X-ray contrast agent kit, method for manufacturing an X-ray contrast agent, X-ray imaging method, and X-ray contrast agent

Abstract

To provide an X-ray contrast agent kit using a metal oxide sol that can obtain CT images with higher contrast and greater clarity. [Solution] The X-ray absorption coefficient at 12 keV is 10 cm -1 An X-ray contrast agent kit comprising a first reagent containing a metal oxide sol and a second reagent containing a gelling agent, wherein the volume change ratio after mixing the first reagent and the second reagent and gelling is 0.98 or more and 1.02 or less.

Description

[Technical Field] 【0001】 The present invention relates to an X-ray contrast agent kit, a method for producing an X-ray contrast agent, an X-ray imaging method, and an X-ray contrast agent. [Background technology] 【0002】 X-ray microcomputed tomography (CT) is a non-destructive technique for obtaining three-dimensional images of objects. Compared to MRI, X-ray micro-CT has a much higher resolution, and unlike fluorescence imaging, which observes sliced ​​specimens, it can image the entire tissue in three dimensions. Because X-ray micro-CT also has high spatial resolution, it is expected to be used in cutting-edge medical fields as a powerful 4D (three-dimensional + time) imaging technology. 【0003】 In X-ray micro-CT, when imaging biological tissues such as capillaries, a technique is used in which acrylic angiographic contrast agents are injected into blood vessels, molded, and then imaged to obtain clear images of their fine structure. Organic polymer-based contrast agents (for example, acrylic angiographic contrast agents such as Batson's #17 Anatomical Corrosion Kit (Polysciences) and Mercox II resin (Ladd)) are widely used as such injection contrast agents, but the contrast is insufficient. Therefore, a technique is known to improve contrast by performing a degreasing (tissue dissociation) process to remove the tissue surrounding the blood vessels using a base such as KOH. However, this process can damage or destroy fragile capillaries, making it difficult to obtain clear images. 【0004】 Patent Document 1 discloses an X-ray contrast agent comprising layered double hydroxide nanoparticles and a dispersion medium, wherein the layered double hydroxide nanoparticles are stably dispersed in the dispersion medium at a concentration of 100 mg / mL or more. In addition, Patent Document 1 discloses that according to the X-ray contrast agent, nanoparticles of a layered double hydroxide having fine and high X-ray absorption ability are stably dispersed in a dispersion medium at a high concentration of 100 mg / mL or more, so that high and / or uniform contrast can be achieved. 【Prior Art Document】 【Patent Document】 【0005】 【Patent Document 1】 Japanese Patent Application Laid-Open No. 2021-17419 【Summary of the Invention】 【Problems to be Solved by the Invention】 【0006】 The present inventors have intensively studied X-ray contrast agents. As a result, it has been found that higher contrast can be obtained by using a metal oxide sol having a large X-ray absorption coefficient. 【0007】 However, a contrast agent using a metal oxide sol has high fluidity in defective tissues, and the contrast agent may be biased during X-ray imaging. Furthermore, new problems have arisen, such as the contrast agent leaking from blood vessels into tissues, resulting in an inability to obtain clear CT images. 【0008】 The present invention has been made in view of the above-described problems, and an object thereof is to provide an X-ray contrast agent using a metal oxide sol, an X-ray contrast agent kit, which have higher contrast and can obtain clear CT images. Another object is to provide a method for producing the X-ray contrast agent. Still another object is to provide an X-ray imaging method using the X-ray contrast agent and the X-ray contrast agent kit. 【Means for Solving the Problems】 【0009】 The first aspect of the present invention provides the following. [1] A first reagent containing a metal oxide sol having an X-ray absorption coefficient of 10 cm -1 or more at 12 keV, and A second reagent containing a gelling agent and comprising An X-ray contrast agent kit, characterized in that the volume change ratio after mixing the first reagent and the second reagent to cause gelation is 0.98 or more and 1.02 or less. 【0010】 According to the X-ray contrast agent kit, a gellable X-ray contrast agent can be obtained by mixing the first reagent and the second reagent. The X-ray contrast agent obtained by mixing the first reagent and the second reagent uses a metal oxide sol having an X-ray absorption coefficient of 10 cm -1 or more at 12 keV, so that a CT image having a higher contrast can be obtained. Further, since the first reagent and the second reagent are mixed to gelate the metal oxide sol into an X-ray contrast agent, it is possible to suppress the contrast agent from being biased within the defective tissue. Also, it is possible to suppress the X-ray contrast agent from leaking from the blood vessel into the tissue. As a result, a clear CT image can be obtained. In addition, the volume change ratio after mixing the first reagent and the second reagent to cause gelation is 0.98 or more and 1.02 or less, and the volume change is small compared to before gelation. Since the shrinkage amount during gelation is small, it is possible to suppress the formation of a gap between the blood vessel membrane. As a result, the image accuracy can be improved. 【0011】 Furthermore, the first aspect of the present invention provides the following. [2] The X-ray contrast agent kit according to [1], wherein the metal oxide sol is a ceria sol. 【0012】 Ceria sol has a higher X-ray absorption coefficient among metal oxide sols. Therefore, when the metal oxide sol is a ceria sol, a CT image having an even higher contrast can be obtained. 【0013】 Furthermore, the first aspect of the present invention provides the following. [3] The X-ray contrast agent kit according to [2], characterized in that the CeO2 concentration in the first reagent is 10% by mass or more and 35% by mass or less. 【0014】 If the CeO2 concentration in the first reagent is 10% by mass or more and 35% by mass or less, a CT image with even higher contrast can be obtained due to the concentration effect. 【0015】 Furthermore, the first invention provides the following: [4] An X-ray contrast agent kit according to any one of [1] to [3] above, characterized in that the average particle size of the metal oxide sol is 4 nm or more and 14 nm or less. 【0016】 When the average particle size of the metal oxide sol is 4 nm or more and 14 nm or less, it can be suitably gelled when mixed with the gelling agent. 【0017】 Furthermore, the first invention provides the following: [5] NO3 in the first reagent - An X-ray contrast agent kit according to any one of the above [1] to [4], characterized in that the molar ratio of / CeO2 is 0.00258 or more and 0.00260 or less. 【0018】 NO3 in the first reagent - The metal oxide sol can be stabilized if the molar ratio of / CeO2 is between 0.00258 and 0.00260. 【0019】 Furthermore, the first invention provides the following: [6] The X-ray contrast agent kit according to any one of [1] to [5] above, characterized in that the viscosity of the first reagent at 25°C is 10 mPa·s or less. 【0020】 If the viscosity of the first reagent at 25°C is 10 mPa·s or less, the X-ray contrast agent can be easily filled into biological tissue before gelation. 【0021】 Furthermore, the first invention provides the following: [7] The X-ray contrast agent kit according to any one of [1] to [6] above, characterized in that the gelling agent is one or more selected from the group consisting of urea, itaconic acid, and hexamethylenetetramine. 【0022】 If the gelling agent is one or more selected from the group consisting of urea, itaconic acid, and hexamethylenetetramine, the metal oxide sol can be suitably gelled. 【0023】 Furthermore, the first invention provides the following: [8] An X-ray contrast agent kit according to any one of [1] to [7], characterized in that the viscosity after mixing the first reagent and the second reagent and waiting for 1 minute at 25°C is 300 mPa·s or less. 【0024】 If the viscosity after mixing the first reagent and the second reagent and allowing 1 minute at 25°C is 300 mPa·s or less, the X-ray contrast agent can be easily filled into biological tissue before gelation. 【0025】 Furthermore, the first invention provides the following: [9] Step 1 of preparing the X-ray contrast agent kit described in any one of [1] to [8] above, A method for producing an X-ray contrast agent, characterized by comprising step 2 of mixing the first reagent and the second reagent. 【0026】 By mixing the first reagent and the second reagent, a gellable X-ray contrast agent can be obtained. 【0027】 Furthermore, the first invention provides the following:

[10] Step 3 of preparing the X-ray contrast agent kit described in any one of [1] to [8] above, Step 4 involves mixing the first reagent and the second reagent to obtain an X-ray contrast agent, Step 5 involves injecting the obtained X-ray contrast agent into the specimen, Step 6 involves gelling the X-ray contrast agent injected into the specimen, Step 7 involves performing X-ray imaging on the sample after the X-ray contrast agent has been gelled. An X-ray imaging method characterized by including [a certain element]. 【0028】 According to the above-described X-ray imaging method, an X-ray contrast agent obtained by mixing the first reagent and the second reagent is injected into the specimen, the X-ray contrast agent injected into the specimen is gelled, and X-ray imaging is performed on the specimen after gelling. The X-ray contrast agent obtained by mixing the first reagent and the second reagent has an X-ray absorption coefficient of 10 cm at 12 keV. -1 Because the above-mentioned metal oxide sol is used, CT images with higher contrast can be obtained. Furthermore, by mixing the first reagent and the second reagent and gelling the metal oxide sol to form an X-ray contrast agent, it is possible to suppress uneven distribution of the contrast agent within the defective tissue. In addition, it is possible to suppress the leakage of the X-ray contrast agent from blood vessels into the tissue. As a result, clear CT images can be obtained. Furthermore, the volume change after mixing the first reagent and the second reagent and allowing them to gel is between 0.98 and 1.02, indicating less volume change compared to before gelation. Because the amount of shrinkage during gelation is small, the formation of gaps between the reagent and the vascular membrane can be suppressed. As a result, image accuracy can be improved. 【0029】 Furthermore, the second aspect of the present invention provides the following:

[11] The X-ray absorption coefficient at 12 keV is 10 cm -1 The above metal oxide sols and Gelling agent and Includes, An X-ray contrast agent characterized by having a volume change ratio of 0.98 to 1.02 after gelation. 【0030】 The aforementioned X-ray contrast agent contains a metal oxide sol and a gelling agent, and is therefore capable of gelling. The aforementioned X-ray contrast agent has an X-ray absorption coefficient of 10 cm² at 12 keV. -1Because it contains the above-mentioned metal oxide sol, a CT image with higher contrast can be obtained. Furthermore, because the X-ray contrast agent contains a gelling agent, it can suppress the uneven distribution of the contrast agent within the defective tissue. It can also suppress the leakage of the X-ray contrast agent from blood vessels into the tissue. As a result, clear CT images can be obtained. Furthermore, the volume change after gelation is between 0.98 and 1.02, indicating less volume change compared to before gelation. Because the amount of shrinkage during gelation is small, the formation of gaps between the material and the vascular membrane can be suppressed. As a result, image accuracy can be improved. 【0031】 Furthermore, the second aspect of the present invention provides the following:

[12] The X-ray contrast agent according to

[11] , characterized in that the metal oxide sol is a ceria sol. 【0032】 If the metal oxide sol is a ceria sol, a CT image with even higher contrast can be obtained. 【0033】 Furthermore, the second aspect of the present invention provides the following:

[13] The X-ray contrast agent according to

[12] , characterized in that the CeO2 concentration is 25% by mass or more and 35% by mass or less. 【0034】 When the CeO2 concentration is 25% by mass or higher, a CT image with even higher contrast can be obtained due to the concentration effect. 【0035】 Furthermore, the second aspect of the present invention provides the following:

[14] The X-ray contrast agent according to any one of

[11] to

[13] , characterized in that the average particle size of the metal oxide sol is 4 nm or more and 14 nm or less. 【0036】 When the average particle size of the metal oxide sol is 4 nm or more and 14 nm or less, it can be suitably gelled when mixed with the gelling agent. 【0037】 Furthermore, the second invention provides the following.

[15] NO3 - The X-ray contrast agent according to any one of

[11] to

[14] above, characterized in that the NO3 / CeO2 molar ratio is 0.00258 or more and 0.00260 or less. 【0038】 NO3 - When the NO3 / CeO2 molar ratio is 0.00258 or more and 0.00260 or less, the metal oxide sol can be stabilized. 【0039】 Furthermore, the second invention provides the following. The X-ray contrast agent according to any one of

[11] to

[16] above, characterized in that the gelling agent is one or more selected from the group consisting of urea, itaconic acid, and hexamethylenetetramine. 【0040】 When the gelling agent is one or more selected from the group consisting of urea, itaconic acid, and hexamethylenetetramine, the metal oxide sol can be preferably gelled. 【0041】 Furthermore, the second invention provides the following.

[17] Step 8 of preparing the X-ray contrast agent according to any one of

[11] to

[16] above; Step 9 of injecting the X-ray contrast agent into a specimen; Step 10 of gelling the X-ray contrast agent injected into the specimen; An X-ray imaging method comprising Step 11 of performing X-ray imaging on the specimen after gelling the X-ray contrast agent. 【0042】 According to the X-ray imaging method, an X-ray contrast agent is injected into a specimen, the X-ray contrast agent injected into the specimen is gelled, and X-ray imaging is performed on the specimen after gelling. The X-ray contrast agent contains a metal oxide sol having an X-ray absorption coefficient of 10 cm -1 or more at 12 keV, so that a CT image having a higher contrast can be obtained. Furthermore, because the X-ray contrast agent contains a gelling agent, it can suppress the uneven distribution of the contrast agent within the defective tissue. It can also suppress the leakage of the X-ray contrast agent from blood vessels into the tissue. As a result, clear CT images can be obtained. Furthermore, the volume change after gelation is between 0.98 and 1.02, indicating less volume change compared to before gelation. Because the amount of shrinkage during gelation is small, the formation of gaps between the material and the vascular membrane can be suppressed. As a result, image accuracy can be improved. [Effects of the Invention] 【0043】 According to the present invention, it is possible to provide an X-ray contrast agent using a metal oxide sol and an X-ray contrast agent kit that can obtain CT images with higher contrast and greater clarity. Furthermore, it is possible to provide a method for manufacturing the X-ray contrast agent. Furthermore, it is possible to provide an X-ray imaging method using the X-ray contrast agent and the X-ray contrast agent kit. [Brief explanation of the drawing] 【0044】 [Figure 1] This is a cross-sectional image obtained by X-ray micro-CT using the X-ray contrast agent in Example 2. [Modes for carrying out the invention] 【0045】 Embodiments of the present invention will be described below. However, the present invention is not limited to these embodiments. In this specification, the expressions "containing" and "including" include the concepts of "containing," "including," "substantially consisting of," and "consisting only of." Also, unless otherwise specified, "%" means mass percent. 【0046】 The maximum and minimum values ​​of the content of each component shown below are, independently of the content of other components, the preferred maximum and preferred minimum values ​​of the present invention. Furthermore, the maximum and minimum values ​​of the various parameters (measured values, etc.) shown below are, independently of the content (composition) of each component, the preferred maximum and minimum values ​​of the present invention. 【0047】 The following describes embodiments of the X-ray contrast agent kit corresponding to the first aspect of the present invention. However, the X-ray contrast agent kit of the first aspect of the present invention is not limited to the following examples. 【0048】 [X-ray contrast agent kit] The X-ray contrast agent kit according to this embodiment is The X-ray absorption coefficient at 12 keV is 10 cm -1 The first reagent, which contains the metal oxide sol described above, Second reagent containing a gelling agent and Equipped with, The volume change ratio after mixing the first reagent and the second reagent and allowing them to gel is between 0.98 and 1.02. 【0049】 The X-ray contrast agent kit comprises the first reagent and the second reagent. The first reagent is housed in a container (hereinafter also referred to as container A). The second reagent is housed in another container (hereinafter also referred to as container B). In the X-ray contrast agent kit according to this embodiment, a gellable X-ray contrast agent can be obtained by mixing the first reagent contained in container A and the second reagent contained in container B. 【0050】 The containers A and B are not particularly limited as long as they are capable of containing the first reagent and the second reagent, respectively, and examples include glass, resin, metal, and paper containers. Specifically, examples include ampoules, vials, syringes, and cartridges. 【0051】 As for the mixing method, the second reagent may be added to and mixed with container A containing the first reagent, or the first reagent may be added to and mixed with container B containing the second reagent. Alternatively, the first reagent and the second reagent may be placed in a separately prepared container and mixed. 【0052】 The first reagent has an X-ray absorption coefficient of 10 cm at 12 keV. -1 The above includes metal oxide sols. The X-ray absorption coefficient at 12 keV is 10 cm -1 Since the first reagent contains the metal oxide sol described above, using the X-ray contrast agent obtained by mixing the first reagent and the second reagent allows for the acquisition of CT images with higher contrast. 【0053】 The X-ray absorption coefficient of the metal oxide sol at 12 keV is preferably 15 cm⁻¹. -1 More preferably 30cm -1 More preferably 40 cm -1 The above, and especially preferably 43 cm -1 In particular, 45 cm -1 In particular, 47 cm is preferred. -1 That's all. The X-ray absorption coefficient of the metal oxide sol at 12 keV is preferably as large as possible, for example, 120 cm². -1 Below, 110cm -1 Below, 100cm -1 Below, 90cm -1 The following are some examples. The X-ray absorption coefficient of the metal oxide sol at 12 keV is preferably 15 cm⁻¹. -1 More than 120cm -1 More preferably 30cm -1 More than 110cm -1 Further preferably 40 cm -1 More than 100cm -1 The following is particularly preferable: 43 cm -1 More than 90cm -1 The following is particularly preferable: 45 cm -1 More than 90cm -1The following applies: 【0054】 The aforementioned metal oxide sol has an X-ray absorption coefficient of 10 cm at 12 keV. -1 The above are not particularly limited, but for example, CeO2 (36.1), ZrO2 (15.6), Fe2O3 (32.2), Co3O4 (36.1), CuO (45.9), ZnO (50.1), HfO2 (79.6), WO3 (68.6), PtO2 (62.7), Au2O3 (67.7), La2O3 (43.3), Pr6O 11 Examples include combinations of two or more of the following: (47.2), Nd2O3 (51.1), Yb2O3 (76.1). The numbers in parentheses after each oxide listed above represent the X-ray absorption coefficient at 12 keV for a 30% concentration sol. For example, "Yb2O3 (76.1)" indicates that the X-ray absorption coefficient of a 30% concentration Yb2O3 sol is 76.1. In particular, ceria sols and zirconia sols using CeO2 and ZrO2 are preferred as X-ray contrast agents because they are stable in the concentration range of this invention and exhibit excellent uniformity after gelation. Furthermore, if the metal oxide sol is a ceria sol, it is even more preferable because it allows for the acquisition of CT images with high contrast. 【0055】 The concentration of the metal oxide sol in the first reagent is preferably 20% by mass or more and 40% by mass or less in terms of oxide. If the concentration of the metal oxide sol in the first reagent is 20% by mass or higher, a CT image with even higher contrast can be obtained due to the concentration effect. The concentration of the metal oxide sol in the first reagent is more preferably 30% by mass or more, and even more preferably 35% by mass or more. The concentration of the metal oxide sol in the first reagent is more preferably 37% by mass or less, and even more preferably 36% by mass or less. The concentration of the metal oxide sol in the first reagent is more preferably 30% by mass or more and 37% by mass or less, and even more preferably 30% by mass or more and 36% by mass or less. 【0056】 When the metal oxide sol is a ceria sol, the CeO2 concentration in the first reagent is preferably 10% by mass or more and 50% by mass or less. If the CeO2 concentration in the first reagent is 10% by mass or higher, a CT image with even higher contrast can be obtained due to the concentration effect. When the metal oxide sol is a ceria sol, the CeO2 concentration in the first reagent is more preferably 27% by mass or more, even more preferably 29% by mass or more, and particularly preferably 30% by mass or more. When the metal oxide sol is a ceria sol, the CeO2 concentration in the first reagent is more preferably 40% by mass or less, even more preferably 35% by mass or less, and particularly preferably 33% by mass or less. When the metal oxide sol is a ceria sol, the CeO2 concentration in the first reagent is more preferably 27% by mass or more and 40% by mass or less, even more preferably 29% by mass or more and 35% by mass or less, and particularly preferably 30% by mass or more and 33% by mass or less. 【0057】 The dispersion medium for the metal oxide sol is not particularly limited and includes water, methanol, ethanol, 2-propanol, acetone, dimethyl ether, and other hydrophilic organic solvents, as well as a mixture of one or more of the aforementioned hydrophilic organic solvents. Preferably, the dispersion medium for the metal oxide sol is water (pure water or deionized water). 【0058】 The first reagent preferably contains nitric acid. The inclusion of nitric acid in the first reagent allows the metal oxide sol to be stabilized in the dispersion medium. 【0059】 NO3 in the first reagent - The molar ratio of / CeO2 is preferably 0.00258 or higher and 0.00260 or lower. NO3 in the first reagent - The metal oxide sol can be stabilized if the molar ratio of / CeO2 is between 0.00258 and 0.00260. NO3 in the first reagent - The molar ratio of / CeO2 is more preferably 0.002585 or higher. NO3 in the first reagent - The molar ratio of / CeO2 is more preferably 0.002595 or less. NO3 in the first reagent - The molar ratio of / CeO2 is more preferably 0.002585 or higher and 0.002595 or lower. 【0060】 The pH of the dispersion medium for the metal oxide sol is not particularly limited, but is generally preferred to be 7 or less, and more preferably 3 to 6. 【0061】 The average particle size of the metal oxide sol is preferably 4 nm or more and 14 nm or less. When the average particle size of the metal oxide sol is 4 nm or more and 14 nm or less, it can be suitably gelled when mixed with the gelling agent. The average particle size of the metal oxide sol is determined by diluting the sol with deionized water to 1.0% by mass in terms of metal oxide, and then placing it in a device (dynamic light scattering particle size distribution analyzer ("Zetasizer Nano ZS", manufactured by Malvern Panalytical) to measure the particle size D 50 This refers to values ​​measured using the (volume frequency distribution criterion). <Measurement conditions> Measurement temperature: 25℃ Scattering angle: 173° Dispersed phase: The aforementioned metal oxide Dispersion medium: water Cell: Genuine disposable cell Number of repetitions: 3 (particle size D) 50 (This is the average of 3 measurements) 【0062】 The viscosity of the first reagent at 25°C is preferably 100 mPa·s or less. If the viscosity of the first reagent at 25°C is 100 mPa·s or less, the X-ray contrast agent can be easily filled into biological tissue before gelation. The viscosity of the first reagent at 25°C is more preferably 80 mPa·s or less, even more preferably 50 mPa·s or less, particularly preferably 30 mPa·s or less, especially preferably 10 mPa·s or less, and exceptionally preferably 5 mPa·s or less. The viscosity of the first reagent at 25°C should preferably be low, for example, 0.5 mPa·s or higher, 1 mPa·s or higher, 2 mPa·s or higher, 3 mPa·s or higher, etc. The viscosity of the first reagent at 25°C is more preferably 0.5 mPa·s to 80 mPa·s, even more preferably 1 mPa·s to 50 mPa·s, particularly preferably 1 mPa·s to 30 mPa·s, especially preferably 1 mPa·s to 10 mPa·s, and exceptionally preferably 1 mPa·s to 5 mPa·s. The viscosity mentioned above refers to the value obtained by the method described in the examples. 【0063】 The second reagent contains a gelling agent. Since the second reagent contains a gelling agent, the metal oxide sol can be gelled by mixing it with the first reagent. Because the metal oxide sol is gelled to form an X-ray contrast agent, uneven distribution of the contrast agent within the defective tissue can be suppressed. Furthermore, leakage of the X-ray contrast agent from blood vessels into the tissue can be suppressed. As a result, clear CT images can be obtained. 【0064】 The gelling agent is not particularly limited as long as it can gel the metal oxide sol, but it is preferably one or more selected from the group consisting of urea, itaconic acid, oxalic acid, malonic acid, succinic acid, and hexamethylenetetramine (HMTA). If the gelling agent is one or more selected from the group consisting of urea, itaconic acid, and hexamethylenetetramine, the metal oxide sol can be suitably gelled. 【0065】 When the gelling agent is urea or hexamethylenetetramine, the metal oxide sol can be gelled by increasing its pH. Urea and hexamethylenetetramine react with water in the metal oxide sol, generating ammonia over time. This ammonia generation changes the pH, reducing the positive charge on the particle surface of the metal oxide sol, decreasing interparticle repulsion, leading to aggregation and gelation. Because ammonia is generated over time, the initial viscosity is low, maintaining high fluidity, and after a certain period of time, it gels to a state suitable for contrast imaging. 【0066】 When the gelling agent is urea, the amount of gelling agent added is preferably 0.5 to 2.5 by weight relative to the solid content of the metal oxide sol. Setting it to 2.5 or less prevents the gelling rate from being too fast. Setting it to 0.5 or more results in a more suitable gelling rate. For example, if it is less than 0.5, gelling may not occur even after 90 hours. The weight ratio is more preferably 0.8 or higher, even more preferably 1.0 or higher, and particularly preferably 1.2 or higher. The aforementioned weight ratio is more preferably 2.4 or less, even more preferably 2.2 or less, and particularly preferably 2.0 or less. The weight ratio is more preferably 0.8 to 2.4, even more preferably 1.0 to 2.2, and particularly preferably 1.2 to 2.0. 【0067】 When the gelling agent is hexamethylenetetramine, the amount of gelling agent added is preferably 0.015 to 0.046 by weight relative to the solid content of the metal oxide sol. Setting it to 0.046 or less prevents the gelling rate from being too fast. Setting it to 0.015 or more results in a more suitable gelling rate. For example, if it is greater than 0.046, gelling may occur in about 10 minutes, making it unusable. For example, if it is less than 0.015, gelling may take 24 hours or more, making it unusable. The aforementioned weight ratio is more preferably 0.017 or higher, even more preferably 0.019 or higher, and particularly preferably 0.020 or higher. The weight ratio is more preferably 0.045 or less, even more preferably 0.040 or less, and particularly preferably 0.035 or less. The weight ratio is more preferably 0.017 to 0.045, even more preferably 0.019 to 0.040, and particularly preferably 0.020 to 0.035. 【0068】 When the gelling agent is itaconic acid, the metal oxide sol can be gelled by substituting itaconic acid with the nitric acid that stabilizes the metal oxide sol. The substitution of nitric acid with itaconic acid on the particle surface of the metal oxide sol reduces the repulsion between particles, leading to aggregation and gelation. The initial viscosity is low, high fluidity is maintained, and after a certain period of time, the substitution with nitric acid causes gelation, resulting in a state suitable for contrast imaging. 【0069】 When the gelling agent is itaconic acid, the amount of gelling agent added is preferably 0.015 to 0.15 by weight relative to the solid content of the metal oxide sol. A ratio of 0.015 or higher results in a more favorable gelling rate. For example, if the ratio is less than 0.015, gelling may not occur even after 96 hours, making the solution unusable. A ratio of 0.15 or lower prevents the gelling rate from becoming too fast. The aforementioned weight ratio is more preferably 0.017 or higher, and even more preferably 0.020 or higher. The aforementioned weight ratio is more preferably 0.14 or less, and even more preferably 0.13 or less. The weight ratio is more preferably 0.017 or more and 0.14 or less, and even more preferably 0.020 or more and 0.13 or less. 【0070】 In this specification, "gelled" means that when 3 ml of the mixture of the first reagent and the second reagent is placed in a screw-cap tube (manufactured by Maruemu Co., Ltd., model: 5-00.98-06, inner diameter × body diameter × total length: φ14.5 × φ24 × 50 mm) and tilted at a 45° angle, the surface of the mixture does not move (the surface tilts 45° from the horizontal as the screw-cap tube is tilted). 【0071】 In the aforementioned X-ray contrast agent kit, the volume change after mixing the first reagent and the second reagent and gelling is between 0.98 and 1.02. Because the volume change after mixing the first reagent and the second reagent and gelling is between 0.98 and 1.02, the volume change is small compared to before gelling. Since the amount of shrinkage during gelling is small, it is possible to suppress the formation of gaps between the contrast agent and the vascular membrane. As a result, image accuracy can be improved. 【0072】 The volume change ratio after mixing the first reagent and the second reagent and gelling is preferably as close to 1 as possible. The aforementioned volume change rate is preferably 0.99 or higher. The aforementioned volume change rate is preferably 1.01 or less. The aforementioned volume change rate is preferably 0.99 or more and 1.01 or less. The volume change rate mentioned above refers to the value obtained by the method described in the example. 【0073】 In the X-ray contrast agent kit, it is preferable that the viscosity after mixing the first reagent and the second reagent and allowing 1 minute to pass at 25°C is 300 mPa·s or less, and more preferably 100 mPa·s or less. If the viscosity after mixing the first reagent and the second reagent and allowing 1 minute at 25°C is 300 mPa·s or less, the X-ray contrast agent can be easily filled into biological tissue before gelation. 【0074】 After mixing the first reagent and the second reagent, the viscosity after 1 minute at 25°C is more preferably 50 mPa·s or less, and even more preferably 10 mPa·s or less. After mixing the first reagent and the second reagent, the viscosity after 1 minute at 25°C is preferably as low as possible, for example, 1 mPa·s or more, or 5 mPa·s or more. After mixing the first reagent and the second reagent, the viscosity after 1 minute at 25°C is more preferably 1 mPa·s to 100 mPa·s, even more preferably 1 mPa·s to 50 mPa·s, and particularly preferably 5 mPa·s to 10 mPa·s. The viscosity obtained after mixing the first reagent and the second reagent and allowing 1 minute to pass at 25°C is the value obtained by the method described in the examples. 【0075】 The following describes an example of a method for producing an X-ray contrast agent corresponding to the first aspect of the present invention. However, the method for producing an X-ray contrast agent according to the first aspect of the present invention is not limited to the following examples. 【0076】 [Method for manufacturing X-ray contrast agents] The method for producing the X-ray contrast agent according to this embodiment is as follows: Step 1 involves preparing the aforementioned X-ray contrast agent kit, The process includes step 2 of mixing the first reagent and the second reagent. 【0077】 <Process 1> First, prepare the X-ray contrast agent kit described above. 【0078】 <Process 2> Next, the first reagent and the second reagent are mixed. This yields an X-ray contrast agent (X-ray contrast agent before gelation) in which the first reagent and the second reagent are mixed. 【0079】 When mixing the first reagent and the second reagent, it is preferable to use temperature conditions that prevent immediate gelation after mixing. This allows the metal oxide sol to spread to every corner of the sample while maintaining high fluidity. The temperature conditions for mixing the first reagent and the second reagent can be set appropriately according to the compositions of the first and second reagents, but since use at room temperature is usually assumed, the temperature conditions for mixing are preferably 20°C to 35°C. 【0080】 The following describes an example of an X-ray imaging method corresponding to the first aspect of the present invention. However, the X-ray imaging method of the first aspect of the present invention is not limited to the following examples. 【0081】 [X-ray imaging method] The method for producing the X-ray contrast agent according to this embodiment is as follows: Step 3 involves preparing the aforementioned X-ray contrast agent kit, Step 4 involves mixing the first reagent and the second reagent to obtain an X-ray contrast agent, Step 5 involves injecting the obtained X-ray contrast agent into the specimen, Step 6 involves gelling the X-ray contrast agent injected into the specimen, Step 7 involves performing X-ray imaging on the sample after the X-ray contrast agent has been gelled. Includes. 【0082】 <Process 3> First, prepare the X-ray contrast agent kit described above. 【0083】 <Step 4> Next, the first reagent and the second reagent are mixed to obtain an X-ray contrast agent. 【0084】 <Process 5> Next, the X-ray contrast agent obtained in step 4 is injected into the specimen. 【0085】 <Process 6> Next, the X-ray contrast agent injected into the specimen is gelled. 【0086】 In step 4, it is preferable that the temperature conditions for mixing the first reagent and the second reagent are such that gelation does not occur immediately after mixing (as detailed in temperature condition A below). This allows the metal oxide sol to spread to every corner of the sample in step 5 while maintaining high fluidity. 【0087】 In step 5, the time required to inject the X-ray contrast agent into the specimen varies depending on the specimen, but is usually within the range of 5 minutes to 40 minutes. Therefore, in step 4, the temperature conditions for mixing the first reagent and the second reagent (hereinafter also referred to as "temperature condition A") are preferably such that the time from mixing the first reagent and the second reagent until gelation occurs is 5 minutes or more and 100 minutes or less. By allowing more than 5 minutes between mixing and gelation, the metal oxide sol can be spread to every corner of the sample in a highly fluid state during step 5. In other words, by completing step 5 before gelation occurs, the metal oxide sol can be spread to every corner of the sample in a highly fluid state. Furthermore, by limiting the gelation time to 100 minutes or less, the X-ray contrast agent can be quickly gelled in the next step 6. The time until gelation occurs is more preferably 10 minutes or more, and even more preferably 15 minutes or more. The time until gelation occurs is more preferably 80 minutes or less, and even more preferably 60 minutes or less. The time until gelation occurs is more preferably 10 minutes to 80 minutes, even more preferably 15 minutes to 60 minutes, particularly preferably 20 minutes to 60 minutes, and especially preferably 25 minutes to 50 minutes. 【0088】 The temperature condition A can be set appropriately according to the composition of the first and second reagents, but since the X-ray contrast agent obtained by mixing the first and second reagents is intended for use at room temperature, a temperature of 15°C to 30°C is preferred. The temperature condition A is more preferably 20°C or higher and 25°C or lower. 【0089】 After step 5, in step 6, one simply needs to wait until the X-ray contrast agent injected into the sample gels. Alternatively, heating (for example, heating to a temperature of 50°C or lower) may be performed as needed. 【0090】 The above explanation described the case where steps 3 through 6 are carried out at a constant temperature under temperature condition A. However, the X-ray imaging method according to this embodiment is not limited to this example. For example, under the above temperature condition A, step 4 may be set to a condition where gelation does not occur (or a condition where the gelation rate is very slow), and then in step 6, the condition may be changed to one where gelation proceeds rapidly. For example, in step 4, the temperature condition may be set to 2°C or higher and 25°C or lower, and then the temperature may be increased in step 6 to change it to a range of 30°C or higher and 60°C or lower. Furthermore, it is preferable that the viscosity of the X-ray contrast agent in step 4 does not exceed 100 mPa·s (it is less than 50 mPa·s) at that temperature. By making the viscosity of the X-ray contrast agent less than 100 mPa·s in step 4, it becomes easier to fill the biological tissue with the X-ray contrast agent. 【0091】 In step 5, the method for injecting the X-ray contrast agent into the specimen can be any conventionally known and available device (e.g., syringe, perfusion set, etc.) that is appropriate. The pressure used when injecting the X-ray contrast agent into the specimen should be set within a range that ensures the X-ray contrast agent reaches every corner of the specimen, and can be appropriately set within the range of 690 kPa to 2240 kPa. 【0092】 Examples of specimens include small animals or biological tissues extracted from living organisms. Examples of biological tissues include soft tissues, more specifically, vascular systems, tubular organs, tumors, etc. Examples of vascular systems include the vascular system (including the heart) and the lymphatic system (including lymph nodes). The vascular system includes the vascular system within the tumor. Examples of the tubular organs include the digestive tract, respiratory system, and urinary tract. Examples of the small animals include laboratory animals, specifically mice, rats, hamsters, guinea pigs, and rabbits. Examples of the laboratory animals include disease model animals, specifically circulatory disease model animals, digestive disease model animals, tumor model animals, and so on. 【0093】 <Process 7> Subsequently, X-ray imaging is performed on the sample after the X-ray contrast agent has been gelled. While there are no particular limitations as long as X-ray imaging can be performed, X-ray micro-CT is preferred from the viewpoint of high resolution and the ability to image the entire tissue in three dimensions. 【0094】 The method for producing an X-ray contrast agent according to this embodiment has been described above. 【0095】 Next, embodiments of the X-ray contrast agent corresponding to the second aspect of the present invention will be described. However, the X-ray contrast agent of the second aspect of the present invention is not limited to the following examples. 【0096】 The X-ray contrast agent of this embodiment differs from the X-ray contrast agent kit described above in that, while the X-ray contrast agent kit described above uses metal oxide sol and gelling agent as separate reagents without mixing them, the X-ray contrast agent of this embodiment uses metal oxide sol and gelling agent in a pre-mixed form. In other respects, they are similar. 【0097】 In other words, the X-ray contrast agent in this embodiment is a mixture of the first reagent and the second reagent in the X-ray contrast agent kit described above. The X-ray contrast agent in this embodiment is the same as the X-ray contrast agent kit described above, except that it is contained in a single container with a metal oxide sol and a gelling agent mixed together. Therefore, detailed explanations of the common points will be omitted as they would be redundant. 【0098】 [X-ray contrast agent] The X-ray contrast agent according to this embodiment is The X-ray absorption coefficient at 12 keV is 10 cm -1 The above metal oxide sols and Gelling agent and Includes, The volume change rate after gelation is between 0.98 and 1.02. 【0099】 The metal oxide sol is preferably a ceria sol. 【0100】 The CeO2 concentration of the X-ray contrast agent is preferably 10% by mass or more and 35% by mass or less. 【0101】 The average particle size of the metal oxide sol is preferably 4 nm or more and 14 nm or less. 【0102】 NO3 in the aforementioned X-ray contrast agent - The molar ratio of / CeO2 is preferably 0.00258 or higher and 0.00260 or lower. 【0103】 The gelling agent is preferably one or more selected from the group consisting of urea, itaconic acid, and hexamethylenetetramine. 【0104】 Next, an example of a method for producing an X-ray contrast agent corresponding to the second aspect of the present invention will be described. However, the method for producing an X-ray contrast agent according to the second aspect of the present invention is not limited to the following examples. 【0105】 [Method for manufacturing X-ray contrast agents] The method for producing the X-ray contrast agent according to this embodiment is as follows: Step 8 involves preparing the aforementioned X-ray contrast agent, Step 9 involves injecting the aforementioned X-ray contrast agent into the specimen, Step 10 involves gelling the X-ray contrast agent injected into the aforementioned specimen, Step 11: Performing X-ray imaging on the sample after the X-ray contrast agent has been gelled. Includes. 【0106】 <Process 8> First, prepare the X-ray contrast agent as described above. 【0107】 The gelation reaction between a metal oxide sol and a gelling agent is irreversible. Therefore, before use, the product should be stored under conditions that prevent the gelation reaction from proceeding between the metal oxide sol and the gelling agent. For example, it should be stored at a low temperature (e.g., refrigerated at 5°C or below). In step 8, an X-ray contrast agent is prepared that has been stored under conditions in which a gelling reaction does not proceed between the metal oxide sol and the gelling agent. 【0108】 <Process 9~Process 11> Steps 9 to 11 are the same as steps 5 to 7 described above, so their explanation is omitted here. Step 9 may be carried out at a low temperature, or it may be carried out after raising the temperature to the conditions under which the gelation reaction proceeds (temperature condition A). [Examples] 【0109】 The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist of the invention. 【0110】 The maximum and minimum values ​​of the content of each component shown in the following examples should be considered as the preferred maximum and minimum values ​​of the present invention, regardless of the content of other components. Furthermore, the maximum and minimum values ​​of the measurements shown in the following examples should be considered as preferred maximum and minimum values ​​of the present invention, regardless of the content (composition) of each component. 【0111】 [Preparation of X-ray contrast agent kits and X-ray contrast agents] (Example 1) As the first reagent, 3 ml of ceria sol (manufactured by Daiichi Rare Elements Chemical Industry Co., Ltd., CESL-30N) with a concentration of 30.2% by mass was prepared. Note that the first reagent contains nitric acid, and its content is shown in Table 1 as "NO3 - The molar ratio of CeO2 is as stated. Furthermore, the particle size of the ceria sol is as shown in Table 1. In addition, 0.20 ml of a 1.0 mol / L hexamethylenetetramine aqueous solution was prepared as the second reagent. Both the first and second reagents were prepared at room temperature. This set of the first reagent and the second reagent was designated as the X-ray contrast agent kit according to Example 1. 【0112】 The first and second reagents prepared were mixed at room temperature (25°C). This mixture was used as the X-ray contrast agent according to Example 1. 【0113】 (Example 2) The X-ray contrast agent kit and X-ray contrast agent according to Example 2 were obtained in the same manner as in Example 1, except that 0.3 ml of 0.7 mol / L itaconic acid aqueous solution was prepared as the second reagent instead of 1.0 mol / L hexamethylenetetramine aqueous solution. 【0114】 (Example 3) The X-ray contrast agent kit and X-ray contrast agent according to Example 3 were obtained in the same manner as in Example 1, except that 3 ml of 30.2% by mass ceria sol (Daiichi Rare Elements Chemical Industry Co., Ltd., CESL-16) was prepared as the first reagent instead of 30.2% by mass ceria sol (Daiichi Rare Elements Chemical Industry Co., Ltd., CESL-30N). 【0115】 (Example 4) An X-ray contrast agent kit and an X-ray contrast agent according to Example 4 were obtained in the same manner as in Example 1, except that the amount of 1.0 mol / L hexamethylenetetramine aqueous solution as the second reagent was changed to 0.1 ml. 【0116】 (Example 5) As the first reagent, 3 ml of ceria sol (manufactured by Daiichi Rare Elements Chemical Industry Co., Ltd., CESL-30N) with a concentration of 30.2% by mass was prepared. Note that the first reagent contains nitric acid, and its content is shown in Table 1 as "NO3 - The molar ratio of CeO2 is as stated. Furthermore, the particle size of the ceria sol is as shown in Table 1. In addition, 0.03 mol of solid urea was prepared as a second reagent. Both the first and second reagents were prepared at room temperature. This set of the first reagent and the second reagent was designated as the X-ray contrast agent kit according to Example 5. 0.03 mol of urea (solid), which was the second reagent, was dissolved in the prepared first reagent at room temperature, and this was used as the X-ray contrast agent according to Example 5. 【0117】 (Example 6) An X-ray contrast agent kit and an X-ray contrast agent according to Example 6 were obtained in the same manner as in Example 1, except that 3 ml of ceria sol (CESL-30N, manufactured by Daiichi Rare Elements Chemical Industry Co., Ltd.) with a concentration of 25% by mass was used as the first reagent. 【0118】 (Example 7) As the first reagent, 3 ml of zirconia sol with a concentration of 29.7% by mass (manufactured by Daiichi Rare Elements Chemical Industry Co., Ltd., as described in Example 1 of Patent No. 6732947) was prepared. In addition, 1.5 ml of a 0.7 mol / L itaconic acid aqueous solution was prepared as a second reagent. This set of the first reagent and the second reagent was designated as the X-ray contrast agent kit according to Example 7. 【0119】 The first and second reagents prepared were mixed. This mixture was used as the X-ray contrast agent according to Example 7. 【0120】 (Example 8) An X-ray contrast agent kit and an X-ray contrast agent according to Example 8 were obtained in the same manner as in Example 1, except that 3 ml of ceria sol (CESL-30N, manufactured by Daiichi Rare Elements Chemical Industry Co., Ltd.) with a concentration of 10% by mass was used as the first reagent. 【0121】 (Comparative Example 1) An X-ray contrast agent kit and an X-ray contrast agent according to Comparative Example 1 were obtained in the same manner as in Example 1, except that 3 ml of ceria sol (CESL-30N, manufactured by Daiichi Rare Elements Chemical Industry Co., Ltd.) with a concentration of 5% by mass was used as the first reagent. 【0122】 (Comparative Example 2) An X-ray contrast agent kit and X-ray contrast agent according to Comparative Example 2 were obtained in the same manner as in Example 1, except that the amount of 1.0 mol / L hexamethylenetetramine aqueous solution as the second reagent was changed to 0.5 ml. Heterogeneous aggregation occurred during gelation. 【0123】 (Comparative Example 3) An X-ray contrast agent kit and X-ray contrast agent according to Comparative Example 3 were obtained in the same manner as in Example 1, except that 3 ml of a 30% by mass titania complex sol (manufactured by Nissan Chemical Corporation, Nano-Use OT-RA305W7-20) was used as the first reagent. 【0124】 (Comparative Example 4) An X-ray contrast agent kit and X-ray contrast agent according to Comparative Example 4 were obtained in the same manner as in Example 1, except that 3 ml of alumina sol (manufactured by Nissan Chemical Corporation, Alumina Sol 520-A) with a concentration of 20.5% by mass was used as the first reagent. 【0125】 (Comparative Example 5) An X-ray contrast agent kit and X-ray contrast agent according to Comparative Example 5 were obtained in the same manner as in Example 1, except that 1 ml of a 30% by mass aqueous solution of polyvinyl alcohol was used as the second reagent instead of a 1.0 mol / L aqueous solution of hexamethylenetetramine. 【0126】 [Calculation of X-ray absorption coefficient] X-ray absorption coefficient of the first reagent (sol) (μ:cm ―1 The X-ray absorption coefficient of the contrast agent after mixing the first and second reagents was calculated using the following formula. The X-ray absorption coefficient was calculated assuming that only metal oxides absorb X-rays. The results are shown in Table 1. 【0127】 【number】 【0128】 Here, ρ is density, Z is atomic number, A is atomic mass, and E is X-ray energy (12 keV). 【0129】 [Viscosity measurement] The viscosity of the first reagent (viscosity of the first reagent before mixing with the second reagent) was measured. Additionally, under room temperature (25°C) conditions, the viscosity was measured 1 minute after mixing the first and second reagents. Viscosity was measured using a tuning fork vibrating viscometer (manufactured by A&D Co., Ltd., product name: SV-10), under the following measurement conditions. The results are shown in Table 1. The viscosity of the first reagent before mixing with the second reagent is shown in the "Before Addition of Gelling Agent" column, and the viscosity after 1 minute following the mixing of the first and second reagents is shown in the "1 Minute After Addition of Gelling Agent" column. Measurements using a tuning fork vibrating viscometer were performed at room temperature (25°C), and the instrument was calibrated using a viscosity standard solution. Viscosity (mPa·s) was calculated by dividing the measurement data by the density of the sample. <Viscosity measurement conditions> Viscometer type: Tuning fork type vibrating viscometer Measurement temperature: 25℃ 【0130】 [Percentage change in volume] The rate of volume change was calculated using the following formula. [Volume change rate] = (Volume after gelation) / (Volume immediately after mixing the first and second reagents) 【0131】 In the above formula, "volume immediately after mixing the first reagent and the second reagent" is the value measured by placing the mixture in a graduated cylinder immediately after mixing the first reagent and the second reagent at 25°C. 【0132】 Furthermore, in the above formula, "volume after gelation" refers to the volume after complete gelation is completed in the graduated cylinder at 25°C, and is the value measured in the graduated cylinder. 【0133】 The results are shown in Table 1. If gelation did not occur or the sample appeared opaque to the naked eye, measurement was impossible, and therefore, "―" is indicated in the table. Furthermore, if the gelled material cracked, measurement was impossible, and therefore indicated with "-" in the table. When cracking occurs, there is significant shrinkage or expansion, and the volume change rate deviates significantly from 1. 【0134】 [Gellation conditions] The X-ray contrast agents (mixtures of the first and second reagents) of Examples 1-8 were gelled under the conditions (temperature, time) listed in Table 1. For example, the X-ray contrast agent of Example 1 gelled after 40 minutes at 25°C following the mixing of the first and second reagents, and was transparent upon visual observation. In addition, the X-ray contrast agent in Example 6 (a mixture of the first and second reagents) did not gel even after 100 days under conditions of 2°C, but it did gel when the temperature was subsequently increased to 25°C. 【0135】 For reference, when the X-ray contrast agent of Example 1 (a mixture of the first and second reagents) was gelled at 37°C for 15 minutes, cracks appeared. Furthermore, when the X-ray contrast agent of Example 1 (a mixture of the first and second reagents) was gelled at 50°C for 15 minutes, cracks appeared. 【0136】 [CT scan] A silica glass capillary tube (100 μm inner diameter, 375 μm outer diameter), simulating a blood vessel, was filled with the sample (X-ray contrast agent before gelation) immediately after mixing the first and second reagents. Gas pressure was applied to the solution to fill the sample. The gas pressure was applied by the experimenter using a syringe (approximately 600 kPa). Subsequently, to prevent evaporation of the sample due to contact with air, the top end of the capillary tube was sealed with clay, and the sample was gelled under the gelation conditions described above. The tube was then sealed until immediately before imaging. Images were taken using 12 keV monochromatic X-rays at the synchrotron radiation facility (Saga Prefectural Kyushu Synchrotron Radiation Research Center (SAGA-LS)), beamline (BL-07). As a result, high-contrast images were obtained in the examples. Furthermore, no gaps or other defects were observed between the capillary tube and the sample, resulting in high-precision images. Figure 1 shows a cross-sectional image obtained by X-ray micro-CT using an X-ray contrast agent in Example 2. Although not shown, similar images were obtained in the other examples as in Example 2. 【0137】 [Table 1]

Claims

[Claim 1] The X-ray absorption coefficient at 12 keV is 10 cm －１ The first reagent contains the metal oxide sol and nitric acid described above, Second reagent containing a gelling agent and Equipped with, The volume change ratio after mixing the first reagent and the second reagent and gelling is 0.98 or more and 1.02 or less. An X-ray contrast agent kit characterized in that the gelling agent is one or more selected from the group consisting of urea, itaconic acid, and hexamethylenetetramine. [Claim 2] The X-ray contrast agent kit according to claim 1, characterized in that the metal oxide sol is a ceria sol. [Claim 3] CeO in reagent 1 ２ The X-ray contrast agent kit according to claim 2, characterized in that the concentration is 10% by mass or more and 35% by mass or less. [Claim 4] The X-ray contrast agent kit according to claim 2, characterized in that the average particle size of the metal oxide sol is 4 nm or more and 14 nm or less. [Claim 5] NO in the first reagent ３ － / CEO ２ The X-ray contrast agent kit according to claim 2, characterized in that the molar ratio is 0.00258 or more and 0.00260 or less. [Claim 6] The X-ray contrast agent kit according to claim 2, characterized in that the viscosity of the first reagent at 25°C is 10 mPa·s or less. [Claim 7] The X-ray contrast agent kit according to claim 1 or 2, characterized in that the viscosity after mixing the first reagent and the second reagent and elapsed at 25°C for 1 minute is 300 mPa·s or less. [Claim 8] Step 1 involves preparing the X-ray contrast agent kit according to claim 1 or 2, A method for producing an X-ray contrast agent, characterized by comprising step 2 of mixing the first reagent and the second reagent. [Claim 9] Step 3 of preparing the X-ray contrast agent kit according to claim 1 or 2, Step 4 involves mixing the first reagent and the second reagent to obtain an X-ray contrast agent, Step 5 involves injecting the obtained X-ray contrast agent into the specimen, Step 6 involves gelling the X-ray contrast agent injected into the aforementioned specimen, Step 7 involves performing X-ray imaging on the sample after the X-ray contrast agent has been gelled. Includes, The X-ray imaging method is characterized in that the specimen is a small animal or living tissue extracted from outside the body. [Claim 10] The X-ray absorption coefficient at 12 keV is 10 cm －１ The above metal oxide sols and Gelling agent and Nitric acid and Includes, The volume change rate after gelation is between 0.98 and 1.

02. An X-ray contrast agent characterized in that the gelling agent is one or more selected from the group consisting of urea, itaconic acid, and hexamethylenetetramine. [Claim 11] The X-ray contrast agent according to claim 10, characterized in that the metal oxide sol is a ceria sol. [Claim 12] CEO ２ The X-ray contrast agent according to claim 11, characterized in that its concentration is 10% by mass or more and 35% by mass or less. [Claim 13] The X-ray contrast agent according to claim 11, characterized in that the average particle size of the metal oxide sol is 4 nm or more and 14 nm or less. [Claim 14] NO ３ － / CeO ２ The X-ray contrast agent according to claim 11, wherein the molar ratio is 0.00258 or more and 0.00260 or less. [Claim 15] Step 8 of preparing the X-ray contrast agent according to claim 10 or 11, Step 9 involves injecting the aforementioned X-ray contrast agent into the specimen, Step 10 involves gelling the X-ray contrast agent injected into the specimen, Step 11: Performing X-ray imaging on the sample after the X-ray contrast agent has been gelled. Includes, The X-ray imaging method is characterized in that the specimen is a small animal or living tissue extracted from outside the body.

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