを用いて、濃度0.6w/v%のアスコルビン酸水溶液を調製した。
滅菌精製水を用いて、濃度0w/v%の尿素水溶液を調製した。
尿素と滅菌精製水とを用いて、濃度2.0w/v%の尿素水溶液を調製した。
滅菌精製水を用いて、濃度0MのD-ヒスチジン水溶液を調製した。
D-ヒスチジンと滅菌精製水とを用いて、濃度0.01M、0.03M、0.05MのD-ヒスチジン水溶液を調製した。
滅菌精製水を用いて、濃度0MのL-ヒスチジン水溶液を調製した。
L-ヒスチジンと滅菌精製水とを用いて、濃度0.01MのL-ヒスチジン水溶液を調製した。
〈例1〉添加剤としてオスモライト(D-マンニトール)を添加した場合
菌液(20μL)、表1に示す各濃度のメチレンブルー溶液(100μL)、および表1に示す各濃度のD-マンニトール水溶液(10μL)を混合して菌・試薬混合液(130μL)を調製し、直ちに、全量(130μL)をヘリコバクター寒天培地(日水製薬株式会社製)に添加し、コンラージ棒で培地に均等塗布した後、5分間暗所に放置した。
5分間放置の後、LED光(波長 660nm、投射量 15J/m2)を4分間照射して、またはしないで、インキュベータで、37℃、4日間培養した。
4日間培養した後、各培地(No.1~40)の生存コロニー数を計測し、ブランク(No.21)と比較し、以下の基準に従って抗菌活性を評価した。
- :効果なし ブランクに比べて生存コロニー数の減少率が20%未満である
+ :効果あり ブランクに比べて生存コロニー数の減少率が20%以上40%未満である
2+ :効果あり ブランクに比べて生存コロニー数の減少率が40%以上60%未満である
3+ :効果あり ブランクに比べて生存コロニー数の減少率が60%以上80%未満である
4+ :効果あり ブランクに比べて生存コロニー数の減少率が80%以上である
5+ :効果あり 生存コロニー数が0である
光照射なしの群(No.21~40)は、メチレンブルーおよび添加剤の添加量に関わらず、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有しない群(No.1、6、11、16;濃度0w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有する群(No.2~5、7~10、12~15、17~20;濃度0.01~0.10w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「3+」~「5+」であり、抗菌活性が認められた。
メチレンブルーを含有する群において、メチレンブルー濃度が同じ場合には、D-マンニトールを含有しない群(濃度0w/v%のD-マンニトール水溶液を添加した群;No.2~5)に比べて、D-マンニトールを含有する群(濃度0.5~2.0w/v%のD-マンニトール水溶液を添加した群;No.7~10、12~14、17~20)は抗菌活性評価が高く、D-マンニトールの添加による抗菌活性の増強が認められた(No.2に対するNo.7、12、17など)。
菌液(20μL)、表2に示す各濃度のメチレンブルー溶液(100μL)、および表2に示す各濃度のアスコルビン酸ナトリウム水溶液(10μL)を混合して菌・試薬混合液(130μL)を調製し、直ちに、全量(130μL)をヘリコバクター寒天培地(日水製薬株式会社製)に添加し、コンラージ棒で培地に均等塗布した後、5分間暗所に放置した。
5分間放置の後、LED光(波長 660nm、投射量 15J/m2)を4分間照射して、またはしないで、インキュベータで、37℃、4日間培養した。
4日間インキュベートした後、各培地(No.1~12)の生存コロニー数を計測し、ブランク(No.7)と比較し、上記「抗菌活性評価の基準」に従って抗菌活性を評価した。
光照射なしの群(No.7~12)は、メチレンブルーおよび添加剤の添加量に関わらず、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有しない群(No.1、4;濃度0w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有する群(No.2、3、5、6;濃度0.05~0.10w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「4+」または「5+」であり、抗菌活性が認められた。
メチレンブルーを含有する群において、メチレンブルー濃度が同じ場合には、アスコルビン酸ナトリウムを含有しない群(濃度0w/v%のアスコルビン酸ナトリウム水溶液を添加した群;No.2、3)に比べて、アスコルビン酸ナトリウムを含有する群(濃度0.6w/v%のアスコルビン酸ナトリウム水溶液を添加した群;No.5、6)は抗菌活性評価が高く、アスコルビン酸ナトリウムの添加による抗菌活性の増強が認められた(No.2に対するNo.5など)。
菌液(20μL)、表3に示す各濃度のメチレンブルー溶液(100μL)、および表3に示す各濃度の尿素水溶液(10μL)を混合して菌・試薬混合液(130μL)を調製し、直ちに、全量(130μL)をヘリコバクター寒天培地(日水製薬株式会社製)に添加し、コンラージ棒で培地に均等塗布した後、5分間暗所に放置した。
5分間放置の後、LED光(波長 660nm、投射量 15J/m2)を4分間照射して、またはしないで、インキュベータで、37℃、4日間培養した。
4日間インキュベートした後、各培地(No.1~16)の生存コロニー数を計測し、ブランク(No.9)と比較し、上記「抗菌活性評価の基準」に従って抗菌活性を評価した。
光照射なしの群(No.9~16)は、メチレンブルーおよび添加剤の添加量に関わらず、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有しない群(No.1、5;濃度0w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有する群(No.2~4、6~8;濃度0.01~0.10w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「3+」~「5+」であり、抗菌活性が認められた。
メチレンブルーを含有する群において、メチレンブルー濃度が同じ場合には、尿素を含有しない群(濃度0w/v%の尿素水溶液を添加した群;No.2~4)に比べて、尿素を含有する群(濃度2.0w/v%の尿素水溶液を添加した群;No.6~8)は抗菌活性評価が高く、尿素の添加による抗菌活性の増強が認められた(No.2に対するNo.6など)。
菌液(20μL)、表4に示す各濃度のメチレンブルー溶液(100μL)、および表4に示す各濃度のD-ヒスチジン水溶液(10μL)を混合して菌・試薬混合液(130μL)を調製し、直ちに、全量(130μL)をヘリコバクター寒天培地(日水製薬株式会社製)に添加し、コンラージ棒で培地に均等塗布した後、5分間暗所に放置した。
5分間放置の後、LED光(波長 660nm、投射量 15J/m2)を4分間照射して、またはしないで、インキュベータで、37℃、4日間培養した。
4日間インキュベートした後、各培地(No.1~24)の生存コロニー数を計測し、ブランク(No.13)と比較し、上記「抗菌活性評価の基準」に従って抗菌活性を評価した。
光照射なしの群(No.13~24)は、メチレンブルーおよび添加剤の添加量に関わらず、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有しない群(No.1、4、7、10;濃度0w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有する群(No.2、3、5、6、8、9、11、12;濃度0.05~0.10w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「4+」または「5+」であり、抗菌活性が認められた。
メチレンブルーを含有する群において、メチレンブルー濃度が同じ場合には、D-ヒスチジンを含有しない群(濃度0MのD-ヒスチジン水溶液を添加した群;No.2、3)に比べて、D-ヒスチジンを含有する群(濃度0.01~0.05MのD-ヒスチジン水溶液を添加した群;No.5、6、8、9、11、12)は抗菌活性評価が高く、D-ヒスチジンの添加による抗菌活性の増強が認められた(No.2に対するNo.5など)。
菌液(20μL)、表5に示す各濃度のメチレンブルー溶液(100μL)、および表5に示す各濃度のD-ヒスチジン水溶液(10μL)を混合して菌・試薬混合液(130μL)を調製し、直ちに、全量(130μL)をヘリコバクター寒天培地(日水製薬株式会社製)に添加し、コンラージ棒で培地に均等塗布した後、5分間暗所に放置した。
5分間放置の後、LED光(波長 660nm、投射量 15J/m2)を4分間照射して、またはしないで、インキュベータで、37℃、4日間培養した。
4日間インキュベートした後、各培地(No.1~8)の生存コロニー数を計測し、ブランク(No.5)と比較し、上記「抗菌活性評価の基準」に従って抗菌活性を評価した。
光照射なしの群(No.5~8)は、メチレンブルーおよび添加剤の添加量に関わらず、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有しない群(No.1、3;濃度0w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「-」であり、抗菌活性は認められなかった。
メチレンブルーを含有する群(No.2、4;濃度0.10w/v%のメチレンブルー溶液を添加した群)は、抗菌活性評価が「4+」または「5+」であり、抗菌活性が認められた。
メチレンブルーを含有する群において、L-ヒスチジンを含有しない群(濃度0MのL-ヒスチジン水溶液を添加した群;No.2)に比べて、L-ヒスチジンを含有する群(濃度0.01MのL-ヒスチジン水溶液を添加した群;No.4)は抗菌活性評価が高く、D-ヒスチジンの添加による抗菌活性の増強が認められた。
11 内視鏡
12 演算・制御装置
13 光源装置
14 送気・送水装置
14a 送気ポンプ
14b 洗浄水タンク
15 送液装置
16 挿入部
16a 先端部
16b 湾曲部
16c 可撓管部
17 操作部
18 ユニバーサルコード
20 先端キャップ
21 観察窓
22a 照明窓
22b 照明窓
23 鉗子出口
24 ウォータージェット出口(WJ出口)
25 噴射ノズル
26 鉗子入口
27 モード切替スイッチ
28 上下湾曲用アングルノブ
29 左右湾曲用アングルノブ
30 送気・送水ボタン
31 ズーム操作部
32 コネクタ
33 モニタ
35 送液タンク
36 送液装置本体
37 送液ポンプ
38 フットスイッチ
39 送液管
40 連結管
41a,41b ライトガイド
42 鉗子チューブ
43 送気・送水チューブ
44 多芯ケーブル
44a 信号ケーブル
44b 外皮
45 ウォータージェットチューブ(WJチューブ)
47b 第2WJ路
51 螺管
52 ネット
53 ゴム
100 殺菌システム
101 演算制御部
102 撮像手段
102a 撮像口
103 撮像方向制御手段
104 光照射手段
104a 光照射口
105 照射方向制御手段
106 組成物噴射手段
106a 噴射口
107 噴射方向制御手段
108,109,110,111,112,113 信号伝達路
200 被検体
201 皮膚または粘膜
202 病変部
203 組成物付着領域
Claims (14)
- ピロリ菌感染症の病変部位に存在するピロリ菌に接触させ、前記ピロリ菌に光を照射することによりピロリ菌感染症を治療する光線力学療法において使用するための光線力学療法用組成物であって、
メチレンブルーと、
オスモライト、還元剤、尿素およびプロトン供与剤からなる群から選択される少なくとも1つの製薬学的に許容しうる添加剤と
を含む光線力学療法用組成物。 - 前記オスモライトがマンニトールであり、前記還元剤がアスコルビン酸であり、かつ、前記プロトン供与剤がヒスチジンである、請求項1に記載の光線力学療法用組成物。
- 前記光が白色光または波長660±10nmのLED光もしくはレーザー光である、請求項1または2に記載の光線力学療法用組成物。
- 前記光の光線投射量が1~200J/cm2である、請求項1~3のいずれか1項に記載の光線力学療法用組成物。
- 皮膚粘膜感染症の病変部位に存在する病原微生物に接触させ、前記病原微生物に光を照射することにより前記皮膚粘膜感染症を治療する光線力学療法において使用するための光線力学療法用組成物であって、
メチレンブルーと、
オスモライトおよび還元剤からなる群から選択される少なくとも1つの製薬学的に許容しうる添加剤と
を含む光線力学療法用組成物。 - 前記オスモライトがマンニトールであり、かつ、前記還元剤がアスコルビン酸である、請求項5に記載の光線力学療法用組成物。
- 前記光が白色光または波長660±10nmのLED光もしくはレーザー光である、請求項5または6に記載の光線力学療法用組成物。
- 前記光の光線投射量が1~200J/cm2である、請求項5~7のいずれか1項に記載の光線力学療法用組成物。
- 請求項1~4のいずれか1項に記載の光線力学療法用組成物をピロリ菌に接触させる工程と、
前記ピロリ菌に白色光または波長660±10nmのLED光もしくはレーザー光を照射する工程と
を備えるピロリ菌の殺菌方法。 - 前記白色光またはLED光もしくはレーザー光の光線投射量が1~200J/cm2である、請求項9に記載のピロリ菌の殺菌方法。
- 請求項5~8のいずれか1項に記載の光線力学療法用組成物を皮膚粘膜感染症の病原微生物に接触させる工程と、
前記病原微生物に白色光または波長660±10nmのLED光もしくはレーザー光を照射する工程と
を備える皮膚粘膜感染症の病原微生物の殺菌方法。 - 前記白色光またはLED光もしくはレーザー光の光線投射量が1~200J/cm2である、請求項11に記載の皮膚粘膜感染症の病原微生物の殺菌方法。
- 撮像手段と、光照射手段と、組成物噴射手段と、前記撮像手段の撮像方向を制御する撮像方向制御手段と、前記光照射手段の光照射方向を制御する照射方向制御手段と、前記組成物噴射手段の噴射方向を制御する噴射方向制御手段と、前記撮像手段、前記光照射手段、前記組成物噴射手段、前記撮像方向制御手段、前記照射方向制御手段および前記噴射方向制御手段を制御する演算・制御部とを備える、ピロリ菌感染症または皮膚粘膜感染症による病変部の殺菌システムであって、
(a)前記撮像方向制御手段および前記照射方向制御手段は、前記演算・制御部からの制御信号に基づいて、前記撮像手段の被観察領域を前記光照射手段が照明するように作動し、
(b)前記撮像手段は、前記演算・制御部からの制御信号に基づいて、皮膚・粘膜を撮像し、映像信号を前記演算・制御部に送信し、
(c)前記演算・制御部は、前記撮像手段から送信された映像信号を受信し、粘膜の正常領域と異常領域との色の差を強調するように映像処理を行い、正常部と病変部とを識別し、病変部の位置を特定し、
(d)前記噴射方向制御手段は、前記演算・制御部からの制御信号に基づいて、前記組成物噴射手段の噴射方向を病変部に合わせるように作動し、
(e)前記組成物噴射手段は、前記演算・制御部からの制御信号に基づいて、請求項1~8のいずれか1項に記載の光線力学療法用組成物を噴射し、
(f)前記照射方向制御手段は、前記演算・制御部からの制御信号に基づいて、前記光照射手段の照射方向を病変部に合わせるように作動し、および
(g)前記光照射手段は、前記演算・制御部からの制御信号に基づいて、白色光または波長660±10nmのLED光もしくはレーザー光を発射する、
ピロリ菌感染症または皮膚粘膜感染症による病変部の殺菌システム。 - 撮像手段と、光照射手段と、組成物噴射手段と、前記撮像手段の撮像方向を制御する撮像方向制御手段と、前記光照射手段の光照射方向を制御する照射方向制御手段と、前記組成物噴射手段の噴射方向を制御する噴射方向制御手段と、前記撮像手段、前記光照射手段、前記組成物噴射手段、前記撮像方向制御手段、前記照射方向制御手段および前記噴射方向制御手段を制御する演算・制御部とを備える、ピロリ菌感染症または皮膚粘膜感染症による病変部の殺菌システムの作動方法であって、
(a)前記撮像手段の被観察領域を前記光照射手段が照明するように、前記演算・制御部からの制御信号に基づいて、前記撮像方向制御手段および前記照射方向制御手段を作動させる工程、
(b)前記撮像手段が、前記演算・制御部からの制御信号に基づいて、皮膚・粘膜を撮像し、映像信号を前記演算・制御部に送信する工程、
(c)前記演算・制御部が、前記撮像手段から送信された映像信号を受信し、粘膜の正常領域と異常領域との色の差を強調するように映像処理を行い、正常部と病変部とを識別し、病変部の位置を特定する工程、
(d)前記組成物噴射手段の噴射方向を病変部に合わせるように、前記演算・制御部からの制御信号に基づいて、前記噴射方向制御手段を作動させる工程、
(e)前記組成物噴射手段が、前記演算・制御部からの制御信号に基づいて、請求項1~8のいずれか1項に記載の光線力学療法用組成物を噴射する工程、
(f)前記光照射手段の照射方向を病変部に合わせるように、前記演算・制御部からの制御信号に基づいて、前記照射方向制御手段を作動させる工程、および
(g)前記光照射手段が、前記演算・制御部からの制御信号に基づいて、白色光または波長660±10nmのLED光もしくはレーザー光を発射する工程
を含む、ピロリ菌感染症または皮膚粘膜感染症による病変部の殺菌システムの作動方法。
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KR101967625B1 (ko) | 2019-04-11 |
KR20170029636A (ko) | 2017-03-15 |
JPWO2016031875A1 (ja) | 2017-05-25 |
JP6412142B2 (ja) | 2018-10-24 |
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