JP2023142440A - Prevention method of erosion or ulcer, treatment method of disease, irradiation gas for erosion or ulcer prevention and generation method of irradiation gas for erosion or ulcer prevention - Google Patents

Abstract

To address such a problem that as for the plasma generator, studies to enhance the healing effect thereof on ulcer, wound, etc. have been made, however, the prevention of disease of erosion or ulcer has not been studied; and to provide a prevention method of the erosion or ulcer by using a plasma generator.SOLUTION: A prevention method of erosion or ulcer includes an irradiation step of applying preventive irradiation gas to a biological tissue once or more, where the preventive irradiation gas contains singlet oxygen generated by plasma, and one-time of irradiation step of applying the irradiation gas to the biological tissue is so performed that an integrated singlet oxygen concentration becomes 10 μ mol/L or more.SELECTED DRAWING: None

Description

The present invention relates to a method for preventing erosions or ulcers, a method for treating diseases, an irradiation gas for preventing erosions or ulcers, and a method for producing an irradiation gas for preventing erosions or ulcers.

2. Description of the Related Art Plasma generators are known that perform treatment, sterilization, etc. using plasma or active species generated by plasma. In a plasma generator, for example, plasma or an irradiation gas containing active species is irradiated onto an affected area to promote healing of a wound or the like.
For example, Patent Document 1 discloses a hand piece for a plasma generator that has a bent portion, and includes an insulating member that is located between internal electrodes and has flexibility and extends along the bent portion. Disclosed. According to the invention of Patent Document 1, the sterilization effect by plasma and the operability are improved.

JP2017-35281A

Up to now, studies have been made to enhance the healing effects of erosions, ulcers, etc. in plasma generators, but there has been no study on prevention of erosions or ulcers.
Therefore, the present invention aims at preventing erosions or ulcers using a plasma generating device.

The present inventors have discovered that irradiation of tissue with an irradiation gas containing singlet oxygen exerts a preventive effect against erosions or ulcers, and has completed the present invention.

The present invention has the following aspects.
<1>
A method for preventing erosions or ulcers, the method comprising an irradiation step of irradiating biological tissue with a preventive irradiation gas one or more times,
The preventive irradiation gas contains singlet oxygen generated by plasma,
A method for preventing erosions or ulcers, wherein in one irradiation step, the preventive irradiation gas is irradiated such that the following integrated singlet oxygen concentration is 10 μmol/L or more.
<Cumulative singlet oxygen concentration>
0.8 mL of TPC (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamide) 0.1 mol/L solution was irradiated with preventive irradiation gas at an arbitrary time and at an arbitrary distance. Thereafter, the singlet oxygen concentration of the solution irradiated with the preventive irradiation gas is measured by the electron spin resonance (ESR) method, and this is defined as the cumulative singlet oxygen concentration (μmol/L).
<2>
The method for preventing erosion or ulcer according to <1>, which is a method for preventing oral mucositis.
<3>
The method for preventing erosion or ulcer according to <2>, wherein the oral mucositis is a disease induced by cancer treatment.
<4>
The method for preventing erosions or ulcers according to any one of <1> to <3>, wherein the irradiation step is performed 1 to 3 times/day for 3 days or more.
<5>
The method for preventing erosions or ulcers according to any one of <1> to <4>, wherein one irradiation step is for 1 to 120 seconds.

<6>
A method for treating a disease, comprising a step of applying the method for preventing erosion or ulcer according to any one of <1> to <5>, and a treatment step capable of inducing the onset of erosion or ulcer,
A method for treating a disease, comprising performing the irradiation step at least once before starting the treatment step.
<7>
The method for treating a disease according to <6>, wherein the irradiation step is performed at least once after the start of the treatment step.
<8>
The method for treating a disease according to <6> or <7>, wherein the treatment step is cancer treatment.

<9>
An irradiation gas for preventing erosions or ulcers, which contains singlet oxygen and has an integrated singlet oxygen concentration below of 10 μmol/L or more.
<Cumulative singlet oxygen concentration>
0.8 mL of TPC (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamide) 0.1 mol/L solution was irradiated with preventive irradiation gas at an arbitrary time and at an arbitrary distance. Thereafter, the singlet oxygen concentration of the solution irradiated with the preventive irradiation gas is measured by the electron spin resonance (ESR) method, and this is defined as the cumulative singlet oxygen concentration (μmol/L).

<10>
The method for producing an irradiation gas for preventing erosions or ulcers according to <9>,
Prevention of erosions or ulcers by supplying plasma generating gas at 1 to 10 L/min to a plasma generating part having an electrode, generating plasma by applying a voltage to the electrode, and generating the singlet oxygen with the generated plasma. How to generate irradiation gas for use.

<11>
an irradiation device that has a pair of electrodes and irradiates an irradiation gas containing singlet oxygen generated by plasma;
a gas supply unit that supplies plasma generation gas to the irradiation device;
a power supply unit that applies voltage to the electrode;
It has a control section,
The control unit controls at least one of the gas supply unit and the power supply unit so that the cumulative singlet oxygen concentration described below is 10 μmol/L or more.
<Cumulative singlet oxygen concentration>
0.8 mL of TPC (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamide) 0.1 mol/L solution was irradiated with preventive irradiation gas at an arbitrary time and at an arbitrary distance. Thereafter, the singlet oxygen concentration of the solution irradiated with the preventive irradiation gas is measured by the electron spin resonance (ESR) method, and this is defined as the cumulative singlet oxygen concentration (μmol/L).

According to the prevention method of the present invention, it is effective in preventing diseases.

FIG. 1 is a schematic diagram of a medical plasma generator according to a first embodiment of the present invention. It is a partial sectional view of the irradiation instrument of the medical plasma generation device concerning a first embodiment of the present invention. FIG. 1 is a block diagram of a medical plasma generator according to a first embodiment of the present invention. It is a graph showing the results of Examples.

The present invention will be explained in detail below. The following embodiments are merely examples for explaining the present invention, and are not intended to limit the present invention only to these embodiments. The present invention can be implemented with various modifications within the scope of its gist.
In addition, in this specification, "~" indicating a numerical range is used to include the numerical values written before and after it as a lower limit value and an upper limit value.
As used herein, the term "prevention" includes treatment aimed at preventing the onset of erosions or ulcers, treatment for mildly suppressing developed erosions or ulcers, and treatment for hastening the healing of developed erosions or ulcers. Includes previous treatment.

The method for preventing erosions or ulcers of the present invention includes an irradiation step of irradiating living tissue with an irradiation gas containing singlet oxygen generated by plasma at least once, and the cumulative singlet oxygen concentration in one irradiation step is determined. The range shall be .
The method of treating a disease of the present invention includes the method of preventing erosion or ulcer of the present invention.
The irradiation gas for prevention of erosions or ulcers of the present invention contains a specific amount of integrated singlet oxygen concentration.
The method of producing an irradiation gas for preventing erosion or ulceration of the present invention includes supplying a plasma generating gas to a plasma generating section having an electrode and applying a voltage to the electrode.
Hereinafter, embodiments will be given of the medical plasma generating device, the method for preventing erosions or ulcers, the method for treating diseases, the irradiation gas for preventing erosions or ulcers, and the method for producing irradiation gas for preventing erosions or ulcers of the present invention. explain.

(Medical plasma generator)
An example of a medical plasma generator used in the present invention will be described with reference to the drawings.
A medical plasma generation device includes a plasma generation section having an electrode, an irradiation port that discharges irradiation gas containing active species generated by plasma generated in the plasma generation section, and a gas supply that supplies plasma generation gas to the plasma generation section. and a power supply unit that applies voltage to the electrodes.

The medical plasma generator 100 shown in FIGS. 1 to 3 includes an irradiation device 10, a supply device 20, and a connection cable 30. Inside the connection cable 30, an electric supply line 32, a grounding line 34, and a gas pipe line 36 are housed.

FIG. 2 is a cross-sectional (longitudinal cross-sectional) view of the surface of the irradiation instrument 10 along the axis.
As shown in FIG. 2, the irradiation device 10 has a plasma generation section 12.

The irradiation device 10 includes an elongated cowling 2, a nozzle 1 protruding from the tip of the cowling 2, and a plasma generating section 12 located within the cowling 2.
The cowling 2 includes a cylindrical body portion 2b and a head portion 2a that closes the tip of the body portion 2b. Note that the body portion 2b is not limited to a cylindrical shape, but may be a polygonal tube such as a square tube, a hexagonal tube, or an octagonal tube.

The head portion 2a gradually narrows toward the tip. That is, the head portion 2a in this embodiment has a conical shape. The head portion 2a is not limited to a conical shape, but may be a polygonal pyramid such as a square pyramid, a hexagonal pyramid, or an octagonal pyramid.
The head portion 2a has a fitting hole 2c at the tip. The fitting hole 2c is a hole that receives the nozzle 1. The nozzle 1 is removably attached to the head portion 2a. The head portion 2a has therein a first active gas flow path 7 extending in the direction of the tube axis O1. The tube axis O1 is the tube axis of the body portion 2b.

The plasma generation section 12 includes a tubular dielectric 3 (dielectric), an internal electrode 4, and an external electrode 5.
The tubular dielectric 3 is a cylindrical member extending in the direction of the tube axis O1. The tubular dielectric 3 has inside thereof a gas flow path 6 extending in the direction of the tube axis O1. In this embodiment, the plasma generating gas flows through the gas flow path 6 in the direction of the tube axis O1. The first active gas flow path 7 and the gas flow path 6 are in communication. Note that the tube axis O1 is the same as the tube axis of the tubular dielectric 3.
The tubular dielectric body 3 includes an internal electrode 4 therein. The internal electrode 4 is a substantially cylindrical member extending in the direction of the tube axis O1. The internal electrode 4 is spaced apart from the inner surface of the tubular dielectric 3.
A part of the outer peripheral surface of the tubular dielectric 3 is provided with an external electrode 5 along the internal electrode 4 . The external electrode 5 is an annular electrode that goes around the outer circumferential surface of the tubular dielectric 3 .
The tubular dielectric 3, the internal electrode 4, and the external electrode 5 are located concentrically around the tube axis O1.
In this embodiment, the outer circumferential surface of the internal electrode 4 and the inner circumferential surface of the external electrode 5 face each other with the tubular dielectric body 3 in between.
Internal electrode 4 is connected to electrical supply line 32 .
The external electrode 5 is connected to a grounding line 34 and is electrically grounded.
Note that although the plasma generating section 12 of this embodiment has electrodes facing in a direction perpendicular to the flow direction of the plasma generating gas, the present invention is not limited thereto. The plasma generation section 12 may be configured with two electrodes facing each other along the flow direction of the plasma generation gas (see Japanese Patent No. 5441066), or may have a configuration with only one electrode to which a voltage is applied. Good (see Japanese translation of PCT publication No. 2018-504202).

The nozzle 1 includes a pedestal portion 1b that fits into a fitting hole 2c, and an irradiation tube 1c that protrudes from the pedestal portion 1b. The pedestal portion 1b and the irradiation tube 1c are integrated. The nozzle 1 has a second active gas flow path 8 therein. The nozzle 1 has an irradiation port 1a at its tip. The second active gas flow path 8 and the first active gas flow path 7 are in communication.

The material of the body portion 2b is not particularly limited, but an insulating material is preferable. Examples of the insulating material include thermoplastic resins and thermosetting resins. Examples of thermoplastic resins include polyethylene, polypropylene, polyvinyl chloride, polystyrene, acrylonitrile-butadiene-styrene resin (ABS resin), and the like. Examples of the thermosetting resin include phenol resin, melamine resin, urea resin, epoxy resin, unsaturated polyester resin, and silicone resin.
The size of the body portion 2b is not particularly limited, and can be set to a size that is easy to hold with fingers.

The material of the head portion 2a is not particularly limited and may or may not have insulation properties. The material of the head portion 2a is preferably a material with excellent wear resistance and corrosion resistance. Examples of materials with excellent wear resistance and corrosion resistance include metals such as stainless steel. The materials of the head portion 2a and the body portion 2b may be the same or different.
The size of the head portion 2a can be determined in consideration of the intended use of the medical plasma generator 100, etc. For example, when the medical plasma generating device 100 is an intraoral treatment instrument, the size of the head portion 2a is preferably such that it can be inserted into the oral cavity.

As the material for the tubular dielectric 3, dielectric materials used in known plasma generators can be used. Examples of the material for the tubular dielectric 3 include glass, ceramics, and synthetic resin. The lower the dielectric constant of the tubular dielectric 3, the more preferable it is.

The inner diameter R of the tubular dielectric 3 can be appropriately determined by taking the outer diameter d of the internal electrode 4 into consideration. The inner diameter R is determined so that a distance s, which will be described later, is within a desired range.

The internal electrode 4 is not particularly limited as long as it has a shape extending in the direction of the tube axis O1. The internal electrode 4 may be, for example, a member with a smooth circumferential surface or a member having irregularities such as threads on the circumferential surface.

The outer diameter d of the internal electrode 4 can be determined as appropriate, taking into consideration the application of the medical plasma generator 100 (that is, the size of the irradiation instrument 10), etc. When the medical plasma generator 100 is an intraoral treatment instrument, the outer diameter d is preferably 0.5 to 20 mm, more preferably 1 to 10 mm. When the outer diameter d is equal to or larger than the above lower limit, the internal electrode 4 can be easily manufactured. In addition, when the outer diameter d is equal to or larger than the above lower limit, the surface area of the internal electrode 4 becomes large, plasma can be generated more efficiently, and healing etc. can be further promoted. When the outer diameter d is equal to or less than the above upper limit value, plasma can be generated more efficiently and healing etc. can be further promoted without making the irradiation instrument 10 excessively large. If the internal electrode is a member having irregularities such as threads on its periphery, the maximum diameter among the external diameters of the internal electrode is defined as the external diameter d.

The height of the thread of the internal electrode 4 can be appropriately determined in consideration of the outer diameter d of the internal electrode 4.
The pitch of the thread of the internal electrode 4 can be appropriately determined by taking into consideration the length, outer diameter d, etc. of the internal electrode 4.

The material of the internal electrode 4 is not particularly limited as long as it is a conductive material, and metals that can be used for electrodes of known plasma generators can be used. Examples of the material for the internal electrodes 4 include metals such as stainless steel, copper, and tungsten, and carbon.

The material of the internal electrode 4 is not particularly limited as long as it is a conductive material, and metals that can be used for electrodes of known plasma generators can be used. Examples of the material for the internal electrodes 4 include metals such as stainless steel, copper, and tungsten, and carbon.

The distance s between the outer surface of the internal electrode 4 and the inner surface of the tubular dielectric 3 is preferably 0.05 to 5 mm, more preferably 0.1 to 1 mm. When the distance s is equal to or greater than the above lower limit, a desired amount of plasma-generating gas can be easily passed through. When the distance s is less than or equal to the above upper limit value, plasma can be generated more efficiently and the temperature of the irradiated gas can be lowered.

The material of the external electrode 5 is not particularly limited as long as it is a conductive material, and metals used for electrodes of known plasma generators can be used. Examples of the material for the external electrode 5 include metals such as stainless steel, copper, and tungsten, and carbon.

The material of the nozzle 1 is not particularly limited and may be insulating or conductive. As the material for the nozzle 1, a material having excellent wear resistance and corrosion resistance is preferable. Examples of materials with excellent wear resistance and corrosion resistance include metals such as stainless steel.

The length of the flow path in the irradiation tube 1c in the nozzle 1 (that is, the distance L2) can be determined as appropriate, taking into consideration the application of the medical plasma generator 100 and the like.
The opening diameter of the irradiation port 1a is preferably, for example, 0.5 to 5 mm. When the opening diameter is equal to or larger than the above lower limit, pressure loss of the irradiation gas can be suppressed. When the opening diameter is equal to or less than the above upper limit value, the flow rate of the irradiation gas can be increased to promote preventive effects and healing effects.
The irradiation tube 1c is bent with respect to the tube axis O1.
The angle θ between the tube axis O2 and the tube axis O1 of the irradiation tube 1c can be determined by taking into consideration the application of the medical plasma generator 100 and the like.
Note that the irradiation tube 1c may be straight from the base end to the distal end, or may be bent in the middle.

The sum of the distance L1 from the tip Q1 of the external electrode 5 to the tip Q2 of the head section 2a and the distance L2 from the tip Q2 to the irradiation port 1a (that is, the distance from the region where plasma is generated to the irradiation port 1a) is: It is determined as appropriate by taking into consideration the size required for the medical plasma generator 100, the temperature of the surface (irradiated surface) that is hit by the irradiated irradiation gas, etc. If the sum of distance L1 and distance L2 is long, the temperature of the irradiated surface can be lowered. If the sum of distance L1 and distance L2 is short, the active species concentration of the irradiation gas can be further increased, and the preventive effect and healing effect on the irradiated surface can be further enhanced. Note that the tip Q2 is the intersection of the tube axis O1 and the tube axis O2.

The supply device 20 includes a power supply section 50, a gas supply section 60, a gas supply source 70, a control section 90, and a housing 21 that accommodates these. Further, the supply device 20 includes an irradiation operation section 9 and a timer 80.

In this embodiment, the irradiation operation section 9 is provided on the upper surface of the housing 21. Examples of the irradiation operation unit 9 include buttons, touch panels, and other switches. Note that the irradiation operation section 9 does not need to be provided on the top surface of the housing 21. The irradiation operation section 9 may be, for example, a foot pedal provided below the supply device 20, or a switch provided on the irradiation instrument 10.

The housing 21 removably houses the gas supply source 70. Thereby, when the gas in the gas supply source 70 housed in the housing 21 runs out, the gas supply source 70 can be replaced.

The power supply unit 50 is connected to a power source such as a 100V household power source, for example. The power supply unit 50 is connected to the internal electrode 4 of the irradiation device 10 via the electric supply line 32.

The power supply section 50 switches between starting and stopping the supply of electricity to the electrodes of the plasma generation section 12 . In addition, the power supply unit 50 adjusts the voltage and frequency applied to the electrodes. Examples of the power feeding unit 50 include a circuit including an inverter.

The timer 80 displays, for example, the irradiation time or manages the irradiation time. Note that the medical plasma generator 100 does not need to include the timer 80.

The gas supply section 60 includes a gas pipe 65 that connects the gas supply source 70 and the gas pipe line 36 . The gas pipe 65 is provided with a solenoid valve 61, a pressure regulator 63, and a flow rate controller 64 (flow rate adjustment section). The flow rate controller 64 and the solenoid valve 61 are connected to a control section 90.

The solenoid valve 61 switches between opening and closing to start and stop the supply of plasma generation gas from the gas supply source 70 to the irradiation device 10 . In the illustrated example, the electromagnetic valve 61 does not have a configuration in which the opening degree of the valve can be adjusted, but can only be switched between opening and closing. Note that the electromagnetic valve 61 may have a configuration in which the valve opening degree can be adjusted.

Pressure regulator 63 is arranged between solenoid valve 61 and gas supply source 70 . The pressure regulator 63 reduces the pressure of the plasma-generating gas flowing from the gas supply source 70 toward the electromagnetic valve 61 (reducing the pressure of the plasma-generating gas).

The flow controller 64 is arranged between the electromagnetic valve 61 and the gas pipe line 36. The flow rate controller 64 adjusts the flow rate (supply amount per unit time) of the plasma generating gas that has passed through the electromagnetic valve 61. The flow rate controller 64 adjusts the flow rate of the plasma generation gas to, for example, 1 to 10 L/min.

A joint 66 is provided at the end of the gas pipe 65 on the gas supply source 70 side. A gas supply source 70 is removably attached to the joint 66. By attaching and detaching the gas supply source 70 to the joint 66, the gas supply source 70 can be replaced while the gas supply unit 60 is fixed to the housing 21. In this case, the common gas supply unit 60 can be used for both the gas supply source 70 before replacement and the gas supply source 70 after replacement. Note that the gas supply unit 60 may be fixed to the gas supply source 70 and may be detachable from the housing 21 integrally with the gas supply source 70.

The gas supply source 70 supplies plasma generating gas to the plasma generating section 12 . The gas supply source 70 is a pressure-resistant container or the like containing a plasma-generating gas therein. The gas supply source 70 is removably attached to the gas supply unit 60 disposed within the housing 21 .
Note that the gas supply source 70 may be located outside the housing 21 or may be a device independent of the medical plasma generator 100.

The control unit 90 is configured using an information processing device. That is, the control unit 90 includes a CPU (Central Processor Unit), a memory, and an auxiliary storage device connected via a bus. The control unit 90 operates by executing a program.

The gas pipe line 36 is a path for supplying plasma generation gas from the supply device 20 to the irradiation device 10. The gas line 36 is connected to the tubular dielectric 3 of the irradiation device 10. The material for the gas pipe line 36 is not particularly limited, and materials used for known gas pipes can be used. Examples of the material for the gas pipe line 36 include resin piping, rubber tubes, etc., and a flexible material is preferable.

The electric supply line 32 includes wiring for supplying electricity from a power source to the plasma generating section 12 of the irradiation device 10.
The material for the electric supply line 32 is not particularly limited, and any material used for known electric wiring can be used. Examples of the material of the electric supply line 32 include a metal conducting wire coated with an insulating material.

The medical plasma generator 100 has a notification section 22. The notification unit 22 may be a member having a visual notification function or a member having an auditory notification function. Examples of the member having a visual notification function include light emitting elements such as LEDs. Examples of members having an auditory notification function include audio devices such as buzzers and alarms.
The notification unit 22 may be provided in the supply device 20, may be provided in the irradiation device 10, or may be provided independently of the supply device 20 and the irradiation device 10. Furthermore, the medical plasma generator 100 does not need to include the notification section 22.

The medical plasma generator 100 is suitable for treating erosions, ulcers, etc., and for preventing erosions or ulcers.

(Prophylactic irradiation gas)
The preventive irradiation gas of the present invention contains singlet oxygen.
The integrated singlet oxygen concentration of the preventive irradiation gas is 10 μmol/L or more, preferably 30 μmol/L or more, and more preferably 60 μmol/L or more. When the integrated singlet oxygen concentration is at least the above lower limit, the preventive effect against erosions or ulcers can be enhanced.
The upper limit of the integrated singlet oxygen concentration of the preventive irradiation gas is, for example, preferably 300 μmol/L or less, more preferably 250 μmol/L or less, and even more preferably 200 μmol/L or less. When the integrated singlet oxygen concentration is below the above-mentioned upper limit, it is possible to prevent erosion or ulcer from worsening due to stimulation by an excessive amount of active species.
The cumulative singlet oxygen concentration of the preventive irradiation gas is adjusted by a combination of the singlet oxygen concentration in the preventive irradiation gas and the irradiation time of the preventive irradiation gas. In addition, the singlet oxygen concentration in the preventive irradiation gas is determined by the combination of the applied voltage of the current supplied to the electrodes of the plasma generation section 12, the type of plasma generation gas, the amount of plasma generation gas supplied to the plasma generation section 12, etc. It can be adjusted by

The method for measuring the cumulative singlet oxygen concentration of the preventive irradiation gas is as follows: After irradiating the prophylactic irradiation gas at an arbitrary distance for a time of Then, it is defined as the cumulative singlet oxygen concentration at any given time and any distance.

The TPC 0.1 mol/L solution (hereinafter sometimes simply referred to as "TPC solution") is an aqueous solution.

The distance at which the TPC solution is irradiated with the prophylactic irradiation gas (the distance from the irradiation port of the plasma irradiator to the water surface of the TPC solution) is determined by the irradiation process of the preventive method described below (in particular, sometimes referred to as the "preventive irradiation process"). It is the same as the irradiation distance in . The distance at which the TPC solution is irradiated with the preventive irradiation gas is, for example, 10 mm.

The time for irradiating the TPC solution with the preventive irradiation gas (irradiation time) is the same as the irradiation time in the preventive irradiation step. That is, the integrated singlet oxygen concentration in the preventive irradiation gas is correlated with the total amount of singlet oxygen irradiated in one preventive irradiation step.

Active species contained in the preventive irradiation gas include, in addition to singlet oxygen, hydroxyl radicals, ozone, hydrogen peroxide, superoxide anion radicals, nitric oxide, nitrogen dioxide, peroxynitrite, peroxynitrite, and trioxide. Examples include dinitrogen. The type of active species contained in the preventive irradiation gas can be adjusted by, for example, the type of plasma-generating gas.

(Method for generating preventive irradiation gas)
Regarding the method of generating the preventive irradiation gas of this embodiment, a method of generating the preventive irradiation gas using the medical plasma generator 100 will be described.
For example, a user such as a doctor turns on the main power of the supply device 20. At this time, if the timer 80 has a function of managing irradiation time, the timer 80 sets the irradiation time of the preventive irradiation gas.
When the user operates the irradiation operation section 9, the control section 90 operates the timer 80, and generates plasma from the gas supply source 70 to the plasma generation section 12 of the irradiation device 10 via the gas supply section 60 and the gas pipe 36. Gas is supplied, the voltage supplied to the plasma generating section 12 is adjusted, and voltage is applied to the electrodes.

The plasma generating gas supplied to the plasma generating section 12 flows into the inner space of the tubular dielectric 3 from behind the tubular dielectric 3 . The plasma-generating gas is ionized at a position where the internal electrode 4 and the external electrode 5 to which a voltage is applied face each other, and becomes plasma.

In this embodiment, the internal electrode 4 and the external electrode 5 face each other in a direction perpendicular to the flow direction of the plasma generating gas. The plasma generated at the position where the outer circumferential surface of the internal electrode 4 and the inner circumferential surface of the external electrode 5 are opposed to each other flows through the gas flow path 6, the first active gas flow path 7, and the second active gas flow path 8. are passed in this order. During this time, the plasma flows through the gas while changing its gas composition, and becomes a preventive irradiation gas containing active species such as radicals.
The generated preventive irradiation gas is discharged from the irradiation port 1a of the nozzle 1. The discharged preventive irradiation gas further activates a part of the gas near the irradiation port 1a to generate active species. The object to be irradiated is irradiated with a preventive irradiation gas containing these active species (irradiation step).
When an arbitrary irradiation time (time set by the timer 80) in the irradiation process has elapsed, the control unit 90 controls at least one of the supply of plasma generation gas to the plasma generation unit 12 and the supply of electricity to the plasma generation unit 12. Stop and finish discharging the preventive irradiation gas. At this time, the supply of electricity to the plasma generation section 12 (that is, the application of voltage to the electrodes) and the supply of plasma generation gas to the plasma generation section 12 can be stopped to stop the instruction by the irradiation operation section 9. preferable. Alternatively, when a predetermined time has elapsed, the notification unit 22 notifies that a predetermined amount of integrated singlet oxygen concentration has been irradiated.

In the irradiation process, when the irradiation operation section 9 transmits an electric signal only once in one operation, the control section 90 controls the electromagnetic valve 61, the flow rate controller 64, the timer 80, and the power supply section as follows, for example. Control 50.
When the control unit 90 receives the electrical signal from the irradiation operation unit 9, the control unit 90 opens the solenoid valve 61 and causes the flow rate controller 64 to adjust the flow rate of the plasma generation gas that has passed through the solenoid valve 61. Further, the control unit 90 controls the power supply unit 50 to apply a voltage to the electrodes of the plasma generation unit 12 . Further, the control unit 90 starts the timer 80. When the timer 80 reaches a predetermined time, the control unit 90 receives a signal from the timer 80 and closes the solenoid valve 61 or stops applying voltage to the electrodes of the plasma generation unit 12. Alternatively, the notification unit 22 notifies that the irradiation has been performed for a predetermined period of time. As a result, when the user operates the irradiation operation section 9 once, a predetermined amount of preventive irradiation gas having an integrated singlet oxygen concentration is discharged from the irradiation port 1a.

In the irradiation process, when the irradiation operation unit 9 continues to transmit electrical signals while continuing to operate, the control unit 90 controls the electromagnetic valve 61, the flow rate controller 64, the timer 80, and the power supply as follows, for example. 50.
While the control unit 90 is receiving the electrical signal from the irradiation operation unit 9, the control unit 90 opens the solenoid valve 61 and causes the flow rate controller 64 to adjust the flow rate of the plasma generation gas that has passed through the solenoid valve 61. Further, the control unit 90 controls the power supply unit 50 to apply a voltage to the electrodes of the plasma generation unit 12 . Further, the control unit 90 starts the timer 80. When the operation of the irradiation operation unit 9 is stopped, the control unit 90 closes the electromagnetic valve 61 or stops applying voltage to the electrodes of the plasma generation unit 12. Alternatively, the notification unit 22 notifies that a predetermined time has passed. As a result, while the user operates the irradiation operation section 9, the preventive irradiation gas is discharged from the irradiation port 1a.

Examples of the plasma generating gas include rare gases (helium, neon, argon, krypton, etc.), nitrogen, oxygen, air, and the like. These gases may be used alone or in combination of two or more.
The plasma generating gas preferably contains nitrogen as a main component. Here, "containing nitrogen as a main component" means that the content of nitrogen in the plasma generation gas is more than 50% by volume.
That is, the nitrogen content in the plasma generating gas is preferably more than 50% by volume, more preferably 70% by volume or more, even more preferably 80 to 100% by volume, and particularly preferably 90 to 100% by volume. Examples of gas components other than nitrogen in the plasma generation gas include oxygen, rare gases, and the like.
The oxygen concentration of the plasma generating gas is preferably 1% by volume or less. When the oxygen concentration is below the upper limit, the generation of ozone can be reduced.

The flow rate of the plasma generating gas introduced into the tubular dielectric 3 in the irradiation step is preferably 1 to 10 L/min, more preferably 2 to 10 L/min, and even more preferably 3 to 10 L/min. When the flow rate of the plasma-generating gas introduced into the tubular dielectric 3 is equal to or higher than the above lower limit value, it is easy to suppress a rise in temperature of the irradiated surface of the irradiated object. If the flow rate of the plasma generating gas is set below the above upper limit value, the voltage applied to the electrodes can be further reduced.

The AC voltage applied between the internal electrode 4 and the external electrode 5 in the irradiation step is preferably 1 kVpp or more and 20 kVpp or less, more preferably 5 kVpp or more and 20 kVpp or less. Here, the unit "Vpp (Volt peak to peak)" representing AC voltage is the potential difference between the highest value and the lowest value of the AC voltage waveform.
When the applied alternating current voltage is below the above upper limit value, the temperature of the generated plasma can be kept low. Plasma can be generated even more efficiently when the applied alternating current voltage is equal to or higher than the above lower limit.

The frequency of the alternating current applied between the internal electrode 4 and the external electrode 5 in the irradiation step is preferably 0.5 kHz or more and 30 kHz or less, more preferably 5 kHz or more and 30 kHz or less, and even more preferably 10 kHz or more and 30 kHz or less. When the frequency of the alternating current is below the upper limit value, the temperature of the generated plasma can be kept low. When the frequency of the alternating current is equal to or higher than the above lower limit, plasma can be generated more efficiently.

The time for irradiating the preventive irradiation gas in the irradiation step (irradiation time) is the time at which the desired integrated singlet oxygen concentration is achieved. The irradiation time is, for example, preferably 1 to 120 seconds, more preferably 3 to 90 seconds, even more preferably 5 to 60 seconds. When the irradiation time is at least the above lower limit, the amount of singlet oxygen in the preventive irradiation gas can be increased, and the preventive effect can be further enhanced. If the irradiation time is below the above upper limit, it is possible to prevent erosion or ulcer from worsening due to stimulation of an excessive amount of active species.
The irradiation time may be set each time the irradiation process is performed, or the control unit 90 may stop at least one of the supply of electricity and the supply of plasma generation gas to the plasma generation unit 12 based on a preset time. You may.

The temperature of the preventive irradiation gas irradiated from the irradiation port 1a of the nozzle 1 is preferably 100°C or lower, more preferably 60°C or lower, and even more preferably 40°C or lower. When the temperature of the preventive irradiation gas irradiated from the irradiation port 1a of the nozzle 1 is below the above-mentioned upper limit, the temperature of the irradiated surface is likely to be 40° C. or below. By setting the temperature of the irradiated surface to 40° C. or lower, even if the irradiated area is an affected area, stimulation to the affected area can be reduced. The lower limit of the temperature of the preventive irradiation gas irradiated from the irradiation port 1a of the nozzle 1 is not particularly limited, and is, for example, 10°C. The temperature of the preventive irradiation gas is a value obtained by measuring the temperature of the preventive irradiation gas at the irradiation port 1a with a thermocouple.

The distance from the irradiation port 1a to the irradiated surface (irradiation distance) is preferably, for example, 1.0 to 10 mm. When the irradiation distance is equal to or greater than the above lower limit, the temperature of the irradiated surface can be lowered, and stimulation to the irradiated surface can be further alleviated. When the irradiation distance is less than or equal to the above upper limit value, the preventive effect can be further enhanced.

The temperature of the irradiated surface at a distance of 1 mm or more and 10 mm or less from the irradiation port 1a is preferably 40° C. or less. When the temperature of the irradiated surface is 40° C. or lower, stimulation to the irradiated surface can be reduced. The lower limit of the temperature of the irradiated surface is not particularly limited, but is, for example, 10°C.
The temperature of the irradiated surface is determined by the AC voltage applied between the internal electrode 4 and the external electrode 5, the discharge amount of the preventive irradiation gas, and the tip Q1 of the area where the internal electrode 4 and external electrode 5 face each other. It can be adjusted by combining the path from to the irradiation port 1a. The temperature of the irradiated surface can be measured using a thermocouple.

The flow rate of the preventive irradiation gas discharged from the irradiation port 1a is preferably 1 to 10 L/min.
When the flow rate of the preventive irradiation gas discharged from the irradiation port 1a is equal to or higher than the above lower limit, the preventive effect and the therapeutic effect can be further enhanced. When the flow rate of the preventive irradiation gas discharged from the irradiation port 1a is below the above upper limit value, it is possible to prevent the temperature of the surface to be irradiated with the preventive irradiation gas from increasing excessively. In addition, if the irradiated surface is wet, rapid drying of the irradiated surface can be prevented. In the medical plasma generation device 100, the flow rate of the preventive irradiation gas discharged from the irradiation port 1a can be adjusted by the amount of plasma generation gas supplied to the plasma generation section 12.

(Method for preventing erosions or ulcers)
The method for preventing erosions or ulcers of the present invention (hereinafter sometimes simply referred to as "preventive method") includes an irradiation step of irradiating a biological tissue with a preventive irradiation gas one or more times.
By including the irradiation step, the onset of erosions or ulcers is prevented or reduced, and if erosions or ulcers develop, the healing of the erosions or ulcers is accelerated.
Targets of the prevention method of the present invention include vertebrates such as mammals and birds. Examples of mammals include humans, dogs, cats, cows, and horses. The prevention method of the present invention may be applied to subjects other than humans.

The preventive irradiation step is performed by the above-mentioned "method for producing preventive irradiation gas."
In the preventive irradiation step, for example, healthy living tissue is irradiated with a preventive irradiation gas (preventive irradiation step).
In one preventive irradiation step, the target surface is irradiated with the preventive irradiation gas so that the cumulative singlet oxygen concentration is 10 μmol/L or more. The integrated singlet oxygen concentration in one preventive irradiation step is 10 μmol/L or more, preferably 30 μmol/L or more, and more preferably 60 μmol/L or more. When the cumulative singlet oxygen concentration is equal to or higher than the above lower limit, the preventive effect can be further enhanced.
The upper limit of the cumulative singlet oxygen concentration in one preventive irradiation step is, for example, preferably 300 μmol/L or less, more preferably 250 μmol/L or less, and even more preferably 200 μmol/L or less. When the integrated singlet oxygen concentration is below the above-mentioned upper limit, it is possible to prevent erosion or ulcer from worsening due to stimulation by an excessive amount of active species.
When the prevention method has two or more preventive irradiation steps, the cumulative singlet oxygen concentration in each preventive irradiation step may be the same or different.

The number of times of the preventive irradiation step in the prevention method may be one or more times, preferably three or more times, and preferably five or more times. When the number of preventive irradiation steps is equal to or greater than the above lower limit, the preventive effect can be further enhanced.
The upper limit of the number of times of the preventive irradiation step is not particularly limited, but is preferably 60 times or less, for example.

When there are multiple prophylactic irradiation steps, the interval between the prophylactic irradiation steps is, for example, preferably 4 to 48 hours, more preferably 6 to 24 hours, and even more preferably 8 to 24 hours. When the interval between the preventive irradiation steps is equal to or greater than the above lower limit, stimulation to the irradiation target surface can be further reduced. When the interval between preventive irradiation steps is equal to or less than the above upper limit, the preventive effect can be further enhanced.

When having multiple prophylactic irradiation steps, the number of preventive irradiation steps per day is preferably 1 to 3 times. When the number of preventive irradiation steps per day is at least the above lower limit, the preventive effect can be further enhanced. When the number of preventive irradiation steps per day is less than or equal to the above upper limit, stimulation to the irradiation target surface can be further reduced.

The irradiation time in the preventive irradiation step is, for example, preferably 1 to 120 seconds, more preferably 3 to 90 seconds, even more preferably 5 to 60 seconds. When the irradiation time is at least the above lower limit, the amount of singlet oxygen in the preventive irradiation gas can be increased, and the preventive effect can be further enhanced. When the irradiation time is at most the above upper limit, it is possible to prevent erosion or ulcer from worsening due to stimulation of an excessive amount of active species.
When the prevention method has two or more preventive irradiation steps, the irradiation time in each preventive irradiation step may be the same or different.

The prevention method of the present invention may include steps other than the preventive irradiation step. The prevention method may include steps such as washing, cleaning, disinfecting, moisturizing, gargling, and dressing the irradiated site.

(Method of treating disease)
The method for treating a disease of the present invention (sometimes simply referred to as a "treatment method") includes a step of applying the preventive method of the present invention (preventive step) and a treatment step that can induce the development of erosions or ulcers.
Examples of treatment steps include medication and radiation therapy. Furthermore, depending on the ingredients of the drug used for cancer treatment and the site where radiation therapy is administered, erosions or ulcers may develop on the lips, skin, gastrointestinal tract, and gastrointestinal tract.
Therefore, medication that may cause erosion or ulceration, treatment of cancer, etc. can be the therapeutic process of the present invention. Among these, the preventive method of the present invention is effective in treating cancers that may cause erosion or ulcers on mucous membranes and the like.

In the treatment method, the preventive step is a step that occurs before the onset of erosion or ulceration. The preventive step may begin and end before the start of the treatment step, or it may end after the start of the treatment step but before the onset of erosion or ulceration.

In the treatment method, at least one preventive irradiation step constituting the preventive step is performed before the start of the treatment step.
The number of times of the preventive irradiation step before the start of the treatment step is 1 or more times, preferably 3 or more times, and more preferably 5 or more times. When the number of preventive irradiation steps before the start of the treatment step is equal to or greater than the above lower limit, the preventive effect can be further enhanced. The upper limit of the number of preventive irradiation steps before the start of the treatment step is, for example, 60 times.

The irradiation target surface is, for example, a place where erosion or ulceration may occur, such as the inside of the oral cavity or the skin.

In the treatment method, after the initiation of the treatment step and the onset of erosion or ulceration, a healing step may be provided in which the affected area of the erosion or ulcer is irradiated with irradiation gas. By providing a healing process, healing of erosions or ulcers is promoted.
In the healing process, irradiation gas is irradiated to the affected area of erosion or ulcer.
The healing irradiation process is similar to the preventive irradiation process.
The cumulative singlet oxygen concentration in the healing irradiation step and the cumulative singlet oxygen concentration in the healing irradiation step may be the same or different.

As described above, according to the prevention method of the present invention, the onset of erosions or ulcers can be suppressed, or the erosions or ulcers can be made mild, and when erosions or ulcers have developed, the subsequent healing of erosions or ulcers can be accelerated. .
The preventive method of the present invention is particularly effective when performed before the start of treatment that may cause erosion or ulceration.

The present invention will be explained in more detail below using Examples, but the present invention is not limited to these Examples.

(Example 1)
Using a medical plasma generator similar to the medical plasma generator 100, a 2.5 cm ² area of the cheek pouches of eight hamsters was irradiated with preventive irradiation gas once per day under the following irradiation conditions ( preventive irradiation process). The cumulative singlet oxygen concentration in one preventive irradiation step was 30 μmol/L. The day when the first preventive irradiation step was performed was defined as day 0, and the preventive irradiation step was performed until the third day. Immediately after the second and fourth preventive irradiation steps, 60 mg/kg of an anticancer drug (5-FU) was administered to the hamsters. On the second and third days, the cheek pouches of the hamsters (the area irradiated with the prophylactic irradiation gas) were scrubbed with an iron brush. On the fourth day, the onset of oral mucositis (erosion) was confirmed in the abraded area. Taking the area of oral mucositis on the 4th day (initial area) as 100%, the ratio (%) of the area of oral mucositis on the 7th, 9th, and 11th days was measured, and the average value is shown in Figure 4. Shown below.
<Irradiation conditions>
- Applied voltage: 20kHz, 5.7kVpp alternating current.
・Flow rate of plasma generation gas: 3L/min. .
・Irradiation time: 15 seconds.
・Irradiation distance: 5mm.
- Plasma generation gas: 100% by volume of nitrogen.
- Cumulative singlet oxygen concentration: 30 μmol/L times.

(Example 2)
The area ratio (%) of oral mucositis was measured in the same manner as in Example 1, except that the irradiation conditions were as follows, and the average value is shown in FIG.
<Irradiation conditions>
- Applied voltage: 20kHz, 7.3kVpp alternating current.
・Flow rate of plasma generation gas: 3L/min. .
・Irradiation time: 15 seconds.
・Irradiation distance: 5mm.
- Plasma generation gas: 100% by volume of nitrogen.
- Cumulative singlet oxygen concentration: 60 μmol/L/time.

(Comparative example 1)
The area ratio (%) of oral mucositis was measured in the same manner as in Example 1, except that the irradiation conditions were as follows, and the average value is shown in FIG.
<Irradiation conditions>
- Applied voltage: None (i.e., irradiation with nitrogen gas only).
・Flow rate of plasma generation gas: 3L/min. .
・Irradiation time: 15 seconds.
・Irradiation distance: 5mm.
- Plasma generation gas: 100% by volume of nitrogen.
- Cumulative singlet oxygen concentration: 0 μmol/L times.

(Comparative example 2)
The area ratio (%) of oral mucositis was measured in the same manner as in Example 1, except that the irradiation conditions were as follows, and the average value is shown in FIG.
<Irradiation conditions>
- Applied voltage: 7kHz, 13.5kVpp alternating current.
・Flow rate of plasma generation gas: 3L/min. .
・Irradiation time: 15 seconds.
・Irradiation distance: 5mm.
- Plasma generation gas: 100% by volume of nitrogen.
- Cumulative singlet oxygen concentration: 6 μmol/L times.

As shown in FIG. 4, in Examples 1 and 2 to which the present invention was applied, the oral mucositis area on Day 7 was 34 to 43% of the initial area.
Comparative Example 1, in which only nitrogen gas was irradiated, had an oral mucositis area of 59% on the 7th day, and Comparative Example 2, in which the integrated singlet oxygen concentration was 6 μmol, had an oral mucositis area of 55% on the 7th day. Ta.
From these results, it was confirmed that by applying the present invention, recovery from erosion can be accelerated.

4 Internal electrode 5 External electrode 12 Plasma generation section 100 Medical plasma generation device

Claims (10)

A method for preventing erosions or ulcers, the method comprising an irradiation step of irradiating biological tissue with a preventive irradiation gas one or more times,
The preventive irradiation gas contains singlet oxygen generated by plasma,
A method for preventing erosions or ulcers (excluding acts on humans), in which the one irradiation step irradiates the preventive irradiation gas so that the following integrated singlet oxygen concentration is 10 μmol/L or more.
<Cumulative singlet oxygen concentration>
0.8 mL of TPC (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamide) 0.1 mol/L solution was irradiated with preventive irradiation gas at an arbitrary time and at an arbitrary distance. Thereafter, the singlet oxygen concentration of the solution irradiated with the preventive irradiation gas is measured by the electron spin resonance (ESR) method, and this is defined as the cumulative singlet oxygen concentration (μmol/L). The method for preventing erosions or ulcers according to claim 1, which is a method for preventing oral mucositis. The method for preventing erosion or ulceration according to claim 2, wherein the oral mucositis is a disease induced by cancer treatment. The method for preventing erosions or ulcers according to any one of claims 1 to 3, wherein the irradiation step is performed 1 to 3 times/day for 3 days or more. The method for preventing erosions or ulcers according to any one of claims 1 to 4, wherein one irradiation step is for 1 to 120 seconds. A method for treating a disease, comprising a step of administering the method for preventing erosions or ulcers according to any one of claims 1 to 5, and a treatment step capable of inducing the onset of erosions or ulcers,
A method for treating a disease (excluding acts on humans), comprising performing the irradiation step at least once before starting the treatment step. The method for treating a disease according to claim 6, wherein the irradiation step is performed at least once after the start of the treatment step. The method for treating a disease according to claim 6 or 7, wherein the treatment step is cancer treatment. An irradiation gas for preventing erosions or ulcers, which contains singlet oxygen and has an integrated singlet oxygen concentration below of 10 μmol/L or more.
<Cumulative singlet oxygen concentration>
0.8 mL of TPC (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamide) 0.1 mol/L solution was irradiated with preventive irradiation gas at an arbitrary time and at an arbitrary distance. Thereafter, the singlet oxygen concentration of the solution irradiated with the preventive irradiation gas is measured by the electron spin resonance (ESR) method, and this is defined as the cumulative singlet oxygen concentration (μmol/L). A method for producing an irradiation gas for preventing erosions or ulcers according to claim 9,
Prevention of erosions or ulcers by supplying plasma generating gas at 1 to 10 L/min to a plasma generating part having an electrode, generating plasma by applying a voltage to the electrode, and generating the singlet oxygen with the generated plasma. How to generate irradiation gas for use.

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