Boron particles for boron pharmaceuticals, method for producing the same, and pharmaceutical for neutron capture therapy containing boron particles for boron pharmaceuticals

Abstract

To provide boron particles for boron pharmaceuticals for use in boron neutron capture therapy that enhances therapeutic efficiency by incorporating boron into boron pharmaceuticals, while achieving a significant reduction in production costs.SOLUTION: The present invention provides boron particles for boron pharmaceuticals for use in boron neutron capture therapy. The boron particles for boron pharmaceuticals have the surface of boron particles covered with a boron nitride layer, with their average particle size of 10-300 nm. The surface of the boron nitride layer is modified with an organic molecule or a macromolecule, which is a biocompatible polymer.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to boron particles for use in boron neutron capture therapy, a method for producing the same, and a drug for neutron capture therapy containing the boron particles for use in boron neutron capture therapy. [Background technology]

[0002] Boron neutron capture therapy (hereinafter referred to as BNCT) is a clinically applied method for treating brain tumors. This method involves injecting boron (mainly boron ions) with high neutron capture ability into the tumor site. 10 B) and irradiating it with neutrons, which triggers a nuclear reaction that only reaches tumor cells of a certain size. This method makes it possible to selectively kill only tumor cells. This method is particularly effective for tumors that grow in a pervasive manner, such as brain tumors, and is known to have a good prognosis. This method is also being considered for use in tumors that occur in areas other than brain tumors where surgery is difficult (such as the head and neck, spleen, and pancreas), and for tumors such as bladder epithelial cancer, which are known to have a poor prognosis.

[0003] The boron drugs used in this BNCT include: (1) boron atoms (isotopes with neutral capture ability) 10 B), (2) selective accumulation in tumor cells, and (3) low toxicity. Currently, two types of boron drugs are known to be in clinical use: BPA (boron-phenylalanine), which contains one boron atom in a molecule in which the boron atom is bound to the amino acid phenylalanine, and BSH (mercaptoundecahydrododecaborate), which contains 12 boron atoms in a molecule in which the boron atoms are arranged in a cage shape.

[0004] In addition, much research is being conducted on the boron agents used in BNCT with the aim of improving their performance, and various new compounds have been developed, including boron carbide nanoparticles (Patent Document 1), nanosilica particles containing boron isotopes (Patent Document 2), and carbon nanohorns containing boron compounds (Patent Document 3). 10 There are known examples of using particles containing B as boron drugs. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2008-266126 [Patent Document 2] Japanese Patent Application Publication No. 2019-163229 [Patent Document 3] International Publication No. 2015 / 156385 Summary of the Invention [Problem to be solved by the invention]

[0006] To improve the therapeutic efficiency of BNCT, it is necessary to increase the boron concentration in tumor cells, and boron drugs containing higher concentrations of boron are needed.

[0007] However, BPA is taken up into cells via amino acid transporters, making it difficult to retain large amounts within tumor cells. Since each molecule contains only one boron atom, large doses are required to deliver and retain the necessary boron within tumor cells, which places a heavy burden on patients. On the other hand, although BSH contains 12 boron atoms per molecule, it cannot penetrate cell membranes and enter cells. As a result, BSH leaks out of the fragile blood vessels in tumor tissue, enters the interstitial fluid, and accumulates around the cells. This makes it difficult for the secondary particles generated by neutron irradiation to reach the cell nucleus, resulting in an insufficient killing effect.

[0008] Also, 10The natural isotopic abundance of B is about 20%, but currently used boron drugs 10 The substance used was enriched to 100% B, which posed a problem in that the production of the boron agent was very costly.

[0009] Therefore, an object of the present invention is to provide boron particles for boron drugs that can be used in boron neutron capture therapy to improve therapeutic efficiency, a method for producing boron particles for boron drugs that can significantly reduce production costs, and a drug for neutron capture therapy that contains boron particles for boron drugs. [Means for solving the problem]

[0010] A first invention relates to boron particles for use in boron drugs used in boron neutron capture therapy, the surfaces of which are covered with a boron nitride layer and the average particle size of which is 10 to 300 nm.

[0011] The average particle size of the boron particles for boron pharmaceuticals is preferably 50 to 100 nm.

[0012] It is also preferable that the surface of the boron nitride layer is modified with a biocompatible polymer. The biocompatible polymer is preferably polyglycerol. The boron nitride layer may be two or more layers.

[0013] The second invention is a method for producing boron particles for boron pharmaceuticals according to the first invention, characterized in that it comprises the steps of dissolving a raw material containing boron nitride-coated boron particles, in which the surfaces of boron particles are coated with boron nitride, in water to obtain a mixed solution, subjecting the mixed solution to ultrasonic dispersion treatment, and then centrifuging the mixture to extract boron nitride-coated boron particles having an average particle size of 10 to 300 nm.

[0014] It is preferable that the method includes, before the step of extracting the boron nitride-coated boron particles having an average particle size of 10 to 300 nm, a step of mixing a raw material containing boron nitride-coated boron particles with a raw material for chemical modification that will become a biocompatible polymer, ultrasonically dispersing the mixture, and then heating and holding the mixture while stirring to obtain a gel-like mixture; a removal step of diluting the gel-like mixture with water, ultrasonically dispersing the resulting modified mixture, and then centrifuging it to remove unreacted raw material for chemical modification and excess biocompatible polymer; and a precipitation step of obtaining a precipitate containing boron nitride-coated boron particles whose surfaces are modified with the biocompatible polymer remaining in the removal step.

[0015] It is preferable that the raw material for chemical modification is glycidol and the biocompatible polymer is polyglycerol.

[0016] It is preferable to repeatedly carry out the steps of recovering the precipitate, diluting the recovered precipitate with water to obtain a modified mixed solution, and subjecting the modified mixed solution to centrifugation.

[0017] A third invention is a drug for neutron capture therapy containing the boron particles for a boron drug according to the first invention. [Effects of the Invention]

[0018] According to the present invention, it is possible to provide boron particles for boron drugs that can be used in boron neutron capture therapy to improve therapeutic efficiency, a method for producing boron particles for boron drugs that can significantly reduce production costs, and a drug for neutron capture therapy that contains boron particles for boron drugs. [Brief explanation of the drawings]

[0019] [Figure 1] Conceptual diagram of boron particles for boron drugs [Figure 2] Schematic diagram of the modification method for boron drugs chemically modified with polyglycerol (PG) [Figure 3] Flow diagram of the manufacturing method for boron particles for boron drugs [Figure 4] Transmission electron microscope (TEM) image of BNNT composite [Figure 5] TEM image of separated boron nitride coated boron particles [Figure 6] TEM image of boron nitride coated boron particles heat treated in air [Figure 7] Scanning transmission electron microscope (STEM) images of the supernatant and precipitate after the fifth centrifugation after PG modification [Figure 8] Thermogravimetric (TG) analysis results of the precipitate obtained from the fifth centrifugation after PG modification [Figure 9] TEM image of the precipitate after centrifuging the fifth time after PG modification at 1190g for 30 minutes. [Figure 10] Elemental analysis results by energy dispersive X-ray spectroscopy (EDS) of the precipitate shown in Figure 9 [Figure 11] Crystal structure simulation results of the precipitate shown in Figure 9 [Figure 12] Fourier transform infrared spectroscopy (FTIR) measurements of the precipitate shown in Figure 9 [Figure 13] NMR measurement results of the precipitate shown in Figure 9 [Figure 14] TEM image of the precipitate after repeated centrifugation of the fifth centrifugation after PG modification [Figure 15] Cytotoxicity test results when using the precipitates (materials) in Figures 9 and 14 [Figure 16] TEM image of the precipitate after repeated centrifugation of the fifth centrifugation after PG modification [Figure 17] Diagram showing the ratio of 10B concentrations in tumors and blood (T / B ratio) [Figure 18] The relative ratio of tumor volume Vt at the time of measurement to tumor volume V0 on the day treatment started is shown. [Figure 19] Tumors on day 28 DETAILED DESCRIPTION OF THE INVENTION

[0020] Hereinafter, one embodiment of the boron particles for a boron drug used in boron neutron capture therapy (BNCT) of the present invention will be described with reference to the drawings.

[0021] First, as shown in the conceptual diagram of Figure 1, the boron particles 1 for boron drugs of the present invention are composed of boron particles 101 (hereinafter referred to as boron nitride-coated boron particles 100) whose surfaces are covered with a boron nitride layer 102. Furthermore, if necessary, the surface of the boron nitride layer 102 of the boron nitride-coated boron particles 100 is modified with a biocompatible polymer such as an organic molecule or a polymer 103.

[0022] Here, the boron nitride-coated boron particles 100 comprise nearly spherical crystalline boron particles 101 and have an average particle diameter of 10 to 300 nm. The EPR effect (Enhanced Permeation and Retention) is known, in which drugs of a certain size accumulate specifically at malignant tumor sites. Blood vessels near tumors have larger holes than other normal cell sites, and particles of a specific size that do not migrate from the blood vessels in normal cells can accumulate in tumors through these vascular holes. To achieve this EPR effect, the particles must be large enough to suppress renal excretion and pass through the gaps between vascular endothelial cells around malignant tumor sites. For these reasons, we have found that the average particle diameter of the boron nitride-coated boron particles 100 used as drugs is 10 to 300 nm. A particle diameter of less than 10 nm results in poor selectivity for malignant tumors, while a particle diameter of more than 300 nm results in poor intercellular passage to malignant tumor sites. From the viewpoint of improving cancer accumulation, the average particle size is preferably 40 to 250 nm, more preferably 50 to 100 nm. The average particle size of the boron nitride-coated boron particles can be measured by dynamic light scattering.

[0023] The boron nitride layer 102 is a hexagonal boron nitride layer, and one or more boron nitride layers 102 cover the boron particles 101 . By using the boron particles 1 for boron drugs as in this embodiment, a sufficient amount 10 It can contain B. This is only a small part of the boron drugs. 10 This is because it is not a molecule that does not contain B, but is composed of boron particles themselves and a boron nitride layer that covers them.10 The content of B will be explained.

[0024] First, BNCT uses 10 B concentration is 20-40 ppm (per cell) 10 B is 1 x 10 9 pieces~2×10 9 It is known that the volume of a cell is 10 -9 cm 3 So, 1×10 18 ~2×10 18 pieces / cm 3 of 10 B concentration is required. The boron nuclide is 10 B and 11 B, but the abundance ratio of each nuclide in natural boron is 10 B is about 20% 11 It is known that B is approximately 80%.

[0025] Here, the boron particles 101 are contained in the boron nitride-coated boron particles, which are coated with three hexagonal boron nitride layers 102. 10 Calculate the B concentration. Assuming that the diameter of the boron particle 101 is 50 nm, the boron particle 101 (6.54 × 10 -17 cm 3 ) 10 The number of B is 1.52 x 10 6 The diameter of the shell of the hexagonal boron nitride layer 102 that covers the boron particle 101 is 50 nm. The hexagonal boron nitride layer 102 is composed of five-membered rings and six-membered rings made of nitrogen and boron, and can be said to have a shape that easily encapsulates boron particles. According to Euler's polyhedron theorem, the number of pentagons in a polyhedron made of pentagons and hexagons is 12. The polyhedron made of the hexagonal boron nitride layer 102 (surface area: 7853.98 nm) 2 ) contained in the five-membered ring (surface area: 0.04 nm 2 ) are 12, and the number of six-membered rings (surface area: 0.05 nm 2 The number of 5- and 6-membered rings is 144,570. 10 The number of B is 86,748, and the number of B atoms is 86,748. The number of B atoms .... The number of B atoms is 86,748. The number of B atoms is 86,748. The number of B atoms is 86,748. The number of B atoms is 86,748. 10The number of B is 260,244 (0.26 × 10 6 pieces).

[0026] Therefore, the boron nitride coated boron particle 100 consisting of the boron particle 101 and the three hexagonal boron nitride layers 102 contains 10 The number of B is 1.78 x 10 6 and its volume is 6.54 × 10 -17 cm 3 Then, per unit volume 10 The number of B's ​​is 2.72 x 10 22 pieces / cm 3 This can be estimated as 10 The B concentration required for BNCT is as described above. 10 This corresponds to approximately 10,000 times the B concentration.

[0027] In this way, if pure boron particles are used as a boron agent, 10 A sufficient number of effective nuclear transmutations can be achieved without enriching B. Furthermore, if a high concentration of boron is contained in the boron agent, it is thought that it will be possible to significantly reduce manufacturing costs.

[0028] Furthermore, pure boron particles are easily oxidized, and the boric acid formed by oxidation is toxic. However, by using boron particles 101 coated with a boron nitride layer 102 as in this embodiment as a boron agent, the oxidation of the boron particles is suppressed, and the formation of toxic boric acid can be prevented.

[0029] On the other hand, when the diameter of a single-layer boron nitride coated boron particle and a multi-layer boron nitride coated boron particle are the same, the boron particles coated with the single layer will be slightly larger. Since the hexagonal boron nitride layer is composed of five-membered and six-membered rings made of nitrogen and boron, the larger the boron particle itself is, the more the boron nitride layer will be. 10 Therefore, even if the boron nitride layer 102 is a single layer, many 10 It may contain B.

[0030] Furthermore, in this embodiment, biocompatibility can be imparted by chemically modifying the surface of the extracted boron nitride-coated boron particles with polyglycerol (PG), a highly hydrophilic polymer. As shown in Figure 2, when boron nitride-coated boron particles 100 are mixed with glycidol 104, the hydroxyl-containing boron nitride-coated boron particles 100 are coated with polyglycerol through ring-opening hyperbranching polymerization of glycidol. Here, the biocompatibility polymer is selected because (1) the boron nitride-coated boron particles after chemical modification with PG are almost non-toxic to the body, and (2) the boron nitride-coated boron particles after chemical modification with PG are easily dissolved in water or phosphate-buffered saline (PBS). In this regard, PG is preferred because it is widely used in foods, for example as an emulsifier and colorant, and is a biocompatible polymer.

[0031] It is also preferable to modify the surface of the boron nitride coated boron particles with a biocompatible polymer, and specifically, tumor selectivity can be imparted by chemically modifying the surface with a biocompatible polymer having tumor selectivity. 10 B has the property of selectively accumulating in tumor cells, and chemical modification of cancer-affinity substances is useful in BNCT. In the present invention, preferred organic molecules include amino acids, proteins, and glycoproteins. Preferred polymers include polyethylene glycol (PEG) and polyglycerol (PG) with amino groups. Compared to PEG, chemical modification with PG is more desirable because nanoparticles chemically modified with PG prevent the nanoparticles from adsorbing to proteins.

[0032] Next, one embodiment of a method for producing boron particles for boron pharmaceuticals will be described.

[0033] To produce the boron particles for boron drugs according to one embodiment of the present invention, for example, a method for producing boron nitride nanotubes (BNNTs) can be applied. Note that the method for producing boron particles for boron drugs is not limited to the example shown below. First, a raw material containing boron nitride with moisture removed and sp 3 A nonionic polymer dispersant having bonding CH groups is mixed with an organic solvent. 3 It is preferable to dissolve a nonionic polymer dispersant having bonding CH groups in an organic solvent to prepare a homogeneous solution in advance. This allows the boron nitride to be uniformly coated with the polymer dispersant. A raw material containing boron nitride is added to this solution, and the solution is then ultrasonically dispersed using a homogenizer or the like, allowing the boron nitride to be uniformly coated with the polymer dispersant. It is preferable to perform this process while cooling the solution to prevent the liquid temperature from rising during ultrasonic dispersion.

[0034] The resulting mixture may contain, for example, 1 part by mass of a raw material containing boron nitride, 1 to 2,000 parts by mass of a nonionic polymer dispersant having sp3-bonded CH groups, and 200 to 100,000 parts by mass of the organic solvent. The lower limit of the amount of dispersant added is determined, for example, by centrifuging the mixture described below and examining SEM images of the supernatant and residue, depending on the separability of by-products. For example, the amount of dispersant added is varied under multiple conditions, and the conditions are set so that, from the respective images after separation, the amount of by-products in the supernatant is relatively large and the amount of by-products in the residue is inconspicuous.

[0035] Next, the resulting mixture is centrifuged. This operation removes by-products, such as BNNTs and h-BN flakes, contained in the solution. Below, we explain in more detail each step of the process for producing boron particles for boron drugs, shown in the flow diagram of Figure 3, i.e., the process for producing boron nitride-coated boron particles modified with a biocompatible polymer.

[0036] [Synthesis of raw materials containing boron nitride] For the synthesis of raw materials containing boron nitride, for example, a small plasma device (TEKNA Plasma Systems A TekNanо-15 plasma torch (manufactured by Inc.) can be used. Specifically, the synthesis is carried out as follows. First, the reactor is purged with argon gas. Then, argon gas (flow rate: 10 L / min) is flowed into the central region, and a mixture of argon (30 L / min) and hydrogen (2.5 L / min) is flowed to form a sheath gas around the outer periphery of the tube that confines the plasma. Nitrogen gas is flowed through both the torch nozzle (10 L / min) and the porous wall (47 L / min) surrounding the reactor. A few minutes after plasma ignition, when the temperature measured by the thermocouple installed between the reactor and the cyclone becomes constant, the raw material, hexagonal boron nitride powder (average particle size: 5 μm), is continuously fed from a feeder installed above the plasma torch using argon (2.5 L / min) as the carrier gas. The feed rate is 0.5 g / min, the operation time is 2 hours, and the pressure inside the reactor chamber is 1 atm. After the synthesis is completed, the apparatus is disassembled and the synthesized material adhering to the plasma torch, reactor, cyclone and filter section is recovered.

[0037] The composite containing boron nitride obtained above was observed under a transmission electron microscope (TEM) as shown in Figure 4. The samples include fibrous BNNTs 201, as shown in the Electron Microscope image, crystalline boron particles covered with multiple layers of boron nitride (h-BN), i.e., boron nitride-coated boron particles 100, and h-BN flakes 203 (sheet-like materials made of hexagonal boron nitride).

[0038] [Extraction of boron nitride coated boron particles] Next, sp 3 A nonionic polymer dispersant having a bonding CH group and an organic solvent are mixed with the above-mentioned boron nitride-containing composite, and the resulting mixture is then dispersed and separated to separate the BNNTs 201 from the boron nitride-coated boron particles 100 and boron nitride flakes 203. In this case, the boron nitride-coated boron particles 100 and boron nitride flakes 203 are extracted as a precipitate. An example of a specific method for separating the boron nitride-coated boron particles 100 from the other BNNTs 201 and boron nitride flakes 203 will be described. 25 mg of polyvinyl butyral (PVB) as a dispersant and 20 cm of benzyl alcohol as an organic solvent were mixed. 3 After mixing, 15 mg of the compound containing boron nitride obtained above is added to this solution. That is, for 1 part by mass of the compound containing boron nitride, 3 The mixture is 1.7 parts by mass of a nonionic polymer dispersant having a bonding CH group and 1,333 parts by mass of the organic solvent. This mixture is dispersed at room temperature using an ultrasonic homogenizer for 20 minutes. It is then centrifuged at a centrifugal acceleration of 30,000 G for 3 hours. This yields a supernatant containing BNNTs 201 and a precipitate containing boron nitride-coated boron particles 100 and boron nitride flakes 203.

[0039] Next, this precipitate is mixed with an organic solvent, and the resulting dispersion is centrifuged to separate the boron nitride-coated boron particles 100 and boron nitride flakes 203. In addition, the polymer dispersant adhering to the extracted boron nitride-coated boron particles 100 is removed by heat treatment in the atmosphere. Next, an example of a specific method for separating the boron nitride coated boron particles 100 and the boron nitride flakes 203 will be described. The precipitate collected above is dried by heat treatment at 300°C for 1 hour in the atmosphere. 14 cm of benzyl alcohol is added. 3 10 mg of this dried precipitate is added to the mixture. This mixture is dispersed for 20 minutes using an ultrasonic homogenizer at room temperature. It is then centrifuged for 3 hours at a centrifugal acceleration of 30,000 G. This allows the boron nitride-coated boron particles 100 and boron nitride flakes 203 to be separated. As a result, only the boron nitride-coated boron particles 100 are obtained, as shown in the TEM image in Figure 5. Next, the PVB adhering to the surface of the boron nitride-coated boron particles 100 is thermally decomposed and removed. This is performed, for example, by heat treatment in the atmosphere at 500°C for 1 hour. As a result, boron nitride-coated boron particles 100 can be obtained, in which the surfaces of the boron particles 101 are covered with multiple boron nitride layers 102, as shown in the TEM image of Figure 6.

[0040] [Chemical modification of biocompatible polymers] Finally, if necessary, the surface of the boron nitride-coated boron particle 100 is modified with a biocompatible polymer. The biocompatible polymer can be an organic molecule or a polymer. For example, polyglycerol (PG), a highly hydrophilic polymer, is suitable as the organic molecule or polymer 103 (see FIG. 1). Here, an example of a specific chemical modification method will be described. First, 10 mg of boron nitride-coated boron particles were mixed with 4 mL of glycidol, a chemical modification raw material that serves as a source of organic molecules or polymers, and ultrasonically dispersed for 1 hour. The modified mixture was then heated and stirred at 140°C for 20 hours, causing the ring-opening polymerization of glycidol, turning the modified mixture into a gel. PG was then modified onto the surface of the boron nitride-coated boron particles. The gel-like modified mixture was then diluted with 10 mL of water and ultrasonically dispersed until the gel dissolved. Next, to remove unreacted glycidol and excess PG that had not been modified onto the surface of the boron nitride-coated boron particles, the diluted modified mixture was centrifuged at a centrifugal acceleration of 50,400 g for 30 minutes. This is called the removal process. This allows the unreacted glycidol and excess PG to be removed as the supernatant, and the PG-modified boron nitride-coated boron particles can be recovered as a precipitate. This recovery process is called the precipitation process. The recovered precipitate may also be diluted with water to obtain a modified mixture, which may then be centrifuged. Repeating this process, for example, five times, can yield highly purified PG-modified boron nitride-coated boron particles. The organic molecules or polymers may be other substances than PG, as long as they are hydrophilic. In this case, a chemical modification source, which serves as the source of the organic molecules or polymers, may be added.

[0041] [Classification of chemically modified boron nitride coated boron particles] Furthermore, the boron nitride-coated boron particles recovered as a precipitate are dissolved in water, and the resulting modified mixture is subjected to ultrasonic dispersion treatment. Then, by repeated centrifugation, the boron nitride-coated boron particles are classified to extract boron nitride-coated boron particles of the desired particle size from a range of average particle sizes of 10 to 300 nm. The precipitate contains boron nitride-coated boron particles of various particle sizes. By undergoing this classification process, it is possible to efficiently extract boron nitride-coated boron particles of a particle size that has good selectivity for malignant tumors and facilitates intercellular passage to malignant tumor sites, as described above. The aforementioned PVB-modified boron nitride-coated boron particles may also be classified in advance by centrifugation. In this embodiment, the classification process is not limited to boron nitride-coated boron particles modified with a biocompatible polymer; it may also be performed on boron nitride-coated boron particles that are not modified with a biocompatible polymer.

[0042] [Another embodiment of extraction, chemical modification, and classification of boron nitride coated boron particles] On the other hand, as another embodiment, a method for separating and extracting PG-modified boron nitride-coated boron particles from a raw material composite containing boron nitride chemically modified with PG will be described. In this method, a raw material composite containing boron nitride is mixed with glycidol, ultrasonically dispersed, and then heated and stirred to obtain a gel-like mixture. This mixture contains unreacted glycidol and excess PG in addition to PG-modified boron nitride. To remove the unreacted glycidol and excess PG, the mixture is diluted with water, ultrasonically dispersed, and then centrifuged to separate the supernatant, which contains a large amount of unreacted glycidol and excess PG, from the precipitate, which contains a large amount of PG-modified boron nitride. The separated precipitate is then diluted with water, ultrasonically dispersed, and then centrifuged. This process is repeated, for example, five times to obtain only PG-modified boron nitride-coated boron nitride particles. The precipitate after five centrifugations primarily contains boron nitride-coated boron nitride particles and boron nitride flakes.

[0043] Next, we will describe a method for separating the boron nitride-coated boron particles and boron nitride flakes contained in this precipitate. The precipitate is dissolved in water, and the modified mixture is subjected to ultrasonic dispersion treatment followed by centrifugation, thereby separating the boron nitride-coated boron particles and the boron nitride flakes. The supernatant liquid mainly contains boron flakes, while the precipitate mainly contains boron nitride-coated boron particles. Furthermore, the modified mixture is dissolved in water, and the mixture is subjected to ultrasonic dispersion treatment followed by repeated centrifugation, thereby classifying the boron nitride-coated boron particles and extracting boron nitride-coated boron particles of the desired particle size from an average particle size range of 10 to 300 nm. [Example]

[0044] Example 1 20 mg of a pre-synthesized boron nitride-containing raw material composite was mixed with 4 mL of glycidol, and the resulting mixture was subjected to ultrasonic dispersion treatment in an ultrasonic cleaner with water cooling for 1 hour. The modified mixture was then heat-treated at 140 °C for 20 hours while stirring with a stirrer. This resulted in a gel-like substance in which the surfaces of BNNTs 201, boron nitride-coated boron particles 100, and boron nitride flakes 203 were modified with PG. To remove unreacted glycidol and excess PG, the gel-like substance was diluted with 10 mL of water. The dispersion was then subjected to ultrasonic dispersion treatment in an ultrasonic cleaner with water cooling until the gel-like substance dissolved. The dispersion was then centrifuged at a centrifugal acceleration of 50,400 g for 30 minutes. The supernatant was then removed and the precipitate was collected. The precipitate was again diluted with 10 mL of water and centrifuged under the same conditions five times.

[0045] Figure 7 shows STEM (scanning transmission electron microscope) images of the supernatant and precipitate after five centrifugation cycles. The left image (A) in Figure 7 shows the supernatant after five centrifugation cycles, and the right image (B) in Figure 7 shows the precipitate after five centrifugation cycles. The supernatant contained mostly fibrous BNNTs 201, while the precipitate contained mostly PG-coated boron nitride particles 100 (boron particles for boron pharmaceuticals) and boron nitride flakes 203.

[0046] The thermogravimetric (TG) measurement results for the precipitate consisting of boron nitride-coated boron particles 100 and boron nitride flakes 203 are shown in Figure 8. The weight loss rate at approximately 500°C, at which the thermal decomposition reaction of PG is completed, was approximately 45 wt%, indicating that approximately 45% of the weight of the precipitate's constituents was coated with PG.

[0047] Furthermore, to extract only the boron nitride-coated boron particles, the precipitate was centrifuged five times, diluted with 20 mL of water, and then subjected to ultrasonic dispersion treatment for 10 minutes using an ultrasonic homogenizer. This was then centrifuged at 1190 G for 30 minutes. A TEM (transmission electron microscope) image of the precipitate after centrifugation is shown in Figure 9. Boron nitride-coated boron particles 100 and boron nitride flakes 203 were present. The average particle size of the boron nitride-coated boron particles was measured by dynamic light scattering using a Nikkiso Nanotrac (UPA EX150) and found to be approximately 150 nm.

[0048] As can be seen from the energy dispersive X-ray spectroscopy (EDS) analysis results shown in Figure 10, boron and trace amounts of nitrogen were detected in the boron nitride-coated boron particle shown in Figure 9. Furthermore, Figure 11 shows a comparison of the electron diffraction image obtained by Fourier transforming the lattice image of boron nitride-coated boron particle 100 with the results of electron diffraction image simulation. The electron diffraction image obtained by Fourier transforming the lattice image of the central part matched the results of the electron diffraction image simulation of boron (B), and the electron diffraction image obtained by Fourier transforming the lattice image of the peripheral part matched the results of the electron diffraction image simulation of hexagonal boron nitride (h-BN). In other words, it was found that boron nitride was coated around the boron.

[0049] Fourier transform infrared spectroscopy (FTIR) of the PG-modified precipitate after centrifugation and the BNNT composite without PG modification shown in Figure 9. The results of infrared spectroscopy are shown in Figure 12. In the PG-modified precipitate, CH (2900 cm) derived from PG was observed. -1) peak was confirmed. In addition, the peak at 1100 cm -1 The peak around 1160 cm is broad, but it is due to BNO (1160 cm) derived from boron nitride. -1 ) peak and COC (1100 cm) derived from PG -1 ) peaks overlapped. This indicates that the precipitate was modified with PG.

[0050] Figure 13 shows the results of nuclear magnetic resonance (NMR) analysis of the precipitate obtained by centrifugation shown in Figure 9. In Figure 13, A is the spectrum of the precipitate, and B is the spectrum of the PG-modified nanodiamond. The 1H peak near 4.5 ppm is derived from heavy water, and the 1H peak near 3.5 ppm is derived from PG. In the PG-modified precipitate, a 1H peak was observed near 3.5 ppm, similar to the PG-modified nanodiamond, confirming that the precipitate was PG-modified boron nitride-coated boron particles.

[0051] Similarly, this precipitate was diluted with 20 mL of water and then subjected to ultrasonic dispersion for 10 minutes using an ultrasonic homogenizer. Then, centrifugal separation was repeated. Figure 14 shows a TEM image of the precipitate after repeated centrifugation at 1190 G for 30 minutes, 3300 G for 10 minutes, 8440 G for 10 minutes, 13190 G for 10 minutes, and 30000 G for 180 minutes. Almost no boron nitride flakes were present, and boron nitride-coated boron particles 100 (boron particles for boron pharmaceuticals) with a particle diameter of approximately 50 nm were present. Thus, by repeating the centrifugation process, the boron nitride-coated boron particles were successfully classified.

[0052] We evaluated the cytotoxicity of the two types of precipitates (materials) shown in Figures 9 and 14. The material in Figure 9 contains boron nitride-coated boron particles with an average particle size of 150 nm mixed with boron nitride flakes. The material in Figure 14 is mostly boron nitride-coated boron particles with an average particle size of 50 nm. The above two types of materials were mixed with culture medium (RPMI-1640), and murine colon cancer cells (ct26) were cultured for one day, after which the viability of the cancer cells was measured. The results are shown in Figure 15. Regardless of particle size, cell viability was over 95%, indicating that the PG-modified boron nitride-coated boron nitride particles and boron nitride flakes have almost no cytotoxicity.

[0053] Example 2 A pre-synthesized composite containing boron nitride was mixed with glycidol in a 5:1 ratio, and the resulting mixture was subjected to ultrasonic dispersion treatment in an ultrasonic cleaner for 1 hour while cooling with water. The modified mixture was then heat-treated at 140°C for 20 hours while stirring with a stirrer. This resulted in a gel-like substance in which the surfaces of BNNTs 201, boron nitride-coated boron particles 100, and boron nitride flakes 203 were modified with PG. To remove unreacted glycidol and excess PG, the gel-like substance was diluted with half the amount of water and then subjected to ultrasonic dispersion treatment in an ultrasonic cleaner while cooling with water until the gel-like substance dissolved. The dispersion was then centrifuged at 50,400 g for 30 minutes. The supernatant was then removed and the precipitate was collected. The precipitate was again diluted with the same amount of water as used for the dilution, and the process of centrifuging under the same conditions was repeated five times.

[0054] The precipitate was then transferred to a centrifuge tube and filled with water to form a mixture. This mixture was then subjected to ultrasonic dispersion for 10 minutes using an ultrasonic homogenizer, followed by repeated centrifugation. Figure 16 shows a TEM image of the precipitate after repeated centrifugation at 1200G for 30 minutes, 3300G for 10 minutes, 8400G for 10 minutes, 13200G for 10 minutes, and 10000G for 10 minutes. Almost no boron nitride flakes were present, and particle size measurement using dynamic light scattering revealed the presence of boron nitride-coated boron particles 100 (boron particles for boron pharmaceuticals) with a particle size of approximately 70 nm. The resulting boron nitride-coated boron particles 100 were diluted with phosphate-buffered saline (PBS) to prepare a boron pharmaceutical.

[0055] The obtained boron drug in tumor and blood 10 The B concentration ratio (T / B ratio) was evaluated. Murine colon cancer cells (ct26) were inoculated into the paws of 10-week-old mice, and a boron drug was administered one week later. The boron particle concentration was 2.0 mg / ml. After drug administration, tumors and blood were removed from the mice 6, 24, and 48 hours later, and neutron-induced prompt gamma-ray analysis (PGA) was performed. The results are shown in Figure 17. To improve the therapeutic efficiency of BNCT, it is necessary to increase the boron concentration in tumor cells. 10 It is necessary to increase the B concentration. In other words, the higher the T / B ratio, the better. In BNCT treatment, a T / B ratio of 3 or more is considered desirable. As a result of the evaluation, it was found that the T / B ratio exceeded 3 6 hours after administration and reached its peak 24 hours after drug administration. Furthermore, even after 48 hours, there was no evidence of B in the tumor tissue. 10 Therefore, by irradiating neutrons near the peak of the T / B ratio, the irradiation time can be shortened and the B in tumor cells can be maintained. 10 By maintaining a high concentration of B for a long period of time, it is expected that there will be benefits such as eliminating the need for long-term administration of large amounts.

[0056] The cancer killing effect of the obtained boron agent when applied to BNCT was verified. Murine colon cancer cells (ct26) were inoculated into the legs of 10-week-old mice, and the boron agent was administered one week later. The boron particle concentration was 11.3 mg / ml. 24 hours after the agent administration, the mice were irradiated with neutrons, and tumor size was measured up to 28 days later. This was set as Example (D), and as comparative examples, (A) mice administered with no agent but only PBS, (B) mice administered with only the agent but not neutron irradiation, and (C) mice administered with only neutron irradiation without the agent were also prepared and verified. Tumor volume at the time of measurement: V compared to tumor volume on the day treatment started: V0. t Relative ratio of tumor volume (V t / V0), Figure 18 shows the V t 19 is a photograph of the tumor after 28 days. (D) is an example in which a drug was administered and neutron beams were irradiated. t / V0 was suppressed to about 4.0 even after 28 days, confirming the cancer killing effect compared with the other (A) to (C). [Explanation of symbols]

[0057] 1. Boron particles for boron drugs 100···Boron nitride coated boron particles 101···Boron particles 102...Boron nitride layer 103... Organic molecules or polymers 201···BNNT 203 Boron nitride flakes

Claims

1. A boron particle for a boron drug used in boron neutron capture therapy, comprising: The boron particles for boron drugs are characterized in that the surfaces of the boron particles are covered with a boron nitride layer and the average particle size is 10 to 300 nm.

2. The boron particles for boron drugs according to claim 1, characterized in that the average particle size of the boron particles for boron drugs is 50 to 100 nm.

3. 2. The boron particle for boron medicines according to claim 1, characterized in that the surface of the boron nitride layer is modified with a biocompatible polymer.

4. The boron particles for boron drugs according to claim 3, characterized in that the biocompatible polymer is polyglycerol.

5. The boron particles for boron drugs according to claim 1, characterized in that the boron nitride layer is two or more layers.

6. A method for producing boron particles for boron drugs according to claim 1, A method for producing boron particles for use in boron pharmaceuticals, comprising the steps of: dissolving a raw material containing boron nitride-coated boron particles, in which the surfaces of boron particles are coated with boron nitride, in water to obtain a mixed solution; subjecting the mixed solution to ultrasonic dispersion treatment; and centrifuging the resultant mixture to extract boron nitride-coated boron particles having an average particle size of 10 to 300 nm.

7. The method for producing boron particles for boron drugs according to claim 6, further comprising the steps of: mixing a raw material containing boron nitride-coated boron particles with a raw material for chemical modification that will become a biocompatible polymer; ultrasonically dispersing the mixture; and heating and holding the mixture while stirring to obtain a gel-like mixture; ultrasonically dispersing the modified mixture obtained by diluting the gel-like mixture with water; centrifuging the resulting modified mixture to remove unreacted raw material for chemical modification and excess biocompatible polymer; and a precipitation step of obtaining a precipitate containing boron nitride-coated boron particles whose surfaces are modified with the biocompatible polymer remaining in the removal step, prior to the step of extracting the boron nitride-coated boron particles having an average particle size of 10 to 300 nm.

8. 8. The method for producing boron particles for boron drugs according to claim 7, characterized in that the raw material for chemical modification is glycidol, and the biocompatible polymer is polyglycerol.

9. A method for producing boron particles for boron pharmaceuticals as described in claim 7 or 8, characterized in that the steps of recovering the precipitate, diluting the recovered precipitate with water to obtain a modified mixed solution, and centrifuging the modified mixed solution are repeated.

10. A drug for neutron capture therapy comprising the boron particles for boron drugs according to any one of claims 1 to 5.

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