Method for producing composition for dosimeter, composition for dosimeter, dosimeter, and radiation verification method

Abstract

One embodiment of the present invention provides a method for producing a composition for a dosimeter, the method comprising a mixing step for mixing at least a portion of a plurality of raw materials for forming a composition for a dosimeter while supplying fine bubbles of an inert gas.

Description

Method for manufacturing a composition for a dosimeter, composition for a dosimeter, dosimeter, and radiation verification method

[0001] The present disclosure relates to a method for producing a composition for a dosimeter, a composition for a dosimeter, a dosimeter, and a radiation verification method.

[0002] In radiation therapy, it is required to irradiate cancer tissue, which is the target of radiation, with an effective dose of radiation, while irradiating normal tissue with either no radiation or as low a dose of radiation as possible to minimize radiation damage. Therefore, when performing radiation therapy, the position, shape, etc. of the cancer tissue in the patient are identified as three-dimensional information in advance using X-ray CT (Computed Tomography), MRI (Magnetic Resonance Imaging), etc., and a radiation therapy plan, including the dose, irradiation position, irradiation method, etc., is formulated based on the identified three-dimensional information.

[0003] To verify a radiation therapy plan, therapeutic radiation is irradiated to a dosimeter in advance based on the radiation therapy plan, and irradiation data obtained by the dosimeter after irradiation is used. Furthermore, irradiation data obtained by a dosimeter is also used to measure the dose output and irradiation position accuracy of a device that irradiates therapeutic radiation. Known dosimeters include polymer gel dosimeters that can measure three-dimensional dose distributions (see, for example, JP 2012-2669 A and JP 2014-185969 A). A polymer gel dosimeter is a dosimeter in which a dosimeter composition is filled in a container, the dosimeter composition comprising a polymerizable monomer that polymerizes upon radiation dispersed within a gel. Irradiating a polymer gel dosimeter with radiation produces a polymer in proportion to the irradiated dose. Therefore, by measuring the amount of polymer produced as the density of white color, the irradiated dose and position can be estimated three-dimensionally. Also known is a gel dosimeter that prevents the residue of substances similar to molecular radical derivatives in order to improve the accuracy of dose measurement (for example, JP 2014-209093 A).

[0004] In polymer gel dosimeters, the reactivity of the polymerizable monomer contained in the dosimeter composition decreases over time, resulting in storage stability problems. This can lead to problems such as insufficient polymer production to function as a dosimeter when a polymer gel dosimeter is irradiated with radiation long after its manufacture. Therefore, when using a polymer gel dosimeter for treatment planning, for example, it is necessary to set a relatively short expiration date, such as within about 10 days of manufacture. This insufficient storage stability and a relatively short expiration date can make the polymer gel dosimeter difficult to handle for users, who must use it immediately upon arrival. Furthermore, manufacturers face problems such as limited sales destinations, such as the inability to ship the dosimeter overseas.

[0005] The present disclosure has been made in view of the above. An object of one embodiment of the present invention is to provide a method for producing a composition for a dosimeter that has excellent storage stability and can be used for a longer period than conventional compositions. An object of another embodiment of the present invention is to provide a composition for a dosimeter that has excellent storage stability and can be used for a longer period than conventional compositions. An object of another embodiment of the present invention is to provide a dosimeter that has excellent storage stability and can be used for a longer period than conventional compositions. A further object of another embodiment of the present invention is to provide a radiation verification method that uses a dosimeter that has excellent storage stability and can be used for a longer period than conventional compositions.

[0006] Specific means for solving the problems include the following aspects: <1> A method for producing a composition for a dosimeter containing a radiation-polymerizable compound and a matrix for dispersing the radiation-polymerizable compound, the method comprising a mixing step of mixing at least some of a plurality of raw materials forming the composition for a dosimeter while supplying fine bubbles of an inert gas. <2> A method for producing a composition for a dosimeter according to <1>, wherein the raw materials include water and a gelling agent that form the matrix, and the radiation-polymerizable compound, and the mixing step comprises mixing the matrix containing the water and the gelling agent with the radiation-polymerizable compound while supplying fine bubbles. <3> A method for producing a composition for a dosimeter according to <1>, wherein the raw materials include water and a gelling agent that form the matrix, the radiation-polymerizable compound, and a crosslinking agent, and the mixing step comprises mixing the matrix containing the water and the gelling agent with the radiation-polymerizable compound and the crosslinking agent while supplying fine bubbles. <4> The method for producing a composition for a dosimeter according to any one of <1> to <3>, wherein the raw materials contain water and a gelling agent that form the matrix, as well as the radiation-polymerizable compound and a deoxidizer, and further comprises, after the mixing step, a deoxidizer mixing step of mixing the deoxidizer with the mixture obtained by the mixing step. <5> The method for producing a composition for a dosimeter according to any one of <1> to <4>, wherein the mixing step includes mixing by stirring. <6> The method for producing a composition for a dosimeter according to any one of <1> to <5>, wherein the inert gas is nitrogen gas. <7> The method for producing a composition for a dosimeter according to any one of <2> to <6>, wherein the gelling agent is gelatin. <8> A composition for a dosimeter, comprising a matrix containing water and a gelling agent, a radiation-polymerizable compound, and fine bubbles of an inert gas. <9> The composition for a dosimeter according to <8>, wherein the composition contains 0.5 mg / L or less of oxygen. <10> The composition for a dosimeter according to <8> or <9>, wherein the radiation-polymerizable compound and the fine bubbles are dispersed in the matrix. <11> The composition for a dosimeter according to any one of <8> to <10>, wherein the gelling agent is gelatin.<12> The dosimeter composition according to any one of <8> to <11>, wherein the radiation-polymerizable compound is a monomer having one or more ethylenically unsaturated double bonds in one molecule. <13> A dosimeter obtained by filling a radiation-transparent storage container with the dosimeter composition according to any one of <8> to <12>. <14> A radiation verification method comprising the steps of irradiating the dosimeter according to <13> with predetermined measurement radiation, and analyzing the dosimeter irradiated with the measurement radiation to obtain dose distribution data corresponding to the dose distribution of the measurement radiation received by the dosimeter. <15> The radiation verification method according to <14>, wherein the predetermined measurement radiation is therapeutic radiation based on a radiation therapy plan.

[0007] According to one embodiment of the present invention, there is provided a method for producing a composition for a dosimeter that has excellent storage stability and can be used for a longer period than conventional compositions. According to another embodiment of the present invention, there is provided a composition for a dosimeter that has excellent storage stability and can be used for a longer period than conventional compositions. According to another embodiment of the present invention, there is provided a dosimeter that has excellent storage stability and can be used for a longer period than conventional compositions. According to another embodiment of the present invention, there is provided a radiation verification method using a dosimeter that has excellent storage stability and can be used for a longer period than conventional compositions.

[0008] FIG. 1 is a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after two days of storage for room-temperature-stored dosimeter 1 and room-temperature-stored dosimeter 2. FIG. 2 is a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after 12 days of storage for room-temperature-stored dosimeter 1, and a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after 14 days of storage for room-temperature-stored dosimeter 2. FIG. 3 is a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after 35 days of storage for room-temperature-stored dosimeter 1, and a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after 20 days of storage for room-temperature-stored dosimeter 2. FIG. 4 is a graph showing the relationship between the storage period [Days] and the slope [1 / (s·Gy)] for room-temperature-stored dosimeter 1 and room-temperature-stored dosimeter 2. Fig. 5 is a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after two days of storage for refrigerated dosimeter 1 and refrigerated dosimeter 2. Fig. 6 is a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after 15 days of storage for refrigerated dosimeter 1, and a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after 14 days of storage for refrigerated dosimeter 2. Fig. 7 is a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after 30 days of storage for refrigerated dosimeter 1, and a graph showing the relationship between the administered dose [Gy] and the R2 value [1 / s] after 29 days of storage for refrigerated dosimeter 2. Fig. 8 is a graph showing the relationship between the storage period [Days] and the slope [1 / (s·Gy)] for refrigerated dosimeter 1.

[0009] The method for producing a composition for a dosimeter, the composition for a dosimeter, the dosimeter, and the radiation verification method of the present disclosure will be described below. However, the present disclosure is not limited to the following embodiments and can be modified as appropriate within the scope of the object of the present disclosure.

[0010] In this specification, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the upper and lower limits. In numerical ranges described in stages in this specification, the upper or lower limit of one numerical range may be replaced with the upper or lower limit of another staged numerical range. Furthermore, in numerical ranges described in this specification, the upper or lower limit of that numerical range may be replaced with a value shown in the Examples. In this specification, when multiple substances corresponding to each component are present in the composition, the amount of each component refers to the total amount of those multiple substances present in the composition, unless otherwise specified. In this specification, "mass" and "weight" are synonymous, and "mass%" and "wt%" are synonymous. In this specification, a combination of two or more preferred embodiments is a more preferred embodiment. In this specification, the term "process" includes not only independent processes, but also processes that cannot be clearly distinguished from other processes, as long as the intended purpose of the process is achieved. In this specification, "fine bubbles," "ultra-fine bubbles," and "microbubbles" are registered trademarks. Hereinafter, the fact that these are registered trademarks will be omitted.

[0011] <Method for Producing Dosimeter Composition> A method for producing a dosimeter composition according to one aspect of the present disclosure is a method for producing a dosimeter composition containing a radiation-polymerizable compound and a matrix for dispersing the radiation-polymerizable compound, and includes a mixing step of mixing at least some of the raw materials for forming the dosimeter composition while supplying fine bubbles of an inert gas. In the case of a polymer gel dosimeter composition, the raw materials for forming the dosimeter composition include a raw material for forming the matrix, a radiation-polymerizable compound, a crosslinking agent, an oxygen scavenger, and other raw materials.

[0012] [Matrix] The matrix preferably holds at least the radiation-polymerizable compound and the crosslinking agent in a dispersed state and is transparent to radiation. For a dosimeter used in verifying a radiation therapy plan, it is preferable that a dosimeter having a case filled with a dosimeter composition containing the matrix can be used as a phantom. Therefore, a preferred matrix is, for example, a gel, and raw materials for forming the gel include a gelling agent and water.

[0013] The gelling agent is preferably one that can form a gel at room temperature and does not inhibit the polymerization of the radiation-polymerizable compound, and can be selected from gelling agents that have been used in conventional polymer gel dosimeters. Usable gelling agents include gelling agents made of natural polymers such as gelatin, gelling agents containing silicates, and gelling agents containing polyvinyl alcohol.

[0014] [Gelling Agents Made of Natural Polymers] Among gelling agents made of natural polymers, examples of the natural polymers include gelatin, agarose, xanthan gum, carrageenan, gellan gum, chitosan, alginic acid, polysaccharides, starch, etc. From the viewpoints of ease of preparation, gel stability at room temperature, etc., it is preferable to use gelatin as the natural polymer.

[0015] As the gelling agent, it is preferable to use a natural polymer, in view of ease of preparation and gel stability at room temperature, and specifically, it is preferable to use gelatin.

[0016] The content of the natural polymer is preferably 0.01% by mass to 30% by mass, more preferably 0.03% by mass to 20% by mass, and even more preferably 1% by mass to 10% by mass, based on the dosimeter composition, i.e., relative to 100% by mass of the dosimeter composition.

[0017] [Gelling Agent Containing Silicate] Among silicate-containing gelling agents, examples of the silicate include gelling agents composed of a water-soluble organic polymer, a silicate, and a silicate dispersant. The water-soluble organic polymer is preferably a water-soluble organic polymer having an organic acid structure, an organic acid salt structure, or an organic acid anion structure. Examples of the organic acid structure include organic acid salt structures of carboxyl groups, sulfonyl groups, and phosphonyl groups. Specific examples include poly(meth)acrylic acid, carboxyvinyl polymers, salts of polystyrene sulfonic acid, and polyvinyl phosphonates. Examples of the organic acid salt structure include sodium salts, ammonium salts, potassium salts, and lithium salts of organic acid groups. Examples of those having an organic acid anion structure include those having a structure in which a cation is dissociated from an organic acid group or an organic acid salt. The water-soluble organic polymer may be a fully neutralized or partially neutralized organic polymer having an organic acid group, or a mixture thereof. Specific examples of the water-soluble organic polymer include a fully neutralized or partially neutralized linear sodium polyacrylate. The content of the water-soluble organic polymer is preferably 0.01% by mass to 20% by mass, more preferably 0.05% by mass to 10% by mass, based on the dosimeter composition.

[0018] The silicate may be water-swellable silicate particles, preferably those that form colloids with water or a water-containing liquid as a dispersion medium. Specific examples include one or more water-swellable silicates selected from the group consisting of smectite, bentonite, vermiculite, and mica. The content of the silicate is preferably 0.01% by mass to 20% by mass, more preferably 0.05% by mass to 10% by mass, based on the dosimeter composition.

[0019] Examples of silicate dispersants include phosphate-based dispersants, carboxylate-based dispersants, dispersants that act as alkalis, and organic dispersants. Specific examples include one or more selected from the group consisting of sodium orthophosphate, sodium pyrophosphate, sodium tripolyphosphate, sodium tetraphosphate, sodium hexametaphosphate, sodium polyphosphate, sodium etidronate, sodium poly(meth)acrylate, ammonium poly(meth)acrylate, sodium acrylate / sodium maleate copolymer, ammonium acrylate / ammonium maleate copolymer, sodium hydroxide, hydroxylamine, sodium carbonate, sodium silicate, polyethylene glycol, polypropylene glycol, sodium humate, sodium lignosulfonate, and potassium salts corresponding to these salts. The content of the silicate dispersant is preferably 0.01% to 20% by mass, and more preferably 0.05% to 10% by mass, based on the dosimeter composition.

[0020] [Gelling Agent Containing Polyvinyl Alcohol] Examples of gelling agents containing polyvinyl alcohol include gels composed of polyvinyl alcohol and glutaraldehyde or borax. The polyvinyl alcohol preferably has a degree of polymerization of 10 to 8,000, more preferably 100 to 5,000, and even more preferably 500 to 3,000, and a degree of saponification of 80% to 99%, more preferably 88% to 99%. The content of polyvinyl alcohol is preferably 70% to 90% by mass, more preferably 75% to 85% by mass, based on the dosimeter composition. The content of borax is preferably 5% to 28% by mass, more preferably 7% to 25% by mass, based on the dosimeter composition.

[0021] [Water] As the water, in order to suppress polymerization of the radiation-polymerizable compound other than during irradiation with radiation, it is preferable to use distilled water, pure water, or ultrapure water that contains as few impurities as possible, such as ions. The water content may be any as long as the resulting gel can be used as a matrix for the composition for a dosimeter, and although it depends on the production environment, such as temperature and humidity, the water content is preferably 70% by mass to 98% by mass, more preferably 80% by mass to 95% by mass, and even more preferably 85% by mass to 90% by mass, based on the composition for a dosimeter at the time of production.

[0022] The gel may be formed by any of covalent bonding, Coulomb force bonding, hydrogen bonding, coordinate bonding, physical entanglement, etc. The gel is the matrix of the composition for a dosimeter and disperses and holds the radiation polymerizable monomer, etc., so the gel preferably has a jelly strength of 10 g or more, more preferably 100 g or more, as measured in accordance with JIS K6503-1996.

[0023] [Radiation-Polymerizable Compound] The radiation-polymerizable compound is a compound that forms a polymer when exposed to radiation, and examples thereof include radiation-polymerizable monomers. The radiation-polymerizable monomer is preferably a compound that forms a polymer by radical polymerization when exposed to radiation, and specifically, is preferably a monomer having one or more acrylic structures, ethylenically unsaturated double bonds, i.e., vinyl structures, etc., per molecule. Furthermore, when the matrix is ​​a gel composed of water and gelatin, the radiation-polymerizable monomer is preferably a water-soluble polymerizable monomer.

[0024] The radiation-polymerizable monomer may be a monomer that forms a polymer by itself when irradiated with radiation, or may be a monomer that forms a polymer together with a crosslinking agent added as a raw material.

[0025] Specific examples of the radiation-polymerizable monomer include methyl methacrylate, ethyl methacrylate, 2-methoxymethyl methacrylate, 2-ethoxyethyl methacrylate, 2-hydroxyethyl methacrylate, triethylene glycol monoethyl ether monomethacrylate, methyl acrylate, ethyl acrylate, butyl acrylate, 2-methoxyethyl acrylate, N-vinylpyrrolidone, acrylamide, acryloylmorpholine, N-isopropylacrylamide, methacryloyl-L-alanine methyl ester, acryloyl-L-proline methyl ester, etc. The content of the radiation-polymerizable monomer is preferably within a range usable as a dosimeter, and is preferably 1 to 20% by mass, more preferably 2 to 10% by mass, and even more preferably 3 to 8% by mass, based on the dosimeter composition.

[0026] [Crosslinking Agent] A crosslinking agent is used as a raw material depending on the type of radiation-polymerizable monomer, etc. Preferred examples of the crosslinking agent include water-soluble acrylamide. A specific preferred example is N,N'-methylenebisacrylamide. When the radiation-polymerizable monomer is acrylamide, N,N'-methylenebisacrylamide is preferably used as the crosslinking agent.

[0027] When a crosslinking agent is used, the content thereof is preferably in a range that enables use as a dosimeter by polymerizing the radiation-polymerizable monomer by radiation, and is preferably 0.5% by mass to 8% by mass, more preferably 1% by mass to 5% by mass, and even more preferably 2% by mass to 4% by mass, based on the dosimeter composition.

[0028] [Oxygen Scavenger] When an oxygen scavenger is used, examples of the oxygen scavenger include ascorbic acid and tetrakis-hydroxymethyl-phosphonium chloride (THPC). The content of the oxygen scavenger is preferably an amount that can sufficiently reduce oxygen contaminating the dosimeter composition during production, oxygen contained in raw materials, and oxygen contaminating from the dosimeter storage container, etc. In polymer gel dosimeters, the reactivity of the polymerizable monomer contained in the dosimeter composition decreases over time, and one of the causes of storage stability problems is the influence of oxygen present in the dosimeter composition. The oxygen present in the dosimeter composition includes oxygen contained in the dosimeter composition itself and oxygen that flows into the dosimeter composition from the outside. For example, when THPC is used, the concentration of THPC based on the amount of water contained in the dosimeter composition is preferably 0.5 mmol / L to 10 mmol / L, more preferably 1.0 mmol / L to 8.0 mmol / L, and even more preferably 1.5 mmol / L to 6.0 mmol / L.

[0029] [Other Raw Materials] The dosimeter composition may contain raw materials other than the matrix-forming raw materials, radiation-polymerizable monomer, crosslinking agent, and oxygen scavenger. Examples of other raw materials include sensitizers and stabilizers. Examples of sensitizers include magnesium salts and water-dispersible inorganic fine particles. Examples of magnesium salts include magnesium chloride and magnesium sulfate. Examples of water-dispersible inorganic fine particles include silica sol. Examples of stabilizers include polymerization inhibitors, radical scavengers, and antioxidants. Examples of stabilizers include hydroquinone, 4-methoxyphenol, and N,N'-diisobutyl-p-phenylenediamine. The content of the other raw materials is preferably 0.1 ppm to 10,000 ppm, more preferably 1 ppm to 5,000 ppm, and even more preferably 10 ppm to 3,000 ppm, based on the mass of the dosimeter composition.

[0030] [Examples of Dosimeter Compositions] Examples of dosimeter compositions combining the above-mentioned raw materials include two types: MAG (Methacrylic Acid & Gelatin) and PAG (Poly-Acrylamide & Gelatin), when a natural polymer is used as a gelling agent. MAG is a dosimeter composition containing water and gelatin as matrix raw materials and methacrylic acid as a radiation-polymerizable monomer. PAG is a dosimeter composition containing water and gelatin as matrix raw materials, a radiation-polymerizable monomer, and a crosslinking agent, and containing acrylamide as the radiation-polymerizable monomer. A dosimeter composition containing acrylamide (AA), N-vinylpyrrolidone (VIP), or N-isopropylacrilamide (NIPAM) as the acrylamide, and N,N'-methylenebisacrylamide (Bis) as the crosslinking agent.

[0031] It is also preferable to use a deoxidizing agent as a raw material for each of the MAG and PAG. MAG using THPC as the deoxidizing agent is called MAGAT (Methacrylic Acid, Gelatin, and THPC). PAG using AA and THPC as the deoxidizing agent is called PAGAT (Poly-Acrylamide, Gelatin, and THPC). PAG using VIP and THPC as the deoxidizing agent is called VIPET (N-vinylpyrrolidone, Gelatin, and THPC). PAG using NIPAM and THPC as the deoxidizing agent is also called NIPAM. For example, in the case of VIPET, the dosimeter composition may have a composition of 85% by mass of water, 7% by mass of gelatin, 4% by mass of VIP, and 4% by mass of Bis, based on the total mass of the dosimeter composition.

[0032] As another example of a composition for a dosimeter, when a silicate is used as a gelling agent, a preferred combination of a water-soluble organic polymer, a silicate, and a silicate dispersant, based on the total mass of the composition for a dosimeter, includes a composition consisting of 0.05% by mass to 10% by mass of fully neutralized or partially neutralized linear sodium polyacrylate having a weight-average molecular weight of 2,500,000 to 5,000,000 as the water-soluble organic polymer, 0.05% by mass to 10% by mass of water-swellable smectite or saponite as the silicate, and 0.5% by mass to 5% by mass of sodium pyrophosphate or sodium etidronate as a silicate dispersant, or 0.5% by mass to 5% by mass of sodium polyacrylate having a weight-average molecular weight of 1,000 to 20,000.

[0033] [Mixing Step] The composition for a dosimeter is produced by mixing the above-mentioned raw materials in a predetermined ratio to obtain a uniform composition. The method for producing a composition for a dosimeter according to an embodiment of the present disclosure includes a mixing step of mixing at least a portion of the above-mentioned multiple raw materials while supplying fine bubbles of an inert gas.

[0034] In the mixing step, the inert gas that forms the fine bubbles preferably does not adversely affect the reaction of the radiation-polymerizable monomer in the dosimeter composition over time. Furthermore, the fine bubbles of the inert gas preferably expel oxygen contained in the dosimeter composition and saturate the dosimeter composition with the inert gas as a gas contained in the dosimeter composition. Therefore, it is preferable to use a gas other than oxygen as the inert gas. Specifically, examples of the inert gas include nitrogen gas, argon gas, helium gas, and nitrous oxide gas, and these may be used alone or in combination. Of these, nitrogen gas is preferred as the inert gas in terms of cost, ease of handling, and the like. This improves the storage stability of the dosimeter composition.

[0035] Here, fine bubbles are those defined in JIS B 8741-1:2019 of the Japanese Industrial Standards. According to this definition, fine bubbles refer to bubbles with a volume-equivalent diameter of less than 100 μm, and include ultrafine bubbles and microbubbles. Note that ultrafine bubbles refer to fine bubbles with a volume-equivalent diameter of less than 1 μm, and microbubbles refer to fine bubbles with a volume-equivalent diameter in the range of 1 μm or more and less than 100 μm. Therefore, inert gas fine bubbles include inert gas microbubbles and inert gas ultrafine bubbles. Note that the volume-equivalent diameter refers to the diameter derived based on the volume of the bubble assuming a spherical shape, and is hereinafter also referred to as the "bubble diameter."

[0036] Fine bubbles of inert gas may be generated with a distribution of various bubble diameters. For example, in a measurement example using a particle characteristic evaluation method using quantitative laser diffraction and scattering of fine bubbles in water, the average diameter D50 was 77 nm. The amount of inert gas generated by the entire fine bubbles is preferably 0.01 L / min to 0.5 L / min per 1 L to 4 L of volume of the target to which the fine bubbles are supplied.

[0037] In the mixing process, at least a portion of the above-mentioned multiple raw materials are mixed while being supplied with fine bubbles of inert gas. The method of supplying fine bubbles to the raw materials to be mixed may be any method that continuously supplies the inert gas as fine bubbles to the raw materials to be mixed. For example, a method is used in which inert gas is introduced into the raw materials to be mixed using a pipe and then discharged from a nozzle capable of generating fine bubbles located at one end of the pipe, thereby supplying the inert gas in the form of fine bubbles into the raw materials. Specifically, a method is used in which inert gas is introduced from an inert gas introducing device through a pipe, and one end of the pipe equipped with a nozzle capable of generating fine bubbles is inserted into a production vessel containing multiple raw materials, so that the nozzle portion is completely immersed in the multiple raw materials, and then the nozzle portion is fixed near the bottom of the production vessel. In this case, it is preferable that the end of the pipe equipped with the nozzle does not come into contact with the bottom of the production vessel to avoid interfering with the generation of fine bubbles. The nozzle portion of the pipe is preferably located 10% to 30% of the overall height of the production vessel from the bottom.

[0038] The fine bubble generator may be any device capable of continuously generating fine bubbles of an inert gas. Preferably, it is a device such as a nozzle installed at the end of a pipe through which the inert gas is introduced. Commercially available fine bubble generators can be used as such fine bubble generators.

[0039] The manufacturing vessel is preferably one that does not leach oxygen into the contents, specifically a glass manufacturing vessel is preferred. The shape of the manufacturing vessel is also preferably one that makes it difficult for oxygen to mix with the contents during mixing, specifically a glass beaker is preferred.

[0040] In the mixing step, mixing of multiple raw materials can be performed by mechanical or manual stirring, ultrasonic stirring, continuous mixing by line mixing, etc. Mechanical stirring can be performed using a magnetic stirrer, propeller stirrer, planetary mixer, disperser, homogenizer, shaker, vortex mixer, ball mill, kneader, ultrasonic oscillator, etc. Among these, mechanical stirring is preferred because it can suppress oxygen contamination during mixing, and a magnetic stirrer is particularly preferred. In mechanical stirring, it is preferable to heat the production vessel using a device with a heating means while stirring, depending on the situation. For example, when the gelling agent is gelatin, a method using a glass production vessel as the production vessel and a magnetic stirrer in a water bath, or a method using a hot stirrer, which is a magnetic stirrer equipped with a hot plate, is preferred. Note that, in industrial-level production, the methods are not limited to those described above, and conventionally known production vessels, stirrers, etc. can also be used.

[0041] In the mixing step, each raw material may be dissolved or dispersed in a solvent as needed. The solvent is not particularly limited as long as it can dissolve or uniformly disperse each component of the dosimeter composition, but water is preferred. Water may be mixed with an aqueous solvent such as methanol, ethanol, isopropanol, or glycerol, but it is preferable to use a solvent that does not contain oxygen as much as possible.

[0042] The temperature during mixing varies depending on the raw materials, but is, for example, the freezing point or boiling point of the aqueous solution or aqueous dispersion, preferably -5°C to 100°C, more preferably 0°C to 60°C.

[0043] In a method for producing a dosimeter composition, when the raw materials for the dosimeter composition include water and a gelling agent that form a matrix, and a radiation-polymerizable monomer, the mixing step preferably includes mixing the matrix containing water and the gelling agent with the radiation-polymerizable monomer while supplying fine bubbles. That is, in the mixing step, it is preferable to first mix water and the gelling agent to form a matrix, and then mix the matrix with the radiation-polymerizable monomer while supplying fine bubbles. By forming the matrix and then mixing it with the radiation-polymerizable monomer, the matrix can be formed sufficiently uniformly by adjusting the temperature of the matrix, etc., and the final dosimeter composition can be made more uniform. Furthermore, fine bubbles of an inert gas can be provided effectively and efficiently.

[0044] In addition, in the method for producing a dosimeter composition, the raw materials for the dosimeter composition preferably include a crosslinker, and the mixing step includes mixing a matrix containing water and a gelling agent with a radiation-polymerizable monomer and a crosslinking agent while supplying fine bubbles. That is, when a crosslinking agent is used as a raw material, the mixing step preferably first forms a matrix by mixing water and a gelling agent, and then mixes the matrix with the radiation-polymerizable monomer and crosslinking agent while supplying fine bubbles. By forming the matrix and then mixing it with the radiation-polymerizable monomer and crosslinking agent, a sufficiently uniform matrix can be formed by adjusting the temperature of the matrix, etc., and the final dosimeter composition can be made more uniform. Furthermore, fine bubbles of an inert gas can be provided effectively and efficiently.

[0045] In the mixing step, even when raw materials other than the matrix, radiation-polymerizable monomer, and crosslinking agent are mixed, that is, raw materials other than the oxygen scavenger, it is preferable to mix the materials while continuously supplying fine bubbles of an inert gas.

[0046] [Oxygen Absorber Mixing Step] Furthermore, the method for producing a dosimeter composition preferably includes a deoxidizer mixing step, in which the deoxidizer is mixed into the mixture obtained by the mixing step, after the mixing step, if the raw materials for the dosimeter composition contain a deoxidizer. That is, if the raw materials for the dosimeter composition contain a deoxidizer, it is preferable to mix the deoxidizer as a raw material last, after mixing the raw materials other than the deoxidizer. In the deoxidizer step, depending on the type of deoxidizer, if the deoxidizer is THPC, providing fine bubbles may have adverse effects such as foaming of the dosimeter composition. Therefore, it is preferable to provide a reduced amount of fine bubbles compared to the mixing step, or to not provide fine bubbles at all. Specifically, it is preferable to mix the raw materials other than the deoxidizer while providing fine bubbles, and then stop the supply of fine bubbles when they are sufficiently mixed, and then immediately introduce THPC. It is preferable to continue mixing even after stopping the supply of fine bubbles.

[0047] As described above, the supply of fine bubbles may be temporarily stopped during the mixing process. For example, it is preferable to stop the supply of fine bubbles when dissolving a gelling agent such as gelatin, adding an oxygen scavenger, etc. On the other hand, in the mixing process, "at least a portion of multiple ingredients" includes a single ingredient, and includes the supply of fine bubbles to a single ingredient. For example, it also includes supplying fine bubbles to the water that is first prepared, and then adding ingredients other than water while continuing to supply fine bubbles.

[0048] By carrying out the mixing step, and in some cases by carrying out the mixing step and the oxygen scavenger mixing step, all of the raw materials for the dosimeter composition are mixed to form the dosimeter composition. When all of the raw materials for the dosimeter composition have been mixed, it is preferable to stop stirring and allow the dosimeter composition to stand. At this time, if the dosimeter composition is in a sol state, it will gel when left standing. In this case, the standing time is preferably 2 to 100 hours. The standing temperature is preferably -5 to 100°C, more preferably 0 to 30°C.

[0049] Furthermore, many radiation-polymerizable monomers are sensitive not only to radiation but also to ultraviolet and visible light (especially short-wavelength blue light), and may become opaque when exposed to fluorescent light or the like. Examples of such interfering light include light with wavelengths in the range of 10 nm to 800 nm (i.e., light in the range of ultraviolet and visible light), and particularly light with wavelengths in the range of 10 nm to 500 nm (i.e., light in the range of blue-green light or violet light to ultraviolet light). Therefore, the dosimeter composition is preferably stored in a dark place at a low temperature (e.g., 30°C or below) until use.

[0050] <Dosimeter Composition> A dosimeter composition according to an embodiment of the present disclosure contains a matrix consisting of water and a gelling agent, a radiation-polymerizable monomer, and fine bubbles of an inert gas. Because the matrix is ​​in a gel state, the radiation-polymerizable monomer and the fine bubbles are dispersed and maintained in the matrix. When the inert gas is nitrogen, the dosimeter composition according to an embodiment of the present disclosure contains fine bubbles of nitrogen.

[0051] Fine bubbles in a dosimeter composition can be measured by known measurement methods. Examples include a method using a laser, a method using electrical resistance, and a method using image analysis. These methods have been proposed by the Fine Bubble Industry Association, a general incorporated association. Of these measurement methods, fine bubbles can be confirmed in a dosimeter composition by a method using a laser.

[0052] Furthermore, the dosimeter composition according to an embodiment of the present disclosure preferably has a dissolved oxygen content of 0.5 mg / L or less under standard conditions (25°C, 1 atmosphere). The dissolved oxygen content can be measured by a diaphragm electrode method. The dissolved oxygen content of the dosimeter composition measured by the diaphragm electrode method is preferably 0.5 mg / L or less, and more preferably 0.3 mg / L or less.

[0053] By including fine bubbles of an inert gas in the dosimeter composition, the dosimeter composition can be maintained free of oxygen or, preferably, with a low oxygen content of 0.5 mg / L or less, thereby preventing deterioration of the radiation-polymerizable monomer and other components over time. This allows the dosimeter composition to have excellent storage stability, a longer shelf life than conventional compositions, and a dosimeter composition that can be used for a long period of time. Specifically, conventional dosimeter compositions containing a radiation-polymerizable monomer that can be polymerized by irradiation and a matrix that disperses the radiation-polymerizable monomer have been subject to deterioration due to oxygen contamination during or after production, resulting in a usable period of approximately 10 days after production. While this is possible for domestic use, it is difficult to use overseas due to transportation time. Furthermore, even when used domestically, the usable period is limited, requiring immediate use.

[0054] In one embodiment of the present disclosure, a dosimeter composition containing a radiation-polymerizable monomer and a matrix dispersing the monomer is produced while supplying fine bubbles. Specifically, an inert gas such as nitrogen is supplied as fine bubbles during production. According to one embodiment of the present disclosure, oxygen mixed in during dosimeter production (e.g., during stirring of solvents) can be removed by the inert gas. Furthermore, the effect of the fine bubbles of inert gas remaining in the dosimeter can prevent deterioration of the dosimeter even if oxygen is mixed in after production. Although the detailed mechanism is unclear, it is known that the bubble surfaces of fine bubbles are negatively charged in water. Therefore, it is thought that oxygen mixed in the dosimeter composition after production is attracted to the fine bubbles and prevented from reacting with the radiation-polymerizable monomer, thereby preventing deterioration of the dosimeter even if oxygen is mixed in after production.

[0055] If the expiration date of a dosimeter can be extended, it will be possible to use it not only domestically but also overseas, thereby increasing marketability. Furthermore, since the usage period for dosimeter users is approximately doubled, dosimeter users have traditionally had to use the dosimeter immediately upon arrival, but the dosimeter of an embodiment of the present disclosure can be used within the extended grace period, improving convenience. Conventionally, dosimeter manufacturers had to manufacture dosimeters by counting back from the user's date of use. However, the extension of the expiration date eliminates this need, allowing manufacturers to manufacture dosimeters according to their own schedule.

[0056] <Dosimeter and Radiation Verification Method> A dosimeter according to an embodiment of the present disclosure comprises a dosimeter composition filled in a radiation-transmitting storage container. The radiation is preferably therapeutic radiation. Examples of therapeutic radiation include X-rays generated from linac devices such as Novalis, Cyberknife, and Tomotherapy; electron beams generated from linac devices; gamma rays generated from cobalt irradiation devices, gamma knives, and the like; proton beams, which are a type of heavy particle obtained from large accelerators such as cyclotrons and synchrotrons; and heavy particle beams and neutron beams obtained from large accelerators similar to proton beams. Therefore, the dosimeter is preferably filled in a storage container that is transmissible to such therapeutic radiation. Furthermore, since the dosimeter measures the irradiated dose using a polymer generated after irradiating the dosimeter with therapeutic radiation, it is preferable to use a storage container that does not interfere with the measurement of the generated polymer. Furthermore, the storage container is preferably made of a material that prevents oxygen from entering after fabrication. Therefore, a storage container that meets these requirements is preferably made of a transparent material with low oxygen permeability, such as glass, acrylic, or PET (Polyethylene terephthalate).

[0057] It is known that polymers produced by irradiation cause changes in the surrounding aqueous environment (e.g., proton spin relaxation time), physical density (e.g., attenuation coefficient), optical density (e.g., absorption coefficient), etc. Therefore, by reading out these changes as a three-dimensional image using an MRI device, an X-ray CT device, an optical CT device, or the like, the three-dimensional absorbed dose distribution of the irradiated radiation can be determined. Specifically, the absorbed dose can be determined from the R2 image obtained from the device using the relationship between the relaxation rate R2 and absorbed dose characteristics, and the absorbed dose distribution of the dosimeter after irradiation can be quantified. Note that when an optical method such as an optical CT device is used to analyze the irradiation dose, it is preferable that the container is transparent.

[0058] Furthermore, the storage container preferably blocks light that adversely affects the dosimeter composition when the dosimeter is not in use, i.e., during transportation, storage, etc. Therefore, the storage container for the dosimeter preferably has a function of blocking interfering light that excites the polymerization reaction of the radiation-polymerizable monomer or the polymer produced by polymerization of this monomer. The function of blocking interfering light may be a function possessed by the material of the container, or may be provided by a coating layer or the like disposed on the container. Furthermore, the dosimeter may be provided with a cover that blocks electromagnetic waves such as radiation and light when the dosimeter is not in use, such as during transportation or storage. When a dosimeter is provided with a cover, the cover may be removed when the dosimeter is in use and the cover may be attached when the dosimeter is not in use.

[0059] Furthermore, by forming the storage container of the dosimeter into the shape of a phantom, the dosimeter itself can be used as a phantom when verifying a radiation therapy plan, etc. Depending on the shape, size, etc. of the phantom, it is preferable to control the viscosity of the dosimeter composition by adjusting the temperature, etc., before filling the storage container that will become the phantom with the dosimeter composition. This makes it possible to produce a preferable phantom that is filled without gaps with the dosimeter composition.

[0060] The dosimeter has a three-dimensional shape, and the polymer generated in the dosimeter composition in response to the radiation dose is dispersed in a gel matrix and is therefore less likely to move. Therefore, after radiation exposure, the dosimeter measures the three-dimensional distribution of the polymer generated on the dosimeter after radiation exposure, thereby enabling the three-dimensional absorbed dose distribution of the radiation dose absorbed by the dosimeter to be determined. The three-dimensional absorbed dose distribution can be read using an MRI device, an X-ray CT device, an optical CT device, or the like, and therefore the dosimeter can be used to evaluate dose profiles, gamma analysis, dose volume histograms (DVH), and the like.

[0061] A radiation verification method according to an embodiment of the present disclosure includes the steps of: irradiating a dosimeter according to an embodiment of the present disclosure with a predetermined measurement radiation; and analyzing the dosimeter irradiated with the measurement radiation to obtain dose distribution data corresponding to the dose distribution of the measurement radiation received by the dosimeter. This allows the irradiation data obtained by the dosimeter to be used to measure the dose output and irradiation position accuracy of a radiation irradiation device.

[0062] The preset measurement radiation may be therapeutic radiation based on a radiation therapy plan. Accordingly, a radiation verification method according to an embodiment of the present disclosure includes the steps of: irradiating a dosimeter with therapeutic radiation based on a radiation therapy plan; and analyzing the dosimeter irradiated with the therapeutic radiation to obtain dose distribution data corresponding to the dose distribution of the therapeutic radiation received by the dosimeter. In the step of irradiating the therapeutic radiation, the dosimeter is irradiated with the therapeutic radiation based on a radiation therapy plan formulated for each patient. Preferably, the dosimeter is a phantom having a shape corresponding to the shape of the area to be irradiated with the therapeutic radiation. Then, the dosimeter is analyzed to obtain dose distribution data, such as a three-dimensional absorbed dose distribution. The radiation therapy plan can be verified by comparing the obtained dose distribution data, such as a three-dimensional absorbed dose distribution, with the dose in the radiation therapy plan.

[0063] Examples of the present disclosure are shown below, but the present disclosure is not limited to the following examples. The abbreviations for the compounds used in the examples of the present disclosure are as follows: VIP: N-vinylpyrrolidone Bis: N,N'-methylenebisacrylamide THPC: tetrakishydroxymethylphosphonium chloride

[0064] Example 1 Production of Dosimeter Composition 1 and Dosimeter 1 Dosimeter Composition 1 and Dosimeter 1 were produced as follows. 850 g of ultrapure water was placed in a 2-L glass beaker, and 70 g of gelatin was mixed into the beaker while stirring with a magnetic stirrer. The beaker was then heated to 40-50°C on a hot stirrer, and the gelatin was dissolved while stirring. After the gelatin was fully dissolved, a pipe generating 0.1 L of fine nitrogen gas bubbles per minute from a nozzle attached to the tip was installed and fixed in the beaker. The nozzle was fixed near the bottom of the beaker (a position 10% below the height of the beaker), and fine bubbles were continuously generated while immersed in the contents of the beaker. While continuing to generate fine bubbles and heating and stirring with the hot stirrer, 40 g of VIP was added as a radiation-polymerizable monomer, followed by 40 g of Bis as a crosslinking agent. After thorough mixing, heating with the hot stirrer was stopped, and fine bubble generation and stirring were continued until the temperature of the contents reached approximately 40°C. When the temperature of the contents reached approximately 40°C, fine bubble generation was stopped, and 0.763 mL of THPC was added as an oxygen scavenger and stirred. The composition after stirring was designated as dosimeter composition 1. Dosimeter composition 1 was sealed in a glass container using a tubing pump to designate dosimeter 1. Multiple dosimeters 1 were manufactured. No gas or bubbles were visible in any of the dosimeters 1.

[0065] <Storage of dosimeter 1> Half of the manufactured dosimeters 1 were stored at room temperature in a thermostatic chamber, and the other half were stored in a refrigerator under refrigeration. The thermostatic chamber for room temperature storage was set to a temperature of 25°C, and the refrigerator for refrigerated storage was set to a temperature of 5°C. The thermostatic chamber and the refrigerator were dark places. The dosimeter 1 stored at room temperature was referred to as the room-temperature-stored dosimeter 1, and the dosimeter 1 stored in the refrigerator was referred to as the refrigerated-stored dosimeter 1.

[0066] [Comparative Example 1] <Production of dosimeter composition 2 and dosimeter 2> A plurality of dosimeter compositions 2 were produced in the same manner as in Example 1, except that fine bubbles were not provided. Dosimeter composition 2 was sealed in a glass container using a tubing pump to produce dosimeter 2. A plurality of dosimeters 2 were produced. No gas or bubbles were visible in any of the dosimeters 2.

[0067] <Storage of Dosimeter 2> As with Dosimeter 1, half of the Dosimeters 2 were stored at room temperature in a thermostatic chamber, and the rest were stored in a refrigerator in a refrigerated state. The storage environment was set at an average temperature of 25°C for the room temperature storage and 5°C for the refrigerated storage. The thermostatic chamber and the refrigerator were dark places. The Dosimeters 2 stored at room temperature were designated as room-temperature-stored Dosimeters 2, and the Dosimeters 2 stored in the refrigerator were designated as refrigerated-stored Dosimeters 2.

[0068] [Evaluation of Changes Over Time During Storage at Room Temperature] To evaluate changes in dosimeter performance over time during storage at room temperature, room-temperature-stored dosimeter 1 was used and irradiated with radiation at doses of 0 Gy, 10 Gy, or 20 Gy after 2 days, 12 days, and 35 days of storage. After irradiation, room-temperature-stored dosimeter 1 was imaged using an MRI device at two different echo times, and the transverse relaxation rate, R2 value [1 / s], was calculated from the signal values ​​of images. The calculation was performed for multiple room-temperature-stored dosimeters 1, and the average of the individual values ​​was used to calculate the R2 value [1 / s]. The results are shown in Table 1. In Table 1, room-temperature-stored dosimeter 1 was labeled "with FB" because it used dosimeter composition 1 to which fine bubbles were applied.

[0069]

[0070] Except for using room-temperature-stored dosimeter 2 instead of room-temperature-stored dosimeter 1, room-temperature-stored dosimeter 2 was used in the same manner as above, and multiple room-temperature-stored dosimeters 2 were irradiated with radiation at doses of 0 Gy, 10 Gy, or 20 Gy after 2 days, 14 days, and 20 days of storage. The R2 value [1 / s] was calculated. The calculation was performed for multiple room-temperature-stored dosimeters 2, and the average of the individual values ​​was used as the calculated R2 value [1 / s]. The results are shown in Table 2. In Table 2, room-temperature-stored dosimeter 2 was marked "without FB" because it used dosimeter composition 2 that did not provide fine bubbles.

[0071]

[0072] As shown in FIG. 1, the solid line in graph 10 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after two days of storage for room temperature stored dosimeter 1, and the dashed line in graph 10 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after two days of storage for room temperature stored dosimeter 2.

[0073] As shown in FIG. 2, the solid line in graph 20 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 12 days of storage for room temperature stored dosimeter 1, and the dashed line in graph 20 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 14 days of storage for room temperature stored dosimeter 2.

[0074] As shown in FIG. 3, the solid line in graph 30 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 35 days of storage for room temperature stored dosimeter 1, and the dashed line in graph 30 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 20 days of storage for room temperature stored dosimeter 2.

[0075] The results shown in Graphs 10 to 30 indicate the following: For room-temperature-stored dosimeter 1, whose results are shown by straight lines in Graphs 10 to 30, the relationship between the administered dose [Gy] and the R2 value [1 / s] was nearly proportional and highly linear. For room-temperature-stored dosimeter 2, whose results are shown by dashed lines in Graph 10, the relationship between the administered dose [Gy] and the R2 value [1 / s] was less linear than for room-temperature-stored dosimeter 1. Furthermore, room-temperature-stored dosimeter 1 exhibited a higher R2 value [1 / s] when irradiated with the same dose, compared to room-temperature-stored dosimeter 2, regardless of whether the dosimeter was stored for 2 days, 12 days, or 35 days. Furthermore, the relationship between the R2 value [1 / s] and the administered dose [Gy] was linear even at a low dose such as 10 Gy, demonstrating desirable values ​​for a dosimeter.

[0076] [Evaluation of Usable Period When Stored at Room Temperature] To evaluate the usable period when stored at room temperature based on the dosimeter performance, the relationship between the administered dose [Gy] and the R2 value [1 / s] for each storage period [Days] was examined using room temperature stored dosimeter 1, and the slope [1 / (s Gy)] of the linear approximation of this relationship was measured. The slope [1 / (s Gy)] was also measured for room temperature stored dosimeter 2 in the same manner as above. The measurement results are shown in Table 3. In Table 3, room temperature stored dosimeter 1 used dosimeter composition 1, in which fine bubbles were provided, and is therefore marked "with FB." Room temperature stored dosimeter 2 used dosimeter composition 2, in which fine bubbles were not provided, and is therefore marked "without FB." Furthermore, in Table 3, cases in which no measurement was performed are marked "-."

[0077]

[0078] As shown in FIG. 4 , the solid line in graph 40 shows the relationship between the storage period [Days] and the slope [1 / (s·Gy)] for room-temperature stored dosimeter 1, and the dashed line in graph 40 shows the relationship between the storage period [Days] and the slope [1 / (s·Gy)] for room-temperature stored dosimeter 2.

[0079] When the slope [1 / (s Gy)] is high, the sensitivity of the dosimeter is relatively high, and when this slope [1 / (s Gy)] is low, the sensitivity of the dosimeter is relatively low. The results shown in graph 40 indicate the following: In graph 40, for room-temperature stored dosimeter 1, whose results are shown by a straight line, and room-temperature stored dosimeter 2, whose results are shown by a dashed line, the slope of both decreases as the storage period increases, indicating that the sensitivity of the dosimeter decreases and deteriorates. However, for all storage periods, the value of the slope [1 / (s Gy)] of room-temperature stored dosimeter 1 was larger than that of room-temperature stored dosimeter 2. Looking at the period when the slope [1 / (s Gy)] becomes 0.05 [1 / (s Gy)], it is the 23rd day for room temperature stored dosimeter 1 and the 11th day for room temperature stored dosimeter 2, which shows that the period until the sensitivity of the dosimeter decreases to the same level as the room temperature stored dosimeter 1 is more than twice as long as that of the room temperature stored dosimeter. The period when the slope [1 / (s Gy)] becomes 0.05 [1 / (s Gy)] is the period that can be set as the expiration date for the dosimeter.

[0080] [Evaluation of the Effect of Refrigerated Storage] To evaluate the effect of refrigerated storage, a plurality of refrigerated dosimeters 1 stored in a refrigerator for periods of 2 days, 15 days, or 30 days were used, and each of the refrigerated dosimeters 1 was irradiated with radiation at an administered dose of 0 Gy, 10 Gy, or 20 Gy. After irradiation, the refrigerated dosimeters 1 were imaged using an MRI device at two different echo times, and the transverse relaxation rate, R2 value [1 / s], was calculated from the signal values. The calculation was performed for each of the plurality of refrigerated dosimeters 1, and the average of the individual values ​​was used as the calculated R2 value [1 / s]. The results are shown in Table 4. In Table 4, the refrigerated dosimeter 1 was labeled "with FB" because it used the dosimeter composition 1 to which fine bubbles were applied.

[0081]

[0082] Except for using refrigerated dosimeter 2 instead of refrigerated dosimeter 1, multiple refrigerated dosimeters 2 stored in a refrigerator for periods of 2 days, 14 days, or 29 days were used in the same manner as above, and each of the multiple refrigerated dosimeters 2 was irradiated with radiation at an administered dose of 0 Gy, 10 Gy, or 20 Gy, and the R2 value [1 / s] was calculated. The calculation was performed for each of the multiple refrigerated dosimeters 1, and the average of the individual values ​​was used as the calculated R2 value [1 / s]. The results are shown in Table 5. In Table 5, refrigerated dosimeter 2 was marked "without FB" because it used dosimeter composition 2 that did not provide fine bubbles.

[0083]

[0084] As shown in FIG. 5, the solid line in graph 50 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after two days of storage for refrigerated dosimeter 1, and the dashed line in graph 50 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after two days of storage for refrigerated dosimeter 2.

[0085] As shown in FIG. 6, the solid line in graph 60 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 15 days of storage for refrigerated dosimeter 1, and the dashed line in graph 60 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 14 days of storage for refrigerated dosimeter 2.

[0086] As shown in FIG. 7, the solid line in graph 70 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 30 days of storage for refrigerated dosimeter 1, and the dashed line in graph 70 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 29 days of storage for refrigerated dosimeter 2.

[0087] The results shown in Graphs 50 to 70 indicate the following: Graphs 50 to 70 show that for refrigerated dosimeter 1, the relationship between the administered dose [Gy] and the R2 value [1 / s] was nearly proportional and highly linear after storage for 2 days, 15 days, and 30 days, and exhibited desirable values ​​for a dosimeter. For refrigerated dosimeter 2, the relationship between the administered dose [Gy] and the R2 value [1 / s] was poor in linearity, with the R2 value [1 / s] being low around 10 [Gy] after storage for 2 days, 14 days, and 29 days.

[0088] [Evaluation of Extended Use Period During Refrigerated Storage] To evaluate the extended use period during refrigerated storage based on the dosimeter performance, the relationship between the administered dose [Gy] and the R2 value [1 / s] for each storage period was examined using the refrigerated storage dosimeter 1, and the slope [1 / (s Gy)] of the linear approximation of this relationship was measured. The relationship between the storage period [Days] (days) and the slope [1 / (s Gy)] for the refrigerated storage dosimeter 1 is shown in graph 80 of FIG. 8.

[0089] From the results shown in graph 80, it was found that the refrigerated dosimeter 1 did not show any decrease in the slope [1 / (s Gy)] even after 30 days of refrigerated storage. Therefore, it was shown that the refrigerated dosimeter 1 shows the same slope [1 / (s Gy)] as that after 2 days from manufacture even after 30 days of refrigerated storage, and therefore there is no problem in its use as a dosimeter.

[0090] As shown in Graphs 10 to 80, the dosimeter 1 stored at room temperature or the dosimeter 1 stored in a refrigerator according to the manufacturing method or composition for a dosimeter of an embodiment of the present disclosure showed less deterioration in the reactivity of the radiation-polymerizable monomer, etc. than conventional dosimeters. Therefore, the composition for a dosimeter, dosimeter, etc. according to an embodiment of the present disclosure have excellent storage stability, and the expiration date can be extended compared to conventional dosimeters.

Claims

1. A method for producing a composition for a dosimeter containing a radiation-polymerizable compound and a matrix for dispersing the radiation-polymerizable compound, the method comprising a mixing step of mixing at least some of the raw materials that form the composition for a dosimeter while supplying fine bubbles of an inert gas.

2. The method for producing a composition for a dosimeter according to claim 1, wherein the raw materials contain water and a gelling agent that form the matrix, and the radiation-polymerizable compound, and the mixing step includes mixing the matrix containing the water and the gelling agent with the radiation-polymerizable compound while supplying the fine bubbles.

3. The method for producing a composition for a dosimeter according to claim 1, wherein the raw materials include water and a gelling agent that form the matrix, as well as the radiation-polymerizable compound and a crosslinking agent, and the mixing step includes mixing the matrix containing the water and the gelling agent with the radiation-polymerizable compound and the crosslinking agent while supplying the fine bubbles.

4. A method for producing a composition for a dosimeter according to claim 1, wherein the raw materials contain water and a gelling agent that form the matrix, as well as the radiation-polymerizable compound and an oxygen scavenger, and the method further comprises, after the mixing step, a deoxidizer mixing step of mixing the deoxidizer into the mixture obtained by the mixing step.

5. The method for producing a composition for a dosimeter according to claim 1, wherein the mixing step includes mixing by stirring.

6. The method for producing a composition for a dosimeter according to claim 1, wherein the inert gas is nitrogen gas.

7. The method for producing a composition for a dosimeter according to claim 2, wherein the gelling agent is gelatin.

8. A composition for a dosimeter, comprising: a matrix containing water and a gelling agent; a radiation-polymerizable compound; and fine bubbles of an inert gas.

9. A dosimeter composition according to claim 8, containing 0.5 mg / L or less of oxygen.

10. The composition for a dosimeter according to claim 8, which contains the radiation polymerizable compound and the fine bubbles dispersed in the matrix.

11. The dosimeter composition according to claim 8, wherein the gelling agent is gelatin.

12. The composition for a dosimeter according to claim 8, wherein the radiation-polymerizable compound is a monomer having one or more ethylenically unsaturated double bonds in one molecule.

13. A dosimeter comprising a radiation-transmitting storage container filled with the composition for a dosimeter according to any one of claims 8 to 12.

14. A radiation verification method comprising the steps of: irradiating a dosimeter according to claim 13 with preset measurement radiation; and analyzing the dosimeter irradiated with the measurement radiation to obtain dose distribution data corresponding to the dose distribution of the measurement radiation received by the dosimeter.

15. The radiation verification method according to claim 14, wherein the preset measurement radiation is therapeutic radiation based on a radiation therapy plan.

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