Method for manufacturing a dosimeter composition, dosimeter composition, 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

Technical Field

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

Background Art

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

[0003] In order to verify a radiation therapy plan, therapeutic radiation irradiation based on the radiation therapy plan is performed on a dosimeter in advance, and irradiation data obtained by the dosimeter after irradiation is used. Also, irradiation data obtained by a dosimeter is used for measuring the dose output of a device that performs therapeutic radiation irradiation and the accuracy of the irradiation position. As a dosimeter, a polymer gel dosimeter capable of measuring a three-dimensional dose distribution is known (for example, JP-A-2012-2669, JP-A-2014-185969). The polymer gel dosimeter is a dosimeter in which a container is filled with a composition for a dosimeter in which a polymerizable monomer that polymerizes by radiation is dispersed in a gel. By irradiating the polymer gel dosimeter with radiation, polymers are generated in proportion to the irradiated dose, so that the irradiated dose and position can be estimated three-dimensionally by measuring the amount of polymer generated as the density of white. Also, a gel dosimeter in which substances of the same kind as molecular radicals are not left in order to improve the accuracy of dose measurement is known (for example, JP-A-2014-209093). [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] In polymer gel dosimeters, the reactivity of polymerizable monomers contained in the dosimeter composition sometimes decreased over time, leading to problems with storage stability. This sometimes led to problems where, even after irradiating polymer gel dosimeters that had been manufactured a long time ago, sufficient polymer was not generated to function as a dosimeter. Therefore, for example, when using polymer gel dosimeters for treatment planning, it was necessary to set a relatively short expiration date, such as using the polymer gel dosimeter within approximately 10 days of its manufacture. Thus, due to insufficient storage stability and relatively short expiration dates, polymer gel dosimeters were difficult for users to handle, requiring immediate use upon arrival. Furthermore, manufacturers faced limitations on sales channels, such as the inability to transport the products internationally.

[0005] This disclosure is made in view of the above. The problem that one embodiment of the present invention aims to solve is to provide a method for manufacturing a dosimeter composition that has excellent storage stability and can be used for a longer period than conventional methods. Furthermore, another embodiment of the present invention aims to solve the problem of providing a dosimeter composition that has excellent storage stability and can be used for a longer period than conventional compositions. Furthermore, another embodiment of the present invention aims to solve the problem of providing a dosimeter that has excellent storage stability and can be used for a longer period than conventional dosimeters. Furthermore, another embodiment of the present invention aims to solve the problem of providing a radiation verification method using a dosimeter that has excellent storage stability and can be used for a longer period than conventional methods. [Means for solving the problem]

[0006] The following are examples of specific means for solving the problem: <1> A method for producing a dosimeter composition comprising a radiation polymerizable compound and a matrix in which the radiation polymerizable compound is dispersed, the method comprising a mixing step of mixing at least a portion of a plurality of raw materials forming the dosimeter composition while supplying fine bubbles of an inert gas. <2> The raw materials comprise water and a gelling agent forming 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 the fine bubbles. <1> A method for producing the dosimeter composition described above. <3> The raw materials include water and a gelling agent forming the matrix, and the radiation polymerizable compound and 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. <1> A method for producing the dosimeter composition described above. <4> The raw materials include water and a gelling agent that form the matrix, as well as the radiation polymerizable compound and an oxygen scavenger, and the process further includes an oxygen scavenger mixing step in which the oxygen scavenger is mixed into the mixture obtained in the mixing step after the mixing step. <1> ~ <3> A method for producing a dosimeter composition as described in any one of the following. <5> The mixing step includes mixing by stirring. <1> ~ <4> A method for producing a dosimeter composition as described in any one of the following. <6> The inert gas is nitrogen gas. <1> ~ <5> A method for producing a dosimeter composition as described in any one of the following. <7> The gelling agent is gelatin. <2> ~ <6> A method for producing a dosimeter composition as described in any one of the following. <8> A dosimeter composition comprising a matrix containing water and a gelling agent, a radiation polymerizable compound, and fine bubbles of an inert gas. <9> Contains oxygen of 0.5 mg / L or less <8> The dosimeter composition described above. <10> The radiation polymerizable compound and the fine bubbles are contained in the matrix in a dispersed state. <8> or <9> The dosimeter composition described above. <11> The gelling agent is gelatin. <8> ~ <10> A dosimeter composition as described in any one of the following. <12> The radiation-polymerizable compound is a monomer having one or more ethylenically unsaturated double bonds in one molecule. <8> ~ <11> A dosimeter composition as described in any one of the following. <13> <8> ~ <12> A dosimeter comprising filling a radiation-transmitting storage container with a dosimeter composition described in any one of the above. <14> <13> A radiation verification method comprising the steps of: irradiating a dosimeter described above with a predetermined measuring radiation; and analyzing the dosimeter irradiated with the measuring radiation to obtain dose distribution data corresponding to the dose distribution of the measuring radiation received by the dosimeter. <15> The pre-set measurement radiation is therapeutic radiation based on the radiation therapy plan. <14> The radiation verification method described. [Effects of the Invention]

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

[0008] [Figure 1] Figure 1 is a graph showing the relationship between the administered dose [Gy] and the R² value [1 / s] after 2 days of storage for room temperature storage dosimeter 1 and room temperature storage dosimeter 2. [Figure 2]Figure 2 shows a graph illustrating the relationship between the administered dose [Gy] and the R2 value [1 / s] after 12 days of storage using room temperature storage dosimeter 1, and a graph illustrating the relationship between the administered dose [Gy] and the R2 value [1 / s] after 14 days of storage using room temperature storage dosimeter 2. [Figure 3] Figure 3 shows a graph illustrating the relationship between the administered dose [Gy] and the R2 value [1 / s] after 35 days of storage using room temperature storage dosimeter 1, and a graph illustrating the relationship between the administered dose [Gy] and the R2 value [1 / s] after 20 days of storage using room temperature storage dosimeter 2. [Figure 4] Figure 4 is a graph showing the relationship between storage period [Days] and slope [1 / (s·Gy)] for room temperature storage dosimeter 1 and room temperature storage dosimeter 2. [Figure 5] Figure 5 is a graph showing the relationship between the administered dose [Gy] and the R² value [1 / s] after 2 days of storage in refrigerated dosimeter 1 and refrigerated dosimeter 2. [Figure 6] Figure 6 shows a graph illustrating the relationship between the administered dose [Gy] and the R2 value [1 / s] after 15 days of storage using refrigerated dosimeter 1, and a graph illustrating the relationship between the administered dose [Gy] and the R2 value [1 / s] after 14 days of storage using refrigerated dosimeter 2. [Figure 7] Figure 7 shows a graph illustrating the relationship between the administered dose [Gy] and the R2 value [1 / s] after 30 days of storage using refrigerated dosimeter 1, and a graph illustrating the relationship between the administered dose [Gy] and the R2 value [1 / s] after 29 days of storage using refrigerated dosimeter 2. [Figure 8] Figure 8 is a graph showing the relationship between the storage period [Days] and the slope [1 / (s·Gy)] in the refrigerated dosimeter 1. [Modes for carrying out the invention]

[0009] The following describes the method for manufacturing the dosimeter composition, the dosimeter composition, the dosimeter, and the radiation verification method of this disclosure. However, this disclosure is not limited in any way to the embodiments described below, and can be modified and implemented as appropriate within the scope of the purpose of this disclosure.

[0010] In this specification, a numerical range represented by "~" means a range including the numerical values described before and after "~" as the lower limit value and the upper limit value. In the numerical ranges described stepwise in this specification, the upper limit value or the lower limit value described in one numerical range may be replaced with the upper limit value or the lower limit value of another numerically described range. Also, in the numerical ranges described in this specification, the upper limit value or the lower limit value of that numerical range may be replaced with the value shown in the examples. In this specification, the amount of each component in the composition means the total amount of the plurality of substances corresponding to each component in the composition when there are a plurality of substances corresponding to each component in the composition, unless otherwise specified. In this specification, "mass" and "weight" are synonymous, and "mass%" and "weight%" are synonymous. In this specification, a combination of two or more preferred embodiments is a more preferred embodiment. In this specification, the term "step" includes not only independent steps but also cases where it cannot be clearly distinguished from other steps, as long as the intended purpose of the step is achieved. In this specification, "fine bubble", "ultra-fine bubble", and "micro-bubble" are registered trademarks respectively. Hereinafter, the description that these are registered trademarks will be omitted.

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

[0012] 〔Matrix〕 The matrix preferably holds at least a radiopolymerizable compound and a crosslinking agent in a dispersed state and is radiotransmitting. Furthermore, for dosimeters used for verifying radiotherapy plans, it is preferable that a dosimeter containing the matrix and filled into a case can be used as a phantom. Therefore, a preferred matrix is, for example, a gel, and the raw materials for forming the gel are a gelling agent and water.

[0013] Preferably, the gelling agent is one that can form a gel at room temperature and does not inhibit the polymerization of radiation-polymerizable compounds. It can be selected from gelling agents conventionally used in polymer gel dosimeters. Examples of usable gelling agents include gelling agents made from natural polymers such as gelatin, gelling agents containing silicates, and gelling agents containing polyvinyl alcohol.

[0014] [Gelling agent made from natural polymers] Examples of gelling agents made from natural polymers include gelatin, agarose, xanthan gum, carrageenan, gellan gum, chitosan, alginic acid, polysaccharides, and starch. Due to its ease of preparation and the stability of the gel at room temperature, gelatin is preferred as the natural polymer.

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

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

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

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

[0019] Examples of silicate dispersants include phosphate-based dispersants, carboxylate-based dispersants, those that act as alkalis, and organic demagnetizers. Specifically, 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 ligninsulfonate, and potassium salts corresponding to these salts. The silicate dispersant content is preferably 0.01% to 20% by mass, and more preferably 0.05% to 10% by mass, based on the composition for dosimeters.

[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 8000, more preferably 100 to 5000, and even more preferably 500 to 3000, and a degree of saponification of 80% to 99%, more preferably 88% to 99%. The polyvinyl alcohol content is preferably 70% to 90% by mass, more preferably 75% to 85% by mass, based on the dosimeter composition, and the borax content is preferably 5% to 28% by mass, more preferably 7% to 25% by mass, based on the dosimeter composition.

[0021] 〔water〕 As for the water, it is preferable to use distilled water, pure water, or ultrapure water that contains as few impurities as possible, such as ions, in order to suppress the polymerization of radiation-polymerizable compounds at times other than when irradiated with radiation. The water content is such that the resulting gel can be used as a matrix for the dosimeter composition. While it depends on the manufacturing environment, including temperature and humidity, a water content of 70% to 98% by mass is preferred, 80% to 95% by mass is more preferred, and 85% to 90% by mass is even more preferred, based on the dosimeter composition.

[0022] Any method of gel formation may be used, including covalent bonding, Coulomb bonding, hydrogen bonding, coordination bonding, and physical entanglement. The gel is the matrix of the dosimeter composition and disperses and holds radiation-polymerizable monomers, etc. Therefore, the gel has a gel strength of 10 g or more, and more preferably 100 g or more, as measured in accordance with JIS K6503-1996.

[0023] [Radiation-polymerizable compounds] Radiation-polymerizable compounds are compounds that produce polymers upon exposure to radiation, and examples include radiation-polymerizable monomers. Radiation-polymerizable monomers are preferably compounds that produce polymers through radical polymerization when irradiated with radiation. Specifically, they are preferably monomers having one or more acrylic structures, ethylenically unsaturated double bonds, i.e., vinyl structures, in a single molecule. Furthermore, if the matrix is ​​a gel composed of water and gelatin, the radiation-polymerizable monomer is preferably a water-soluble polymerizable monomer.

[0024] Radiation-polymerizable monomers may produce polymers on their own by irradiation with radiation, or they may be monomers that produce polymers in combination with a crosslinking agent added as a raw material.

[0025] Specific examples of radiation-polymerizable monomers 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, and acryloyl-L-proline methyl ester. The content of radiation-polymerizable monomers is preferably within a range suitable for use 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] Depending on the type of radiation-polymerizable monomer, a crosslinking agent is used as a raw material. Water-soluble acrylamide is a preferred crosslinking agent. A specific 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 should preferably be within a range suitable for use as a dosimeter by polymerizing the radiation-polymerizable monomer with radiation. Based on the dosimeter composition, the content is preferably 0.5% to 8% by mass, more preferably 1% to 5% by mass, and even more preferably 2% to 4% by mass.

[0028] [Oxygen absorber] When using an oxygen absorber, examples of oxygen absorbers include ascorbic acid and tetrakis-hydroxymethyl-phosphonium chloride (THPC). It is preferable to use an amount of oxygen absorber that is sufficient to reduce the oxygen introduced during the manufacturing of the dosimeter composition, the oxygen contained in the raw materials, and the oxygen introduced from the dosimeter storage container, etc. In polymer gel dosimeters, the reactivity of polymerizable monomers contained in the dosimeter composition decreases over time, and one of the reasons for 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 relative to the 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 ingredients] The dosimeter composition may also contain other raw materials besides the matrix-forming raw materials, radiation-polymerizable monomers, crosslinking agents, and oxygen scavengers. 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 sols. 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 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 when using natural polymers as gelling agents: MAG (Methacrylic Acid & Gelatin) and PAG (Poly-Acrylamide & Gelatin). 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 comprising water and gelatin as matrix raw materials, a radiation-polymerizable monomer and a crosslinking agent, and acrylamide as the radiation-polymerizable monomer. The acrylamide is one of acrylamide (AA), N-vinylpyrrolidone (VIP), or N-isopropylacrylamide (NIPAM), and the dosimeter composition comprises N,N'-methylene-bis-acrilamode (Bis) as the crosslinking agent.

[0031] Furthermore, it is preferable to use an oxygen absorber as a raw material in both MAG and PAG. MAG that uses THPC as an oxygen absorber is called MAGAT (Methacrylic Acid, Gelatin, And THPC). PAG that uses AA and THPC as an oxygen absorber is called PAGAT (Poly-Acrylamide, Gelatin, And THPC). PAG that uses VIP and THPC as an oxygen absorber is called VIPET (N-vinylpyrrolidone, Gelatin, And THPC). PAG that uses NIPAM and THPC as an oxygen absorber is also called NIPAM. For example, in the case of VIPET, the dosimeter composition can have a composition of 85% water by mass, 7% gelatin by mass, 4% VIP by mass, and 4% Bis by mass, based on the total mass of the dosimeter composition.

[0032] Furthermore, as an example of another dosimeter composition, when a silicate is used as a gelling agent, a preferred combination of a water-soluble organic polymer, a silicate, and a silicate dispersant is a composition consisting of, based on the total mass of the dosimeter composition, 0.05% to 10% by mass of a fully neutralized or partially neutralized linear sodium polyacrylate with a weight-average molecular weight of 2.5 million to 5 million as the water-soluble organic polymer, 0.05% to 10% by mass of a water-swellable smectite or saponite as the silicate, and 0.5% to 5% by mass of sodium pyrophosphate or sodium etidronate, or 0.5% to 5% by mass of sodium polyacrylate with a weight-average molecular weight of 1,000 to 20,000 as the silicate dispersant.

[0033] [Mixing process] The dosimeter composition is manufactured by mixing the above-mentioned raw materials in predetermined proportions to obtain a uniform composition. A method for producing a dosimeter composition according to one embodiment of the present disclosure comprises a mixing step of mixing at least a portion of the above-mentioned plurality of raw materials while supplying fine bubbles of an inert gas.

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

[0035] Here, "fine bubble" refers to the fine bubble defined in the Japanese Industrial Standard JIS B 8741-1:2019. According to this definition, a fine bubble means a bubble with a volume-equivalent diameter of less than 100 μm, and includes ultrafine bubbles and microbubbles. 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, fine bubbles of inert gases include microbubbles of inert gases and ultrafine bubbles of inert gases. Furthermore, the diameter equivalent to the volume refers to the diameter derived based on the volume of a bubble assuming a spherical shape, and will hereafter also be called the "bubble diameter."

[0036] Fine bubbles of inert gases can be generated in a distributed manner with various bubble sizes. For example, in a measurement example using a quantitative laser diffraction / scattering method to evaluate particle characteristics of fine bubbles in water, the average diameter D50 was 77 nm. In terms of generation rate, the total amount of inert gas generated from the fine bubbles is preferably 0.01 L / min to 0.5 L / min per 1 L to 4 L of the material to which the fine bubbles are supplied.

[0037] In the mixing process, at least a portion of the above-mentioned raw materials are mixed while supplying fine bubbles of inert gas. As for the method of supplying fine bubbles to the raw materials to be mixed, any method that continuously supplies inert gas in the form of fine bubbles to the raw materials to be mixed is acceptable. For example, one method involves introducing inert gas into the raw materials using a pipe and discharging the inert gas from a nozzle capable of generating fine bubbles placed at one end of the pipe, thereby supplying the inert gas, which has become fine bubbles, to the raw materials. Specifically, the method involves introducing an inert gas from an inert gas introduction device through a pipe, inserting one end of the pipe, which is fitted with a nozzle capable of generating fine bubbles, into a manufacturing container containing multiple raw materials, ensuring that the nozzle is completely immersed in the multiple raw materials, and then fixing the nozzle near the bottom of the manufacturing container. In this case, it is preferable that the end of the pipe fitted with the nozzle does not come into contact with the bottom of the manufacturing container in order to avoid hindering the generation of fine bubbles. It is preferable that the nozzle portion of the pipe be positioned at a location 10% to 30% from the bottom of the manufacturing container, relative to the entire height of the manufacturing container.

[0038] Any device capable of continuously generating fine bubbles of inert gas is acceptable as a fine bubble generating device. 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 generating devices.

[0039] The manufacturing container is preferably one that does not allow oxygen to leach into the contents, and specifically, a glass manufacturing container is preferred. Furthermore, the shape of the manufacturing container is also preferably one that does not easily mix oxygen into the contents during mixing, and specifically, a glass beaker is preferred.

[0040] In the mixing process, the mixing of multiple raw materials can be done by mechanical or manual stirring, ultrasonic stirring, or continuous mixing by line mixing. For mechanical stirring, magnetic stirrers, propeller-type stirrers, rotational / revolving mixers, dispersers, homogenizers, shakers, vortex mixers, ball mills, kneaders, ultrasonic oscillators, etc., can be used. Of these methods, mechanical stirring is preferred because it can suppress the incorporation of oxygen during mixing, and a magnetic stirrer is preferred among them. In mechanical stirring, it is sometimes preferable to stir while heating the manufacturing container with equipment that has a heating means. For example, when the gelling agent is gelatin, it is preferable to use a glass manufacturing container as the manufacturing container and to use a magnetic stirrer in a water bath, or to use a hot stirrer which is a magnetic stirrer equipped with a hot plate. In addition, in industrial-level manufacturing, conventionally known manufacturing containers, agitators, etc., can be used, not limited to those mentioned above.

[0041] In the mixing process, 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. An aqueous solvent such as methanol, ethanol, isopropanol, or glycerol may be mixed with water, but it is preferable to use a solvent that contains as little oxygen as possible.

[0042] The mixing temperature depends 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, and more preferably 0°C to 60°C.

[0043] Preferably, as a method for producing a dosimeter composition, if the raw materials for the dosimeter composition include water and a gelling agent forming a matrix and a radiation-polymerizable monomer, the mixing step includes mixing the matrix containing water and a gelling agent with the radiation-polymerizable monomer while supplying fine bubbles. In other words, in the mixing process, it is preferable to first form a matrix by mixing water and a gelling agent, and then mix the matrix with the radiation-polymerizable monomer while supplying fine bubbles. By forming a matrix and then mixing it with radiation-polymerizable monomers, the matrix can be formed sufficiently uniformly through temperature control and other means, making the final dosimeter composition more uniform. Furthermore, fine bubbles of inert gas can be provided effectively and efficiently.

[0044] Furthermore, as a method for producing a dosimeter composition, preferably the raw materials of the dosimeter composition include a crosslinking agent, 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. In other words, when using a crosslinking agent as a raw material, it is preferable in the mixing process to first form a matrix by mixing water and a gelling agent, and then mix the matrix with the radiation-polymerizable monomer and the crosslinking agent while supplying fine bubbles. By forming a matrix and then mixing it with radiation-polymerizable monomers and crosslinking agents, the matrix can be formed sufficiently uniformly through temperature control and other means, making the final dosimeter composition more uniform. Furthermore, fine bubbles of inert gas can be provided effectively and efficiently.

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

[0046] [Oxygen absorber mixing process] Furthermore, as a method for producing a dosimeter composition, if the raw materials for the dosimeter composition include an oxygen absorber mixing step, the method preferably includes an oxygen absorber mixing step after the mixing step, in which the oxygen absorber is mixed into the mixture obtained in the mixing step. In other words, when a dosimeter composition contains an oxygen absorber as a raw material, it is preferable to mix the other raw materials first, and then mix the oxygen absorber last as a raw material. In the oxygen absorber process, depending on the type of oxygen absorber, if the oxygen absorber is THPC, the provision of fine bubbles may cause 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 process, or to not provide fine bubbles at all. Specifically, it is preferable to mix the raw materials other than the oxygen absorber while providing fine bubbles, stop supplying the fine bubbles when these are sufficiently mixed, and then immediately introduce the 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 gelling agents such as gelatin or when adding oxygen absorbers. On the other hand, the mixing process includes, in the case of at least a portion of multiple raw materials, a single raw material, and includes providing fine bubbles to the single raw material. For example, it may include supplying fine bubbles to the water being prepared first, and then adding raw materials other than water while continuing to supply fine bubbles.

[0048] By performing a mixing process, or in some cases a mixing process and an oxygen absorber mixing process, all the raw materials for the dosimeter composition are mixed to form the dosimeter composition. When all the raw materials for the dosimeter composition are mixed, it is preferable to stop stirring and allow the dosimeter composition to stand. If the dosimeter composition is in a sol state at this time, it will gel upon standing. In this case, the standing time is preferably 2 to 100 hours. The standing temperature is preferably -5°C to 100°C, and more preferably 0°C 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 cloudy when exposed to light from fluorescent lamps, etc. These interfering lights are, for example, light in the wavelength range of 10 nm to 800 nm (i.e., light in the ultraviolet and visible light range), and especially light in the wavelength range of 10 nm to 500 nm (i.e., light in the blue-green or violet to ultraviolet range). Therefore, it is preferable to store the dosimeter composition in a dark place at a low temperature (for example, 30°C or below) until use.

[0050] <Composition for dosimeters> A dosimeter composition according to one embodiment of the present disclosure contains a matrix comprising water and a gelling agent, a radiation-polymerizable monomer, and fine bubbles of an inert gas. Since the matrix is ​​gel-like, the radiation-polymerizable monomer and the fine bubbles are held dispersed in the matrix. When the inert gas is nitrogen, the dosimeter composition of one embodiment of the present disclosure includes fine bubbles of nitrogen.

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

[0052] Furthermore, the dosimeter composition of one embodiment of this disclosure preferably has a dissolved oxygen content of 0.5 mg / L or less under standard conditions (25°C, 1 atm). The dissolved oxygen content can be measured by the diaphragm electrode method. Based on the value measured by the diaphragm electrode method, the dosimeter composition preferably has a dissolved oxygen content of 0.5 mg / L or less, and more preferably 0.3 mg / L or less.

[0053] By including fine bubbles of inert gas in the dosimeter composition, it is possible to maintain a state where oxygen is absent or, preferably, at a low level of 0.5 mg / L or less, thereby preventing the deterioration of radiation-polymerizable monomers and other components over time. As a result, the dosimeter composition exhibits excellent storage stability, has a longer shelf life than conventional compositions, and can be used for extended periods. Specifically, conventional dosimeter compositions containing radiation-polymerizable monomers and matrices dispersing these monomers deteriorate due to oxygen contamination during or after manufacturing, resulting in a usable period of only about 10 days after production. While this is feasible for domestic use, it is difficult for overseas use due to transportation time constraints. Furthermore, even for domestic use, the limited usable period necessitates immediate use.

[0054] In one embodiment of this disclosure, a dosimeter composition containing a radiation-polymerizable monomer and a matrix in which the monomer is dispersed is manufactured while supplying fine bubbles. Specifically, during manufacturing, an inert gas such as nitrogen is supplied as fine bubbles. According to one embodiment of this disclosure, oxygen introduced during the manufacturing of a dosimeter (for example, during stirring of solvents) can be removed by an inert gas. Furthermore, the effect of fine bubbles from the inert gas remaining in the dosimeter can prevent deterioration of the dosimeter even if oxygen is introduced after manufacturing. Although the detailed mechanism is not clear, it is known that fine bubbles have a negatively charged surface in water. Therefore, it is thought that oxygen mixed into the dosimeter composition after manufacturing is attracted to the fine bubbles and its reaction with the radiation-polymerizable monomer is suppressed, thus preventing the deterioration of the dosimeter even if oxygen is mixed in after manufacturing.

[0055] Extending the expiration date of dosimeters would allow for use not only domestically but also internationally, increasing their market potential. Furthermore, since the usage period for dosimeters would be approximately doubled, users would no longer need to use the dosimeter immediately upon arrival. With the dosimeter of one embodiment of this disclosure, however, they could be used within the extended grace period, improving convenience. Manufacturers of dosimeters previously had to calculate their production schedule backward from the user's intended use date, but with the extended expiration date, this requirement is eliminated, allowing manufacturers to produce according to their own schedule.

[0056] <Dosimeters and radiation verification methods> A dosimeter according to one embodiment of the present disclosure comprises a dosimeter composition filled into a radiation-transmitting storage container. The radiation is preferably therapeutic radiation. Examples of therapeutic radiation include X-rays generated from linear accelerators such as Novalis, CyberKnife, and TomoTherapy; electron beams generated from linear accelerators; gamma rays generated from cobalt irradiation devices, gamma knives, etc.; proton beams, which are a type of heavy particle obtained from large accelerators such as cyclotrons and synchrotrons; heavy particle beams and neutron beams obtained from large accelerators similar to those used for proton beams. Therefore, the dosimeter is preferably filled into a storage container that is transparent to these therapeutic radiations. 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. The storage container is preferably made of a material that prevents oxygen from entering after the product has been prepared. Therefore, a storage container that satisfies these requirements is preferably made of a transparent material with low oxygen permeability, such as glass, acrylic, or PET (polyethylene terephthalate).

[0057] Polymers produced by radiation irradiation are known to alter the surrounding aquatic environment (e.g., proton spin relaxation time), physical density (e.g., attenuation coefficient), and optical density (e.g., absorption coefficient). Therefore, by reading these changes as a three-dimensional image using an MRI device, X-ray CT device, optical CT device, etc., 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 relaxation rate R2 and absorbed dose characteristics, and the absorbed dose distribution of the dosimeter after irradiation can be quantified. Furthermore, when using optical methods such as optical CT scanners for radiation dose analysis, it is preferable that the container be transparent.

[0058] Furthermore, it is preferable that the storage container blocks light that could adversely affect the dosimeter composition when the dosimeter is not in use, i.e., during transportation, storage, etc. Therefore, it is preferable that the storage container for the dosimeter has a function to block interfering light to the radiation polymerizable monomer or the polymer produced by the polymerization of this monomer, such as light that excites the polymerization reaction of the radiation polymerizable monomer. The function of blocking interfering light may be a function inherent in the material of the container, or it may be due to a coating layer or the like applied to the container. Furthermore, dosimeters may be equipped with a cover to block electromagnetic waves such as radiation and light when not in use, such as during transport or storage. Dosimeters equipped with a cover may have the cover removed when in use and the cover attached when not in use.

[0059] Furthermore, by making the storage container of the dosimeter phantom-shaped, the dosimeter itself can be used as a phantom for purposes such as verifying radiation therapy plans. Furthermore, depending on the shape and size of the phantom, it is preferable to control the viscosity of the dosimeter composition by adjusting its temperature, etc., before filling the storage container that will become the phantom. This makes it possible to produce a desirable phantom in which the dosimeter composition is filled without any gaps.

[0060] Dosimeters have a three-dimensional shape, and the polymer generated in the dosimeter composition according to the radiation dose is dispersed in the gel matrix and does not easily move. Therefore, in a dosimeter after radiation irradiation, the three-dimensional absorbed dose distribution of the radiation absorbed by the dosimeter can be determined by measuring the three-dimensional distribution of the polymer generated relative to the dosimeter after radiation irradiation. Since the three-dimensional absorbed dose distribution can be read using MRI, X-ray CT, optical CT, etc., dose profiles, gamma analysis, dose volume histograms (DVH), etc., can be evaluated using a dosimeter.

[0061] A radiation verification method according to one embodiment of the present disclosure comprises the steps of: irradiating a dosimeter according to one embodiment of the present disclosure with a preset measuring radiation; and obtaining dose distribution data corresponding to the dose distribution of the measuring radiation received by the dosimeter by analyzing the dosimeter irradiated with the measuring radiation. This allows the use of irradiation data obtained from a dosimeter to measure the dose output and irradiation position accuracy of the radiation irradiation device.

[0062] The pre-set radiation for measurement may be therapeutic radiation based on a radiation therapy plan. Accordingly, a radiation verification method according to one embodiment of the present disclosure comprises the steps of irradiating a dosimeter with therapeutic radiation based on a radiation therapy plan, and obtaining dose distribution data corresponding to the dose distribution of therapeutic radiation received by the dosimeter by analyzing the dosimeter that has been irradiated with therapeutic radiation. In the process of irradiating with therapeutic radiation, therapeutic radiation is irradiated to the dosimeter based on a radiation therapy plan formulated for each individual patient. Preferably, the dosimeter is a phantom with a shape that corresponds to the shape of the area to be irradiated with therapeutic radiation. Subsequently, by analyzing the dosimeter, dose distribution data, such as a three-dimensional absorbed dose distribution, can be obtained. By comparing the obtained dose distribution data, such as the three-dimensional absorbed dose distribution, with the dose in the radiation therapy plan, the radiation therapy plan can be verified. [Examples]

[0063] The following are examples of the embodiments of this disclosure, but this disclosure is not limited to the following embodiments. The abbreviations for the compounds used in the examples of this disclosure are shown below. VIP: N-vinylpyrrolidone Bis:N,N'-Methylenebisacrylamide THPC: Tetrakishydroxymethylphosphonium chloride

[0064] [Example 1] <Manufacturing of dosimeter composition 1 and dosimeter 1> The dosimeter composition 1 and the dosimeter 1 were manufactured as follows. 850g of ultrapure water was placed in a 2L glass beaker, and 70g of gelatin was mixed in while stirring with a magnetic stirrer. Then, the beaker was heated to 40°C to 50°C on a hot stirrer, and the gelatin was dissolved while stirring. After the gelatin had completely dissolved, a pipe was placed inside the beaker and secured, with a nozzle attached to its tip that generated 0.1 L of nitrogen gas fine bubbles per minute. The nozzle was fixed near the bottom of the beaker (10% of the beaker's height) and continuously generated fine bubbles while immersed in the beaker's contents. While continuing to generate fine bubbles and heating and stirring with a hot stirrer, 40g of VIP was added as a radiation-polymerizable monomer, and then 40g of Bis was added as a crosslinking agent. After thorough mixing, heating with a hot stirrer was stopped, and fine bubble generation and stirring were continued until the contents reached a temperature of approximately 40°C. When the contents reached approximately 40°C, fine bubble generation was stopped, and 0.763 mL of THPC was added as an oxygen absorber and stirred. The resulting composition was designated as Dosimeter Composition 1. Composition 1 for dosimeters was sealed in a glass container using a tubing pump to create dosimeter 1. Multiple dosimeters 1 were manufactured. No gas or bubbles were visually observed in any of the dosimeters 1.

[0065] <Storage of Dosimeter 1> Half of the manufactured dosimeters were stored at room temperature in a temperature-controlled cabinet, and the other half were stored in a refrigerator. The temperature-controlled cabinet for room temperature storage was set to 25°C, and the refrigerator for refrigerated storage was set to 5°C. Both the cabinet and the refrigerator were kept in darkness. Dosimeter 1 stored at room temperature was designated as room temperature storage dosimeter 1, and dosimeter 1 stored in the refrigerator was designated as refrigerator storage dosimeter 1.

[0066] [Comparative Example 1] <Manufacturing of dosimeter composition 2 and dosimeter 2> Multiple dosimeter compositions 2 were manufactured in the same manner as in Example 1, except that they did not provide fine bubbles. Composition 2 for dosimeters was sealed in a glass container using a tubing pump to create dosimeter 2. Multiple dosimeters 2 were manufactured. No gas or bubbles were visually observed in any of the dosimeters 2.

[0067] <Storage of Dosimeter 2> Regarding Dosimeter 2, similar to Dosimeter 1, half were stored at room temperature in a constant temperature chamber, and the remainder were stored refrigerated in a refrigerator. The storage environment was such that the average temperature for room temperature storage was 25°C, depending on the set temperature, and the average temperature for refrigerated storage was 5°C. Both the constant temperature chamber and the refrigerator were kept in darkness. Dosimeter 2 stored at room temperature was designated as room temperature storage dosimeter 2, and dosimeter 2 stored in the refrigerator was designated as refrigerator storage dosimeter 2.

[0068] [Evaluation of changes over time during storage at room temperature] To evaluate the change in the performance of a dosimeter over time during storage at room temperature, a room-temperature stored dosimeter 1 was used, and radiation was administered to the dosimeter 1 at doses of 0 Gy, 10 Gy, and 20 Gy, respectively, at storage periods of 2 days, 12 days, and 35 days. The transverse relaxation velocity (R² value [1 / s]) was calculated from the signal values ​​of images acquired using an MRI device with two different echo times for each of the dosimeters 1 stored at room temperature after irradiation. The calculation was performed for multiple dosimeters 1, and the average of the individual values ​​was used as the R² value [1 / s] result. The obtained results are shown in Table 1. In Table 1, the dosimeter 1 stored at room temperature is labeled "FB present" because it uses the dosimeter composition 1 that provided the fine bubbles.

[0069] [Table 1]

[0070] Except for using room-temperature storage dosimeter 2 instead of room-temperature storage dosimeter 1, the same procedure as above was followed, and multiple room-temperature storage dosimeters 2, stored at room temperature, were irradiated with radiation at doses of 0 Gy, 10 Gy, and 20 Gy, respectively, for storage periods of 2 days, 14 days, and 20 days. The R² value [1 / s] was calculated. The calculation was performed for each of the multiple room-temperature storage dosimeters 2, and the average of the individual values ​​was used as the R² value [1 / s] result. The obtained results are shown in Table 2. In Table 2, room-temperature storage dosimeter 2 is labeled "no FB" because it uses dosimeter composition 2 that does not provide fine bubbles.

[0071] [Table 2]

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

[0073] As shown in Figure 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 using room-temperature storage dosimeter 1, while 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 using room-temperature storage dosimeter 2.

[0074] As shown in Figure 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, while 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: In Graphs 10 to 30, the results for room-temperature stored dosimeter 1, shown by a straight line, showed a nearly proportional relationship between administered dose [Gy] and R² value [1 / s], indicating high linearity. In Graph 10, the results for room-temperature stored dosimeter 2, shown by a dashed line, showed less linearity between administered dose [Gy] and R² value [1 / s] than in the case of room-temperature stored dosimeter 1. Furthermore, room-temperature stored dosimeter 1 showed a higher R2 value [1 / s] compared to room-temperature stored dosimeter 2 when irradiated with the same dose, regardless of whether it was stored for 2 days, 12 days, or 35 days. In addition, the relationship between the R2 value [1 / s] and the administered dose [Gy] showed linearity even at low doses such as 10 Gy, indicating a desirable value for a dosimeter.

[0076] [Evaluation of usable period when stored at room temperature] To evaluate the usable period under room temperature storage based on the performance of the dosimeter, a room temperature storage dosimeter 1 was used to examine the relationship between administered dose [Gy] and R² value [1 / s] for each storage period [Days], and the slope [1 / (s·Gy)] when these relationships were approximated by a straight line was measured. The slope [1 / (s·Gy)] of the room-temperature stored dosimeter 2 was also measured in the same manner as described above. The measurement results are shown in Table 3. In Table 3, room temperature storage dosimeter 1 uses dosimeter composition 1, which provides fine bubbles, and is therefore labeled "FB present". Room temperature storage dosimeter 2 uses dosimeter composition 2, which does not provide fine bubbles, and is therefore labeled "FB absent". In addition, "-" is indicated in Table 3 when no measurement was performed.

[0077] [Table 3]

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

[0079] A high slope [1 / (s·Gy)] indicates relatively high sensitivity as a dosimeter, while a low slope [1 / (s·Gy)] indicates relatively low sensitivity as a dosimeter. The results shown in Graph 40 indicate the following: In Graph 40, both 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, show a decrease in slope as the storage period lengthens, indicating that the sensitivity of the dosimeter decreases and it deteriorates. However, across all storage periods, room-temperature stored dosimeter 1 had a larger slope [1 / (s·Gy)] than room-temperature stored dosimeter 2. When examining the period during which the slope [1 / (s·Gy)] becomes 0.05[1 / (s·Gy)], it was 23 days for room-temperature stored dosimeter 1 and 11 days for room-temperature stored dosimeter 2. This shows that the period during which the sensitivity of the dosimeter decreases to the same level as the dosimeter is more than twice as long for room-temperature stored dosimeter 1 compared to room-temperature stored dosimeter 2. Furthermore, the period during which the slope [1 / (s·Gy)] is 0.05 [1 / (s·Gy)] can be set as the expiration date for use as a dosimeter.

[0080] [Evaluation of the effectiveness of refrigerated storage] To evaluate the effectiveness of refrigerated storage, multiple refrigerated dosimeters 1, stored under refrigeration for periods of 2 days, 15 days, or 30 days, were used. Each of the multiple refrigerated dosimeters 1 was then irradiated with radiation at doses of 0 Gy, 10 Gy, or 20 Gy, respectively. The transverse relaxation velocity (R² value [1 / s]) was calculated from the signal values ​​of images acquired using an MRI device with two different echo times for each of the refrigerated dosimeters 1 after irradiation. The calculation was performed for multiple dosimeters 1, and the average of the individual values ​​was used as the R² value [1 / s] calculation result. The results obtained are shown in Table 4. In Table 4, the refrigerated dosimeter 1 uses the dosimeter composition 1 that provided fine bubbles, and is therefore labeled "with FB".

[0081] [Table 4]

[0082] Except for using refrigerated dosimeter 2 instead of refrigerated dosimeter 1, multiple refrigerated dosimeters 2 were stored in a refrigerator for periods of 2 days, 14 days, or 29 days, respectively. Each of the multiple refrigerated dosimeters 2 was irradiated with radiation at doses 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 result of the R² value [1 / s] calculation. The results obtained are shown in Table 5. In Table 5, the refrigerated dosimeter 2 uses dosimeter composition 2 that does not provide fine bubbles, so it is labeled "no FB".

[0083] [Table 5]

[0084] As shown in Figure 5, the solid line in Graph 50 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 2 days of storage in Refrigerated Dosimeter 1, while the dashed line in Graph 50 shows the relationship between the administered dose [Gy] and the R2 value [1 / s] after 2 days of storage in Refrigerated Dosimeter 2.

[0085] As shown in Figure 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 using refrigerated dosimeter 1, while 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 using refrigerated dosimeter 2.

[0086] As shown in Figure 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 in Refrigerated Dosimeter 1, while 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 in Refrigerated Dosimeter 2.

[0087] The results shown in Graphs 50 to 70 indicate the following: From graphs 50 to 70, it can be seen that in refrigerated dosimeter 1, the relationship between administered dose [Gy] and R2 value [1 / s] was almost proportional and highly linear after 2 days, 15 days, and 30 days of storage, respectively, indicating a desirable value for a dosimeter. In the refrigerated dosimeter 2, the relationship between administered dose [Gy] and R2 value [1 / s] after storage for 2 days, 14 days, and 29 days showed poor linearity, with the R2 value [1 / s] being low around 10 [Gy].

[0088] [Evaluation of extending shelf life in refrigerated storage] To evaluate the extension of the shelf life during refrigerated storage based on the performance of the dosimeter, the relationship between the administered dose [Gy] and the R² value [1 / s] was investigated for each storage period using refrigerated storage dosimeter 1, and the slope [1 / (s·Gy)] when these relationships were approximated by a straight line was measured. In the refrigerated dosimeter 1, the relationship between the storage period [Days] and the slope [1 / (s·Gy)] is shown in graph 80 of Figure 8.

[0089] As shown in Graph 80, the chilled dosimeter 1 did not show a decrease in its slope [1 / (s·Gy)] even after 30 days of chilled storage. Therefore, chilled dosimeter 1, when stored in a refrigerator, showed the same slope [1 / (s·Gy)] as it did 2 days after manufacture, even after 30 days, indicating that it is perfectly usable as a dosimeter.

[0090] As shown in Graphs 10-80, the room-temperature storage dosimeter 1 or refrigerated storage dosimeter 1 according to the manufacturing method or dosimeter composition of one embodiment of the present disclosure showed suppressed degradation of the reactivity of radiation polymerizable monomers, etc., compared to conventional dosimeters. Therefore, the dosimeter composition, dosimeter, etc. according to one embodiment of the present disclosure have excellent storage stability and were able to extend the shelf life compared to conventional dosimeters.

Claims

1. A method for producing a dosimeter composition comprising a radiation polymerizable compound and a matrix in which the radiation polymerizable compound is dispersed, A method for producing a dosimeter composition, comprising a mixing step of mixing at least a portion of a plurality of raw materials forming the dosimeter composition while supplying fine bubbles of an inert gas.

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

3. The raw materials include water and a gelling agent that form the matrix, and the radiation polymerizable compound and crosslinking agent. The method for producing a dosimeter composition according to claim 1, comprising the mixing step of 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. The raw materials include water and a gelling agent that form the matrix, and the radiation polymerizable compound and oxygen scavenger. A method for producing a dosimeter composition according to claim 1, further comprising an oxygen scavenger mixing step of mixing the oxygen scavenger with the mixture obtained in the mixing step, after the mixing step.

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

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

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

8. A matrix containing water and a gelling agent, Radiation polymerizable compounds, Fine bubbles of inert gas, A dosimeter composition containing the following:

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

10. The dosimeter composition according to claim 8, comprising 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 dosimeter composition 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 filling a radiation-transmitting storage container with the dosimeter composition described in any one of claims 8 to 12.

14. The dosimeter described in claim 13 is irradiated with a preset measuring radiation, The process of obtaining dose distribution data corresponding to the dose distribution of the measuring radiation received by the dosimeter by analyzing the dosimeter irradiated with the measuring radiation, A radiation verification method comprising the following features.

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

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