Pharmaceutical composition, adsorption method, treatment method and prevention method

Abstract

One purpose of the present disclosure is to provide a novel pharmaceutical composition, and preferably, to provide a pharmaceutical composition which makes it possible to adsorb various disease-causing substances inside an organism.　A pharmaceutical composition which comprises two-dimensional particles having one or more layers which include a layer body represented by the formula MmXn (in the formula, M is at least one type of metal belonging to group 3, 4, 5, 6, or 7, X is a carbon atom, a nitrogen atom, or a combination thereof, n is 1-4, inclusive, and m is greater than n and at most 5), and a modification or terminal T (T is at least one group or atom selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom, and a hydrogen atom) present on the surface of the layer body, said pharmaceutical composition being configured so as to be administered orally and as a result, adsorb disease-causing substances inside the organism.

Description

Pharmaceutical compositions, adsorption methods, treatment methods and prevention methods

[0001] The present disclosure relates to pharmaceutical compositions, methods of adsorption, methods of treatment and methods of prevention.

[0002] The number of patients with kidney disease is increasing year by year, and according to statistics from the Japanese Society for Dialysis Therapy, the number of chronic dialysis patients increased by approximately 17% between 2010 and 2020. When kidney function declines due to kidney disease, disease-causing substances accumulate in the blood, which can result in uremia, electrolyte metabolism disorders, autoimmune diseases, etc. To treat the various symptoms associated with kidney disease, hemodialysis-type kidney function substitutes are used, which remove disease-causing substances from the body.

[0003] Non-Patent Document 1 describes an adsorption-type blood purifier that uses cellulose beads with cetylamine immobilized thereon as an adsorbent as a filter used in a hemodialysis-type kidney function substitute.

[0004] On the other hand, as an alternative method of removing disease-causing substances to kidney function substitutes, adsorbents that are taken orally and adsorb toxic substances in the body and then excrete them outside the body are being developed.

[0005] As such an adsorbent, Non-Patent Document 2 describes medicinal charcoal that can adsorb gases and poisons in the digestive tract.

[0006] Non-Patent Documents 3 and 4 describe carbon-based adsorbents that can adsorb uremic toxins present in the digestive tract without being absorbed into the body, and excrete them together with feces.

[0007] Non-Patent Document 5 describes a calcium-type cation exchange resin that can exchange potassium ions in the intestinal tract for calcium ions in the structure, thereby lowering blood potassium levels.

[0008] Non-Patent Document 6 describes a polycationic polymer that can bind to phosphate ions liberated from food in the digestive tract and be excreted in feces without being absorbed.

[0009] Medical device package insert "Rixel," Kaneka Corporation, revised January 2017 (10th edition); Pharmaceutical interview form "Medicinal Charcoal," Nichi-Iko Pharmaceutical Co., Ltd., revised January 2019 (4th edition); Pharmaceutical interview form "Kremezin Rapidly Disintegrating Tablets 500 mg," Tanabe Mitsubishi Pharma Corporation, revised September 2018 (3rd edition); Honda Yoshiteru et al., "Study on the Adsorption Characteristics of Spherical Adsorbent Charcoal (Kremezin Active Ingredient)," Hospital Pharmacy, 1997, Vol. 23, No. 3, pp. 219-224; Pharmaceutical interview form "Kalimate Powder," "Kalimate Dry Syrup 92.59%," "Kalimate Oral Liquid 20%," Kowa Company, Limited, revised September 2020 (20th edition); Pharmaceutical interview form "Phosblock Tablets 250 mg," Kyowa Kirin Co., Ltd., revised November 2020 (1st edition).

[0010] The adsorbent described in Non-Patent Document 1 is intended to function in the blood circuit of a hemodialysis apparatus using extracorporeal circulation. The adsorbents described in Non-Patent Documents 2 to 6 are all intended for adsorbates present in the digestive tract through oral ingestion, enterohepatic circulation, or production via intestinal bacteria. Furthermore, the adsorbents described in Non-Patent Documents 1 to 6 are limited in the types of adsorbates.

[0011] An object of the present disclosure is to provide a novel pharmaceutical composition, preferably a pharmaceutical composition capable of adsorbing various disease-causing substances in vivo. Another object of the present disclosure is to provide a novel method for adsorbing, treating, or preventing disease-causing substances.

[0012] The pharmaceutical composition of the present disclosure comprises a two-dimensional particle having one or more layers, wherein said layers are represented by the following formula: M ｍ X ｎ (wherein M is at least one metal of Group 3, 4, 5, 6 or 7; X is a carbon atom, a nitrogen atom or a combination thereof; n is 1 or more and 4 or less; and m is greater than n and 5 or less), and a modified or terminated T (T is at least one selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom and a hydrogen atom) present on the surface of the layer body, and is used for adsorbing disease-causing substances in a living body by oral administration.

[0013] The present disclosure may provide a novel pharmaceutical composition, preferably a pharmaceutical composition capable of adsorbing disease-causing substances in vivo, and may also provide a novel adsorption method, treatment method, or prevention method.

[0014] The pharmaceutical compositions of the present disclosure include ｍ X ｎ and T, and is capable of adsorbing substances that may cause disease (disease-causing substances), and is therefore useful for the treatment and / or prevention of various diseases.

[0015] In vivo, disease-causing substances such as metabolites, waste products, harmful substances, and excess ionic substances are mainly excreted via two routes: biliary excretion, in which they are incorporated into bile in the liver and then excreted from the bile duct to the duodenum and then into the digestive tract; and urinary excretion via glomerular filtration in the kidney. However, in patients suffering from renal failure, for example, the kidneys are not able to adequately excrete metabolites and the like, necessitating periodic treatment with dialysis (hemodialysis, peritoneal dialysis, etc.), resulting in a significant decrease in quality of life (QOL).

[0016] Although not limited to any particular theory, the two-dimensional particles contained in the pharmaceutical composition of the present disclosure have the ability to preferentially adsorb these disease-causing substances, etc., and are therefore expected to adsorb disease-causing substances in the blood and eliminate them from the bloodstream through the mutual access between the intestinal tract and blood vessels when orally administered. Furthermore, by adsorbing substances that may be converted into harmful substances after being absorbed into the bloodstream from the intestinal tract, it is expected that harmful effects on the body can be preemptively adsorbed and eliminated. Furthermore, since the two-dimensional particles that adsorb disease-causing substances are not believed to be absorbed by the intestinal tract, they are expected to pass through the digestive tract and be excreted intact with feces. As described above, the body naturally possesses two excretory mechanisms: biliary excretion and urinary excretion. However, the metabolic pathway mediated by the pharmaceutical composition of the present disclosure can be considered a third metabolic pathway, and is expected to reduce the need for dialysis therapy in patients with renal failure, for example. Furthermore, the two-dimensional particles of the present disclosure are expected to adsorb disease-causing substances contained in dietary contents in the digestive tract and prevent them from being absorbed by the intestinal tract.

[0017] 1 is a schematic cross-sectional view showing an MXene particle of a layered material in one embodiment of the present disclosure, where (a) shows a single-layer MXene particle and (b) shows a multi-layer (exemplarily two-layer) MXene particle.

[0023] FIG. 1 is a schematic cross-sectional view showing a material in one embodiment of the present disclosure.

[0024] FIG. 1 is a graph showing the results of an MXene administration test in a renal failure model rat, showing (a) changes in urea nitrogen (BUN) values, (b) the rate of change in urea nitrogen (BUN) values, (c) serum creatinine (Cr) values, (d) the rate of change in serum creatinine (Cr) values, and (e) changes in kidney organ weight.

[0025] FIG. 1 is a graph showing the results of an MXene administration test in hypertensive mice, showing the behavioral domains of the mice in cognitive behavioral analysis.

[0026] FIG. 1 is a graph showing the results of an MXene administration test in hypertensive mice, showing the Time of Entries Discrimination Index in cognitive behavioral analysis.

[0018] The pharmaceutical compositions of the present disclosure comprise two-dimensional particles of layered material having one or more layers, the layers having the following formula: M ｍ X ｎ (wherein M is at least one metal of Group 3, 4, 5, 6 or 7; X is a carbon atom, a nitrogen atom or a combination thereof; n is 1 or more and 4 or less; and m is greater than n and 5 or less), and a modified or terminated T (T is at least one selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom and a hydrogen atom) present on the surface of the layer body.

[0019] The pharmaceutical compositions of the present disclosure include ｍ X ｎ and T, and is capable of adsorbing substances that may cause disease (disease-causing substances), and is therefore useful for the treatment and / or prevention of various diseases.

[0020] In the present disclosure, the layered material may be understood as a layered compound, and the layer may be a "M ｍ X ｎ T ｓ" where s is an arbitrary number, and conventionally, x or z is sometimes used instead of s. Hereinafter, the layered material may also be referred to as MXene, the layer may be referred to as an MXene layer, and the two-dimensional particles may be referred to as MXene two-dimensional particles or MXene particles.

[0021] In the present disclosure, when an "atom" is referred to as an element, the oxidation number of the element is not limited to 0, but may be any number within the range of oxidation numbers that the element can have.

[0022] Furthermore, with regard to the symbols in the general formulae shown in the present disclosure, unless otherwise specified, the definition of the same symbol is common to all general formulae containing that symbol.

[0023] The above formula: M ｍ X ｎ In the formula, m may typically be, but is not limited to, 2, 3, 4, or 5. Also, n may be, but is not limited to, 1, 2, 3, or 4. In one embodiment, m may be 3 and n may be 2.

[0024] The above formula: M ｍ X ｎ In the formula (I), M is preferably at least one selected from the group consisting of Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, Sc, W, and Mn, and more preferably at least one selected from the group consisting of Ti, V, Cr, and Mo.

[0025] M ｍ X ｎ The following expression is known as Sc: ２ C, Ti ２ C, Ti ２ N, Zr ２ C, Zr ２ N, Hf ２ C, Hf ２ N.V. ２ C.V. ２ N, Nb ２ C, Ta ２ C, Cr ２ C, Cr ２ N, Mo ２ C, Mo １．３ C, Cr １．３C, (Ti, V) ２ C, (Ti, Nb) ２ C, W ２ C, W １．３ C, Mo ２ N, Nb １．３ C, Mo １．３ Y ０．６ C (In the above formula, "1.3" and "0.6" respectively mean approximately 1.3 (= 4 / 3) and approximately 0.6 (= 2 / 3).), Ti ３ C ２ , Ti ３ N ２ , Ti ３ (CN), Zr ３ C ２ , (Ti, V) ３ C ２ , (Ti ２ Nb)C ２ , (Ti ２ Ta)C ２ , (Ti ２ Mn)C ２ Hf ３ C ２ , (Hf ２ V)C ２ , (Hf ２ [[ID=5​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​２ 、(W ２ Hf)C ２ 、 Ti ４ N ３ 、V ４ C ３ 、Nb ４ C ３ 、Ta ４ C ３ 、(Ti,Nb) ４ C ３ 、(Nb,Zr) ４ C ３ 、(Ti ２ Nb ２ )C ３ 、(Ti ２ Ta ２ )C ３ 、(V ２ Ti ２ )C ３ 、(V ２ Nb ２ )C ３ 、(V ２ Ta ２ )C ３ 、(Nb ２ Ta ２ )C ３ 、(Cr ２ Ti ２ )C ３ 、(Cr ２ V ２ )C ３ 、(Cr ２ Nb ２ )C ３ 、(Cr ２ Ta ２ )C ３ 、(Mo ２ Ti ２ )C ３ 、(Mo ２ Zr ２ )C ３ 、(Mo ２ Hf ２ )C ３ 、(Mo ２ V ２ )C ３ 、(Mo ２ Nb ２ )C ３ 、(Mo ２ Ta ２ )C ３ 、(W ２ Ti２ ) C ３ , (W ２ Zr ２ ) C ３ , (W ２ Hf ２ ) C ３ , (Mo ２．７ V １．３ ) C ３ (In the above formula, "2.7" and "1.3" mean approximately 2.7 (= 8 / 3) and approximately 1.3 (= 4 / 3), respectively.)

[0026] Typically, the above formula: M ｍ X ｎ In the formula, M can be Ti or V, and X can be a carbon atom or a nitrogen atom, or M can be Ti, and X can be a carbon atom. ３ C ２ T ｓ (In other words, M is Ti, X is C, n is 2, and m is 3.) In this case, the precursor of such MXene (also called "MAX phase") can be Ti. ３ AlC ２ It is possible.

[0027] MXene is the MAX phase of the precursor (in one embodiment, M ｍ AX ｎ where M, m, X, and n are as defined above, and A is at least one Group 12, 13, 14, 15, or 16 element), and MXene may contain such A atoms. In one embodiment, the residual amount of A atoms contained in MXene is preferably 10% by mass or less, more preferably 8% by mass or less, and even more preferably 6% by mass or less, based on the content of A atoms in the precursor.

[0028] In another embodiment, the residual amount of A atoms may exceed 10 mass %. For example, particles in which A atoms have been removed from only a portion of the MAX phase are also included in the technical scope of the two-dimensional particles. Such two-dimensional particles include, for example, particles in which A atoms are removed from only a portion of the MAX phase in the planar direction (M contained in the MAX phase). ｍ X ｎExamples of such particles include two-dimensional particles in which A atoms have been removed only from the vicinity of the edge of the particle in the direction parallel to the surface of the layer. In this embodiment, the amount of remaining A atoms may be, for example, 50% by mass or more, further 80% by mass or more, and particularly 90% by mass or more.

[0029] The lithium content of the two-dimensional particles is preferably 0% by mass or more and 0.1% by mass or less, more preferably 0% by mass or more and 0.01% by mass or less, and even more preferably 0% by mass or more and 0.002% by mass or less. Having the lithium content within the above range can improve biocompatibility. The lithium content of the two-dimensional particles can be measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES).

[0030] The two-dimensional particle is an aggregate including one layer of MXene particles (hereinafter simply referred to as "MXene particles") 10a (single-layer MXene particles) as shown in Fig. 1(a). ｍ X ｎ The layer body (M ｍ X ｎ The MXene layer 7a has a main layer 1a and modifications or terminations T3a, 5a present on the surface of the main layer 1a (more specifically, on at least one of the two opposing surfaces of each layer). ｍ X ｎ T ｓ ", where s is an arbitrary number.

[0031] The two-dimensional particles may contain one or more layers. Examples of MXene particles with multiple layers (multilayer MXene particles) include, but are not limited to, two-layer MXene particles 10b, as shown schematically in FIG. 1(b). 1b, 3b, 5b, and 7b in FIG. 1(b) are the same as 1a, 3a, 5a, and 7a in FIG. 1(a). Two adjacent MXene layers (e.g., 7a and 7b) in a multilayer MXene particle do not necessarily need to be completely separated, and may be partially in contact. The single-layer MXene particle 10a is a single layer in which the multilayer MXene particles 10b are individually separated. MXene may be a mixture of the single-layer MXene particles 10a and multilayer MXene particles 10b, with some unseparated multilayer MXene particles 10b remaining. Typically, MXene particles are ｍ X ｎ At least one of the surfaces of the layer body 1a represented by the formula (I) may be planar (two-dimensional), and both surfaces of the layer body 1a may be planar (two-dimensional).

[0032] Although not limiting this embodiment, the thickness of each layer (corresponding to the above-mentioned MXene layers 7a and 7b) contained in the MXene particle is, for example, 0.8 nm to 5 nm, particularly 0.8 nm to 3 nm (this may vary mainly depending on the number of M atomic layers contained in each layer). The thickness of each layer is determined as a number-average size (e.g., a number-average of at least 40 atoms) based on atomic force microscope (AFM) or transmission electron microscope (TEM) images.

[0033] For individual stacks of two-dimensional particles (particularly multi-layered MXene particles that may be included), the interlayer distance (or gap dimension, shown as Δd in FIG. 1( b)) may be, for example, 0.8 nm to 10 nm, particularly 0.8 nm to 5 nm, and more particularly about 1 nm, and the total number of layers may be 2 to 20,000. The interlayer distance in two-dimensional particles can be measured by determining the interplanar distance (the sum of the interlayer distance and the thickness of each layer) from the position of the peak corresponding to the (002) plane of MXene that exists at 2θ=10° (deg) or less in X-ray diffraction measurement of the two-dimensional particles, and then subtracting the thickness of each layer from the interplanar distance.

[0034] The two-dimensional particles may include MXene particles with a small number of layers. The term "small number of layers" refers to, for example, six or fewer MXene layers. Furthermore, the thickness of the multilayer MXene particles with a small number of layers in the stacking direction is preferably 15 nm or less, and more preferably 10 nm or less. Hereinafter, these "multilayer MXene particles with a small number of layers" may be referred to as "few-layered MXene particles." Furthermore, single-layered MXene particles and few-layered MXene particles may be collectively referred to as "single-layered / few-layered MXene particles."

[0035] In the above two-dimensional particles, the proportion of single-layer / few-layer MXene particles having a thickness of 15 nm or less may be 0 vol% or more and 100 vol% or less, further 0 vol% or more and 99 vol% or less, even further 0 vol% or more and 50 vol% or less, and particularly 0 vol% or more and 30 vol% or less.

[0036] (Average value of major axes of two-dimensional surfaces of two-dimensional particles) The major axes of the two-dimensional particles are preferably 1 μm or more and 20 μm or less in a plane parallel to each layer (hereinafter also referred to as "two-dimensional surface"). Hereinafter, the average value of the major axes of the two-dimensional surfaces may be referred to as the "average flake size".

[0037] The larger the average flake size, the better the orientation of the two-dimensional particles in the material containing them. The average major axis of the two-dimensional surface is preferably 1.5 μm or more, more preferably 2.5 μm or more. When MXene is delaminated by ultrasonic treatment, the majority of the MXene is reduced in size to a major axis of approximately several hundred nanometers by the ultrasonic treatment, and therefore the film formed from the single-layer MXene delaminated by ultrasonic treatment is thought to have low orientation of the two-dimensional particles.

[0038] The average value of the major axis of the two-dimensional surface is 20 μm or less, preferably 15 μm or less, and more preferably 10 μm or less, from the viewpoint of dispersibility in the dispersion medium.

[0039] The longest diameter of the two-dimensional plane refers to the longest diameter when each MXene particle is approximated to an ellipse in an electron micrograph obtained by observing the two-dimensional particle from a direction substantially perpendicular to the plane parallel to each layer, and the average longest diameter of the two-dimensional plane refers to the number average of the longest diameters of 80 or more particles. Scanning electron microscopes (SEMs) and transmission electron microscopes (TEMs) can be used as electron microscopes.

[0040] The average major axis of the two-dimensional particles of this embodiment may be measured by dissolving a material containing the two-dimensional particles in a solvent and dispersing the two-dimensional particles in the solvent, or by measuring the average major axis from an SEM image of the material.

[0041] (Average Thickness of Two-Dimensional Particles) The average thickness of the two-dimensional particles of this embodiment is preferably 1 nm or more and 100 μm or less. The thickness is preferably 50 μm or less, and more preferably 20 μm or less. On the other hand, considering the thickness of the monolayer MXene particles, the lower limit of the thickness of the two-dimensional particles can be 1 nm.

[0042] The thickness of the two-dimensional particles can be understood as the length in a direction approximately perpendicular to a plane parallel to each layer, and the average thickness of the two-dimensional particles is determined as a number-average dimension (e.g., a number-average of at least 40 particles) based on atomic force microscope (AFM) or transmission electron microscope (TEM) photographs.

[0043] The two-dimensional particles can be produced by the following production method, but the two-dimensional particles in the present disclosure are not limited to those produced by the following production method.

[0044] In one embodiment, the method for producing the two-dimensional particles includes: (a) forming a compound having the following formula: M ｍ AX ｎ(wherein M is at least one metal of Group 3, 4, 5, 6, or 7; X is a carbon atom, a nitrogen atom, or a combination thereof; A is at least one element of Group 12, 13, 14, 15, or 16; n is 1 or more and 4 or less; and m is greater than n and 5 or less); (b) removing at least a part of the A atoms from the precursor by etching using an etching solution to obtain the etched product; (c) washing the etched product to obtain a washed product; and the method may further include: (d) performing an intercalation treatment on the etched product using a metal-containing compound in a dispersion medium to obtain an intercalation product; and (e) performing a delamination treatment on the intercalation product to obtain a delamination product.

[0045] In one embodiment, the etched product or the delamination product can be used as the two-dimensional particles, and preferably the washed product can be used as the two-dimensional particles.

[0046] Each step will be described below.

[0047] Step (a) First, a predetermined precursor is prepared. The predetermined precursor that can be used in this embodiment is a MAX phase, which is a precursor of MXene, and is represented by the following formula: M ｍ AX ｎ (wherein M is at least one metal of Group 3, 4, 5, 6, or 7; X is a carbon atom, a nitrogen atom, or a combination thereof; A is at least one element of Group 12, 13, 14, 15, or 16; n is 1 or more and 4 or less; and m is greater than n and 5 or less).

[0048] The above M, X, n, and m are as defined above. A is at least one Group 12, 13, 14, 15, or 16 element, and is usually a Group A element, typically a Group IIIA element or a Group IVA element, and more particularly may include at least one element selected from the group consisting of Al, Ga, In, Tl, Si, Ge, Sn, Pb, P, As, S, and Cd, and is preferably Al or Si.

[0049] The MAX phase is M ｍ X ｎ (each X may have a crystal lattice in which it is located in an octahedral array of M) and a layer composed of A atoms is located between them. In the MAX phase, when m=n+1, typically, one layer of X atoms is arranged between each of the n+1 layers of M atoms (these are collectively referred to as "M ｍ X ｎ The repeating unit has a layer of A atoms (also referred to as an "A atom layer") arranged as the next layer after the n+1th layer of M atoms, but is not limited thereto.

[0050] The MAX phase can be produced by a known method. For example, TiC powder, Ti powder, and Al powder are mixed in a ball mill, and the resulting mixed powder is sintered in an Ar atmosphere to obtain a sintered body (a block of the MAX phase). The sintered body is then pulverized with an end mill to obtain the powdered MAX phase for the next step.

[0051] Step (b) In step (b), the above M ｍ AX ｎ An etching process is performed to remove at least a part of the A atoms from the precursor (MAX phase) represented by the formula: ｍ X ｎ An etched product is obtained in which at least a part of the layer composed of A atoms has been removed while the layer is maintained.

[0052] The conditions for the etching treatment are not particularly limited, and known conditions can be used. －The etching can be carried out using an etching solution containing the above. Such an etching solution may contain hydrofluoric acid, hydrochloric acid, phosphoric acid, or the like as an acid. In one embodiment, examples of the etching solution include hydrofluoric acid; a mixture of hydrofluoric acid and hydrochloric acid; a mixture of lithium fluoride and hydrochloric acid, and the like, all of which may further contain phosphoric acid. Water, for example, pure water, may be used as a solvent in the etching solution.

[0053] The etching treatment may be carried out by mixing the precursor with the etching solution to form a slurry.

[0054] In one embodiment, in step (b), an intercalation treatment may be performed simultaneously. By adding a metal-containing compound described later to the etching solution, the etching treatment and the intercalation treatment can be performed simultaneously. In this case, step (e) described later may be further performed.

[0055] In the case where an intercalation treatment is simultaneously performed in step (b), the content of the metal-containing compound in the total of the precursor, the metal-containing compound, and the etching solution can be, for example, 0.001% by mass or more and 10% by mass or less, further 0.01% by mass or more and 1% by mass or less, particularly 0.1% by mass or more and 1% by mass or less.

[0056] Step (c): In step (c), the treated product obtained by the etching treatment is washed to obtain a washed product. By washing, the acid used in the etching treatment and the like can be sufficiently removed.

[0057] The washing is preferably carried out using water. The amount of water to be mixed with the etched product and the washing method are not particularly limited. For example, adding water and stirring, centrifuging, or the like may be performed. Stirring methods include methods using a hand shake, an automatic shaker, a shear mixer, a pot mill, or the like. The degree of stirring, such as the stirring speed and stirring time, may be adjusted depending on the amount and concentration of the etched product to be treated. The washing with water may be carried out one or more times, and it is preferable to wash with water multiple times. For example, the washing with water may be carried out by sequentially performing step (i) adding water (to the treated product or the remaining precipitate obtained in (iii) below) and stirring, step (ii) centrifuging the stirred product, and step (iii) discarding the supernatant after centrifugation. Steps (i) to (iii) may be repeated two or more times, for example, up to 15 times.

[0058] Step (d): In step (d), the etched product is subjected to an intercalation treatment in a dispersion medium using a metal-containing compound containing metal ions to obtain an intercalation-treated product. As a result, the metal ions contained in the metal-containing compound are intercalated between two adjacent M ｍ X ｎ An intercalated product is obtained in which the intercalation occurs between the layers.

[0059] The metal ions may include monovalent metal ions, such as alkali metal ions such as lithium ions, sodium ions, and potassium ions, copper ions, silver ions, and gold ions.

[0060] Examples of the metal-containing compound include ionic compounds in which the metal ions and anions are bonded. Examples include sulfide salts including iodides, phosphates, and sulfates of the metal ions, nitrates, acetates, and carboxylates. The metal ions are preferably lithium ions, and the metal-containing compounds are preferably metal-containing compounds containing lithium ions, more preferably ionic compounds of lithium ions, and even more preferably one or more of iodides, phosphates, and sulfides of lithium ions. If lithium ions are used as the metal ions, it is thought that the water hydrated with lithium ions has the most negative dielectric constant, making it easier to form a monolayer.

[0061] The content of the metal-containing compound in the total of the etched product, the metal-containing compound, and the dispersion medium can be, for example, 0.001% by mass to 10% by mass, more preferably 0.01% by mass to 1% by mass, and particularly preferably 0.1% by mass to 1% by mass. When the content of the metal-containing compound is in this range, the dispersibility in the dispersion medium is good.

[0062] The specific method of intercalation treatment is not particularly limited. For example, the dispersion medium, the etched product, and the metal-containing compound may be mixed and stirred or allowed to stand. For example, stirring at room temperature may be used. Examples of the stirring method include a method using a stirring bar such as a stirrer, a method using a stirring blade, a method using a mixer, and a method using a centrifugal device. The stirring time can be set depending on the production scale of the single-layer / few-layer MXene particles, and can be set, for example, between 12 and 24 hours. The order of mixing the dispersion medium, the etched product, and the metal-containing compound is not particularly limited. In one embodiment, the metal-containing compound may be mixed after mixing the dispersion medium and the etched product. Typically, the etching solution after the etching treatment may be used as the dispersion medium.

[0063] Step (e) In step (e), the intercalation-treated product obtained by the intercalation treatment is subjected to a delamination treatment to obtain a delamination-treated product. The delamination treatment is a process of applying a shear stress to the intercalation-treated product to separate two adjacent Mｍ X ｎ The delamination process involves peeling off at least a portion of the layers. The delamination process can result in the MXene particles being divided into a single layer or a few layers.

[0064] The conditions for the delamination treatment are not particularly limited and can be performed by known methods. For example, a method of applying shear stress to the intercalation-treated material includes dispersing the intercalation-treated material in a dispersion medium and stirring the mixture. Examples of stirring methods include ultrasonic treatment, hand shaking, and stirring using an automatic shaker. The degree of stirring, such as the stirring speed and stirring time, can be adjusted depending on the amount and concentration of the material to be treated. For example, the above-mentioned intercalation-treated slurry can be centrifuged to discard the supernatant, and then pure water can be added to the remaining precipitate, followed by stirring using, for example, a hand shake or an automatic shaker to separate the layers. Removal of unexfoliated material can be achieved by centrifuging the slurry, discarding the supernatant, and then washing the remaining precipitate with water. For example, (i) pure water can be added to the remaining precipitate after discarding the supernatant, followed by stirring, (ii) centrifuging, and (iii) recovering the supernatant. The steps (i) to (iii) can be repeated at least once, preferably at least twice, but not more than 10 times to obtain a supernatant containing single-layer and few-layer MXene particles as a delamination-treated product. Alternatively, the supernatant can be centrifuged and discarded to obtain a clay containing single-layer and few-layer MXene particles as a delamination-treated product.

[0065] In the method for producing two-dimensional particles, if an intercalation treatment is performed, a washing treatment may be further performed at any stage after the intercalation treatment, preferably at a stage after the delamination treatment. By performing such a washing treatment, the metal ions and metal-containing compounds used in the intercalation can be sufficiently removed. Typically, such a washing treatment is performed after step (e).

[0066] In one embodiment, the cleaning treatment after the intercalation treatment may be carried out in the same manner as in step (c) above. In another embodiment, the delamination-treated product may be acid-treated, and then the acid-treated product may be cleaned in the same manner as in step (c) above. In these cases, the etched product in step (c) above may be read as the delamination-treated product or the acid-treated product, respectively, and the cleaning treatment may be carried out.

[0067] The acid treatment can be carried out by mixing the delamination-treated material with an acid solution and stirring the mixture. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydroiodic acid, hydrobromic acid, and hydrofluoric acid; and organic acids such as acetic acid, citric acid, oxalic acid, benzoic acid, and sorbic acid. The acid concentration in the acid solution can be adjusted appropriately depending on the delamination-treated material. The stirring can be carried out using a handshake, automatic shaker, shear mixer, pot mill, or the like. The acid treatment can be carried out one or more times. If necessary, the acid treatment can be carried out by mixing the material with fresh acid solution (an acid solution not used in the acid treatment) and stirring the mixture two or more times, for example, up to 10 times.

[0068] The intermediates and target products in the above-described production methods may be isolated by commonly used purification methods, such as suction filtration, and drying such as heat drying, freeze drying, and vacuum drying.

[0069] The two-dimensional particles were found to be effective in adsorption of Na in adsorption tests using human plasma. ＋ , K. ＋ , Mg ２＋ , Ca ２＋ , P (e.g., PO ４ ３－uremic substances (for example, uremic substances having a molecular weight of 100 or more, particularly, protein-bound uremic substances such as creatinine and homocysteine; and medium-molecular-weight uremic substances such as parathyroid hormone, β2-microglobulin, and tumor necrosis factor (TNF)-α); cytokines such as interleukins, interferons, chemokines, hematopoietic factors, growth factors, and tumor necrosis factors (in one embodiment, inflammatory cytokines such as interleukin-18); proteins such as albumin and M protein; carcinogenic substances; and disease-causing substances such as inflammatory substances. Therefore, pharmaceutical compositions containing the above-mentioned two-dimensional particles are useful for treating or preventing diseases.

[0070] The above diseases include symptoms associated with kidney diseases such as acute kidney injury (including acute renal failure) and chronic kidney disease (including chronic renal failure and end-stage renal failure), and symptoms associated with inflammatory diseases such as vascular dementia, inflammatory bowel disease, hepatitis, and myocarditis; in particular, symptoms associated with kidney injury and symptoms associated with inflammatory diseases, specifically uremia; electrolyte metabolism disorders such as hypernatremia, hyperkalemia, hypermagnesemia, hypercalcemia, and hyperphosphatemia; autoimmune diseases; infectious diseases; inflammatory diseases; endocrine / metabolic diseases; cardiovascular diseases; blood diseases; digestive diseases; neurological diseases; malignant tumors; drug poisoning; vascular dementia, inflammatory bowel disease, hepatitis, and myocarditis.

[0071] Furthermore, because the two-dimensional particles can preferentially adsorb the disease-causing substances, their administration to a subject is expected to adsorb the disease-causing substances in vivo and reduce their presence in the blood. In particular, it is expected that the particles, when orally administered and retained in the intestinal tract, will adsorb and eliminate disease-causing substances in the blood through mutual access between the intestinal tract and blood vessels. Furthermore, the reduction of disease-causing substances in the blood is expected to reduce the need for dialysis therapy and the burden on organs, including the kidneys.

[0072] The pharmaceutical composition according to this embodiment can be made into various dosage forms depending on the method of use, such as powder, granules, fine granules, dry syrup, tablets, capsules, liquids, sublingual preparations, etc., as well as injections, ointments, suppositories, patches, etc.

[0073] The pharmaceutical composition according to this embodiment can be formulated as a pharmaceutical composition further comprising two-dimensional particles as an active ingredient and pharmacologically acceptable additives by known methods depending on the dosage form. Examples of such additives include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers. The pharmaceutical composition of the present disclosure can be prepared by appropriately mixing the two-dimensional particles with the additives, or by diluting and dissolving the two-dimensional particles with the additives.

[0074] The pharmaceutical composition according to this embodiment can be administered systemically or locally, orally or parenterally (intranasally, pulmonary, intravenously, rectally, subcutaneously, intramuscularly, or transdermally). In one aspect, the pharmaceutical composition according to this embodiment can be administered orally.

[0075] When the pharmaceutical composition of the present disclosure is used for treatment, the dosage of the two-dimensional particles, which are its active ingredient, is appropriately determined depending on the patient's age, sex, weight, disease, degree of treatment, etc. For example, in the case of oral administration, the effective dosage is approximately 100 mg to 10 g per body per day for an adult (body weight 60 kg), and may be administered once or in divided doses as appropriate.

[0076] Furthermore, pharmaceutical compositions containing the two-dimensional particles can be used to manufacture medicaments for treating or preventing diseases.

[0077] The present disclosure will be explained in more detail below with reference to examples, but the present disclosure is not limited thereto.

[0078] Example 1 [Preparation of MXene] In Examples 1 and 2, two-dimensional particles were prepared by sequentially carrying out the following steps, as detailed below: (1) preparation of a precursor (MAX), (2) etching of the precursor, and (3) washing and drying.

[0079] (1) Preparation of Precursor (MAX) TiC powder, Ti powder, and Al powder (all manufactured by Kojundo Chemical Laboratory Co., Ltd.) were mixed in a molar ratio of 2:1:1 in a ball mill containing zirconia balls for 24 hours. The resulting mixed powder was sintered at 1,350°C for 2 hours in an Ar atmosphere. The resulting sintered body (block) was then pulverized with an end mill to a maximum size of 40 μm or less. This resulted in the preparation of TiC precursor (MAX). ３ AlC ２ particles were obtained.

[0080] (2) Etching of the precursor Ti prepared by the above method ３ AlC ２ Using particles (powder), etching was performed under the following etching conditions to remove Ti ３ AlC ２ A solid-liquid mixture (slurry) containing solid components derived from the powder was obtained. (Etching conditions) Precursor: Ti ３ AlC ２ (Sieved through a 45 μm mesh) Etching solution composition: 50% by mass HF 6 mL, H ２ O 18 mL HCl (12 M) 36 mL Precursor input amount: 3.0 g Etching container: 100 mL Eye Boy Etching temperature: 35°C Etching time: 24 h Stirrer rotation speed: 400 rpm

[0081] (3) Washing and drying The slurry was divided into two parts and placed in two 50 mL centrifuge tubes, respectively. After centrifuging at 3,500 G using a centrifuge, the supernatant was discarded. 40 mL of pure water was added to each centrifuge tube, and the tubes were centrifuged again at 3,500 G to separate and remove the supernatant. This procedure was repeated 11 times. After the final centrifugation, the supernatant was discarded, and Ti ３ C ２ T ｓ - A water medium clay was obtained. The obtained clay was freeze-dried to dry powder, and a dry powder of two-dimensional particles was obtained.

[0082] In Example 2, (1) a precursor (MAX) was prepared in the same manner as in Example 1, and then the following step (2) was carried out. (3) Cleaning and drying were carried out in the same manner as in Example 1 to produce two-dimensional particles. (1) Precursor preparation: same as in Example 1. (2) Precursor etching: Precursor: Ti ３ AlC ２ (Sieved through a 45 μm mesh) Etching solution composition: 50% by mass HF 5 mL, ２ O 45 mL Precursor input amount: 3.0 g Etching container: 100 mL Eye Boy Etching temperature: 35°C Etching time: 24 hours Stirrer rotation speed: 400 rpm (3) Cleaning: Same as in Example 1

[0083] In Example 3, (1) a precursor (MAX) was prepared in the same manner as in Example 1, and then the following step (2) was carried out, and (3) washing and drying were carried out in the same manner as in Example 1 to produce two-dimensional particles. (1) Precursor preparation: same as in Example 1 (2) Precursor etching Precursor: Ti ３ AlC ２ (Passed through a 45 μm sieve) Etching solution composition: 6 mL of 49% by mass HF aqueous solution, ２ O 9mL 85% by mass H ３ P.O. ４ Aqueous solution: 45 mL Amount of precursor added: 3.0 g Etching container: 100 mL Eye Boy Etching temperature: 35°C Etching time: 24 hours Stirrer rotation speed: 400 rpm (3) Cleaning: Same as in Example 1

[0084] In Example 4, (1) a precursor (MAX) was prepared in the same manner as in Example 1, and then the following step (2) was carried out, and (3) washing and drying were carried out in the same manner as in Example 1 to produce two-dimensional particles. (1) Precursor preparation: same as in Example 1 (2) Precursor etching Precursor: Ti ３ AlC ２(Passed through a 45 μm mesh sieve) Etching solution composition: LiF 4.8 g, HCl (9 M) 60 mL Amount of precursor added: 3.0 g Etching container: 100 mL Eye Boy Etching temperature: 35° C. Etching time: 24 hours Stirrer rotation speed: 400 rpm (3) Cleaning: Same as in Example 1

[0085] Example 5 In Example 5, two-dimensional particles were fabricated by sequentially carrying out the following steps, as detailed below: (1) preparation of a precursor (MAX), (2) etching of the precursor, and (3) washing and drying.

[0086] (1) Preparation of Precursor (MAX) 73 g of Ti powder, 47.2 g of TiN powder, 20.6 g of Al powder, and 9.2 g of C powder (all manufactured by Kojundo Chemical Laboratory Co., Ltd.) were placed in a ball mill containing zirconia balls and mixed for 24 hours. The resulting mixed powder was fired at 1,400 °C for 2 hours in an Ar atmosphere. The fired body (block) thus obtained was pulverized with an end mill to a maximum dimension of 40 μm or less. As a result, TiN powder was prepared as a precursor (MAX). ３ AlCN particles were obtained.

[0087] (2) Etching of the precursor Ti prepared by the above method ３ Etching was performed using AlCN particles (powder) under the following etching conditions to remove Ti. ３ A solid-liquid mixture (slurry) containing solid components derived from the AlCN powder was obtained. (Etching conditions) Precursor: Ti ３ AlCN (passed through a 45 μm sieve) Etching solution composition: 48 mass% HF 6 mL 38.8 mass% HCl 36 mL H ２ O 18 mL Precursor input amount: 3.0 g Etching container: 100 mL Eye Boy Etching temperature: 25°C Etching time: 24 h Stirrer rotation speed: 400 rpm

[0088] (3) Washing and drying The slurry was divided into two parts and placed in two 50 mL centrifuge tubes, respectively. After centrifuging at 3,500 G using a centrifuge, the supernatant was discarded. 40 mL of pure water was added to each centrifuge tube, and the tubes were centrifuged again at 3,500 G to separate and remove the supernatant. This procedure was repeated 11 times. After the final centrifugation, the supernatant was discarded, and Ti ３ CNT ｓ - A water medium clay was obtained. The obtained clay was freeze-dried to dry powder, and a dry powder of two-dimensional particles was obtained.

[0089] Example 6 In Example 6, two-dimensional particles were fabricated by sequentially carrying out the following steps, as detailed below: (1) preparation of a precursor (MAX), (2) etching of the precursor, and (3) washing and drying.

[0090] (1) Preparation of Precursor (MAX) 21.5 g of V powder, 6.3 g of Al powder, and 2.3 g of C powder (all manufactured by Kojundo Chemical Laboratory Co., Ltd.) were placed in a ball mill containing zirconia balls and mixed for 24 hours. The resulting mixed powder was fired at 1,550 °C for 2 hours in an Ar atmosphere. The fired body (block) obtained was crushed in a jaw crusher to a maximum size of 45 μm or less. As a result, V was prepared as a precursor (MAX). ２ AlC particles were obtained.

[0091] (2) Etching of precursor V prepared by the above method ２ Etching was performed using AlC particles (powder) under the following etching conditions. ２ A solid-liquid mixture (slurry) containing solid components derived from the AlC powder was obtained. (Etching conditions) Precursor: V ２ AlC (passed through a 45 μm sieve) Etching solution composition: 48 mass% HF 6 mL 38.8 mass% HCl 24 mL Amount of precursor added: 3.0 g Etching container: 100 mL Eye Boy Etching temperature: 50°C Etching time: 48 hours Stirrer rotation speed: 400 rpm

[0092] (3) Washing and drying The slurry was divided into two parts and placed in two 50 mL centrifuge tubes, respectively. After centrifuging at 3,500 G using a centrifuge, the supernatant was discarded. 40 mL of pure water was added to each centrifuge tube, and the tubes were centrifuged again at 3,500 G to separate and remove the supernatant. This procedure was repeated 11 times. After the final centrifugation, the supernatant was discarded, and the V ２ CT ｓ - A water medium clay was obtained. The obtained clay was freeze-dried to dry powder, and a dry powder of two-dimensional particles was obtained.

[0093] Example 7 In Example 7, two-dimensional particles were fabricated by sequentially carrying out the following steps, as detailed below: (1) preparation of a precursor (MAX), (2) etching of the precursor, and (3) washing and drying.

[0094] (1) Preparation of Precursor (MAX) 105.4 g of Ti powder, 32.7 g of Al powder, and 11.9 g of C powder (all manufactured by Kojundo Chemical Laboratory Co., Ltd.) were placed in a ball mill containing zirconia balls and mixed for 24 hours. The resulting mixed powder was sintered at 1,550 °C for 2 hours in an Ar atmosphere. The resulting sintered body (block) was pulverized with an end mill to a maximum dimension of 40 μm or less. This resulted in the preparation of Ti as a precursor (MAX). ２ AlC particles were obtained.

[0095] (2) Etching of the precursor Ti prepared by the above method ２ Etching was performed using AlC particles (powder) under the following etching conditions to remove Ti. ２ A solid-liquid mixture (slurry) containing solid components derived from the AlC powder was obtained. (Etching conditions) Precursor: Ti ２ AlC (passed through a 45 μm mesh sieve) Etching solution composition: 48 mass% HF 2 mL 38.8 mass% HCl 12 mL H ２ Precursor input amount: 1.0 g Etching container: 100 mL Eye Boy Etching temperature: 35°C Etching time: 24 h Stirrer rotation speed: 400 rpm

[0096] (3) Washing and drying The slurry was divided into two parts and placed in two 50 mL centrifuge tubes, respectively. After centrifuging at 3,500 G using a centrifuge, the supernatant was discarded. 40 mL of pure water was added to each centrifuge tube, and the tubes were centrifuged again at 3,500 G to separate and remove the supernatant. This procedure was repeated 11 times. After the final centrifugation, the supernatant was discarded, and Ti ２ CT ｓ - A water medium clay was obtained. The obtained clay was freeze-dried to dry powder, and a dry powder of two-dimensional particles was obtained.

[0097] Example 8 In Example 8, two-dimensional particles were fabricated by sequentially carrying out the following steps, as detailed below: (1) preparation of a precursor (MAX), (2) etching of the precursor, and (3) washing and drying.

[0098] (1) Preparation of Precursor (MAX) TiC powder, Ti powder, and Al powder (all manufactured by Kojundo Chemical Laboratory Co., Ltd.) were mixed in a molar ratio of 2:1:1 in a ball mill containing zirconia balls for 24 hours. The resulting mixed powder was sintered at 1350°C for 2 hours in an Ar atmosphere. The resulting sintered body (block) was then pulverized with an end mill to a maximum size of 40 μm or less. As a result, TiC powder was obtained as MAX particles. ３ AlC ２ particles were obtained.

[0099] (2) Etching of the precursor Ti prepared by the above method ３ AlC ２ Using particles (powder), etching was performed under the following etching conditions to remove Ti ３ AlC ２ A solid-liquid mixture (slurry) containing solid components derived from the powder was obtained. (Etching conditions) Precursor: Ti ３ AlC ２ (Sieved through a 45 μm mesh) Etching solution composition: 48% HF 6 mL H ２ O 54 mL Precursor input amount: 3.0 g Etching container: 100 mL Eye Boy Etching temperature: 50°C Etching time: 24 h Stirrer rotation speed: 400 rpm

[0100] (3) Washing and drying The slurry was divided into two parts and placed in two 50 mL centrifuge tubes, respectively. After centrifuging at 3500 G using a centrifuge, the supernatant was discarded. 40 mL of pure water was added to the remaining precipitate in each centrifuge tube, and the tubes were centrifuged again at 3500 G to separate and remove the supernatant. This procedure was repeated 11 times. After the final centrifugation, the supernatant was discarded, and Ti ３ C ２ T ｘ - A water-containing clay was obtained. The obtained clay was freeze-dried to dry powder, and a dry powder of two-dimensional particles was obtained.

[0101] Example 9 In Example 9, two-dimensional particles were fabricated by sequentially carrying out the following steps, as detailed below: (1) preparation of a precursor (MAX), (2) etching of the precursor, and (3) washing and drying.

[0102] (1) Preparation of Precursor (MAX) TiC powder, Ti powder, and Al powder (all manufactured by Kojundo Chemical Laboratory Co., Ltd.) were mixed in a molar ratio of 2:1:1 in a ball mill containing zirconia balls for 24 hours. The resulting mixed powder was sintered at 1350°C for 2 hours in an Ar atmosphere. The resulting sintered body (block) was then pulverized with an end mill to a maximum size of 40 μm or less. As a result, TiC powder was obtained as MAX particles. ３ AlC ２ particles were obtained.

[0103] (2) Etching of the precursor Ti prepared by the above method ３ AlC ２ Using particles (powder), etching was performed under the following etching conditions to remove Ti ３ AlC ２ A solid-liquid mixture (slurry) containing solid components derived from the powder was obtained. (Etching conditions) Precursor: Ti ３ AlC ２ (Passed through a 45 μm sieve) Etching solution composition: 48 mass% HF 6 mL 38.8 mass% HCl 38 mL H ２O 16 mL Precursor input amount: 3.0 g Etching container: 100 mL Eye Boy Etching temperature: 50°C Etching time: 24 h Stirrer rotation speed: 400 rpm

[0104] (3) Washing and drying The slurry was divided into two parts and placed in two 50 mL centrifuge tubes, respectively. After centrifuging at 3500 G using a centrifuge, the supernatant was discarded. 40 mL of pure water was added to the remaining precipitate in each centrifuge tube, and the tubes were centrifuged again at 3500 G to separate and remove the supernatant. This procedure was repeated 11 times. After the final centrifugation, the supernatant was discarded, and Ti ３ C ２ T ｘ - A water-containing clay was obtained. The obtained clay was freeze-dried to dry powder, and a dry powder of two-dimensional particles was obtained.

[0105] Example 10 In Example 10, two-dimensional particles were fabricated by sequentially carrying out the following steps, as detailed below: (1) preparation of a precursor (MAX), (2) etching of the precursor, (3) washing, (4) Li intercalation, (5) delamination, and (6) modification with amino groups and drying.

[0106] (1) Preparation of Precursor (MAX) TiC powder, Ti powder, and Al powder (all manufactured by Kojundo Chemical Laboratory Co., Ltd.) were mixed in a molar ratio of 2:1:1 in a ball mill containing zirconia balls for 24 hours. The resulting mixed powder was sintered at 1350°C for 2 hours in an Ar atmosphere. The resulting sintered body (block) was then pulverized with an end mill to a maximum size of 40 μm or less. As a result, TiC powder was obtained as MAX particles. ３ AlC ２ particles were obtained.

[0107] (2) Etching of the precursor Ti prepared by the above method ３ AlC ２ Using particles (powder), etching was performed under the following etching conditions to remove Ti ３ AlC ２ A solid-liquid mixture (slurry) containing solid components derived from the powder was obtained. (Etching conditions) Precursor: Ti ３ AlC ２(Passed through a 45 μm sieve) Etching solution composition: 48 mass% HF 2 mL 38.8 mass% HCl 38 mL H ２ O 16 mL Precursor input amount: 3.0 g Etching container: 100 mL Eye Boy Etching temperature: 50°C Etching time: 24 h Stirrer rotation speed: 400 rpm

[0108] (3) Washing and drying The slurry was divided into two parts and placed in two 50 mL centrifuge tubes, respectively. After centrifuging at 3500 G using a centrifuge, the supernatant was discarded. 40 mL of pure water was added to the remaining precipitate in each centrifuge tube, and the tubes were centrifuged again at 3500 G to separate and remove the supernatant. This procedure was repeated 11 times. After the final centrifugation, the supernatant was discarded, and Ti ３ C ２ T ｘ -Water medium clay was obtained.

[0109] (4) Li intercalation Ti prepared by the above method ３ C ２ T ｘ The clay was mixed with water as a medium, and LiCl was used as the Li-containing compound. The mixture was stirred at 20°C to 25°C for 12 hours under the following conditions to perform Li intercalation. (Li intercalation conditions) ３ C ２ T ｘ - Water medium clay (MXene after washing): solid content 0.75 g LiCl: 0.75 g Intercalation container: 100 mL Eye Boy Temperature: 20 ° C or higher and 25 ° C or lower (room temperature) Time: 10 h Stirrer rotation speed: 800 rpm

[0110] (5) Delamination The above Ti ３ C ２ T ｘ(i) 40 mL of pure water was added to the aqueous clay medium, followed by stirring for 15 minutes with a shaker. (ii) The mixture was centrifuged at 3,500 G, and (iii) the supernatant was collected as a single-layer MXene-containing solution. These steps (i) to (iii) were repeated four times to obtain a single-layer MXene-containing supernatant. This supernatant was then centrifuged at 4,300 G for two hours using a centrifuge, after which the supernatant was discarded, yielding a single-layer / scarce MXene-containing clay as a single-layer / scarce MXene-containing sample.

[0111] (6) Amino group modification and drying 20 mg of 6-aminohexyl phosphate hydrochloride and 5 mL of pure water were added to 0.34 g of single-layer and few-layer MXene-containing clay, and the mixture was stirred at room temperature for 2 hours at a stirrer speed of 800 rpm. The resulting slurry was centrifuged at 8,000 rpm for 8 minutes, and the supernatant was discarded. The same volume of pure water as the discarded supernatant was added, and the mixture was centrifuged at 8,000 rpm for 8 minutes. The procedure of discarding the supernatant, adding the same volume of pure water as the discarded supernatant, and centrifuging at 8,000 rpm for 8 minutes was repeated once. Next, the supernatant was discarded, and the same volume of ethanol as the discarded supernatant was added and dispersed, followed by air drying, to obtain amino group-modified Ti. ３ C ２ Particles (powder) were obtained.

[0112] Comparative Example 1 Spherical adsorptive carbon ("Kremezin Rapidly Disintegrating Tablets 500 mg", manufactured by Kureha Corporation) was powdered using a mortar and subjected to adsorption evaluation.

[0113] Comparative Example 2 An adsorption-type blood purifier ("Rixel", manufactured by Kaneka Corporation) was disassembled, and the removed adsorbent was subjected to adsorption evaluation.

[0114] Comparative Example 3 Medicinal charcoal (manufactured by Nichi-Iko Pharmaceutical Co., Ltd.) was subjected to adsorption evaluation.

[0115] Adsorption Evaluation Method: Human plasma collected from a healthy subject, the two-dimensional particles of the Examples, and the spherical adsorbent carbon, adsorptive blood purifier, or medicinal carbon of the Comparative Examples (hereinafter collectively referred to as "adsorbent") were weighed into a 50 mL centrifuge tube and shaken and stirred for 60 minutes using a thermostatic shaker (Tytec BR-33FL) set at 37°C. Several mL of the mixture was then sampled, and the adsorbent was separated using a syringe filter with a 0.45 μm pore size (Merck Millex Sterilization, diameter 33 mm, pore size 0.45 μm), followed by component analysis. In Examples 1 to 4 and Comparative Examples 1 to 3, the amount of human plasma was 10 mL, and the amount of adsorbent was 0.6 g; in Examples 5 to 8 and 10, the amount of human plasma was 4 mL, and the amount of adsorbent was 0.2 g; and in Example 9, the amount of human plasma was 4 mL, and the amount of adsorbent was 0.2 g.

[0116] In Examples 1 to 4 and Comparative Examples 1 to 3, component analysis was performed for Na, P, K, urea, creatinine, homocysteine, folic acid, parathyroid hormone, β2-microglobulin, interleukin-18, trypsin, TNF-α (tumor necrosis factor-α), α-amylase, and albumin. In Examples 5 to 10, component analysis was performed for albumin, chloride (Cl), serum urea nitrogen (BUN), α-amylase (AMY), lipase, Na, K, inorganic phosphorus (IP), and β2-microglobulin. Measurements of Na, K, and Cl were performed by the electrode method; measurements of P, inorganic phosphorus, α-amylase, lipase, and creatinine were performed by the enzymatic method; measurements of urea and serum urea nitrogen were performed by the urease-GLDH-UV method; measurements of homocysteine ​​were performed by the HPLC method; measurements of folic acid were performed by the CLIA method; measurements of parathyroid hormone were performed by the ECLIA method; measurements of β2-microglobulin were performed by the latex agglutination method; measurements of interleukin-18, trypsin, and TNF-α were performed by the EIA method; and measurements of albumin were performed by the colorimetric method (BGC method).

[0117] The same treatment was also carried out on a centrifuge tube containing only human plasma without any adsorbent, and this was used as a baseline for the component concentration. Ａ１ , the concentration of component A at baseline is C Ａ０ The adsorption and removal rate was calculated based on the following formula. When the adsorption and removal rate was less than 0 mass%, it was set to 0 mass%. Adsorption and removal rate (mass%) = (C Ａ０ -C Ａ１ ) / C Ａ０ ×100

[0118] The results are shown in Tables 1 and 2.

[0119]

[0120]

[0121] It was confirmed that the two-dimensional particles of Examples 1 to 4 exhibit the ability to adsorb disease-causing substances, particularly electrolytes (ionic substances), uremic substances, inflammatory cytokines, and other proteins. Therefore, pharmaceutical compositions containing the two-dimensional particles may be useful for treating diseases. Furthermore, it was confirmed that the two-dimensional particles of Examples 5 to 10 exhibit the ability to adsorb disease-causing substances, particularly electrolytes (ionic substances), uremic substances, and other proteins. Therefore, pharmaceutical compositions containing the two-dimensional particles may be useful for treating diseases.

[0122] Animal Experiment 1: Administration Experiment to Renal Failure Model Rats. Five-sixths of the kidneys were surgically removed, and the two-dimensional particles (MXene) produced in Example 1 were administered to rats in an artificial state of renal failure for 28 days (10% of food intake in the high-dose group and 5% in the low-dose group). The rats' blood urea nitrogen (BUN) and serum creatinine (Cr) were compared to confirm the therapeutic effect on chronic renal failure. As comparative examples, a sham group was prepared in which only laparotomy was performed but no nephrectomy was performed, and a 5 / 6 nephrectomy group was prepared in which nephrectomy was performed but no MXene administration was performed. Lower values ​​for blood urea nitrogen (BUN) and serum creatinine (Cr) indicate better renal function.

[0123] As shown in Figures 3(a) and 3(b), blood urea nitrogen (BUN) values ​​decreased at 15 days of administration in the 5 / 6 nephrectomy group, the high-dose group, and the low-dose group, and were maintained at low values ​​even after administration. Furthermore, the high-dose and low-dose MXene-administered groups showed a more significant decrease. The decrease in blood urea nitrogen (BUN) values ​​was thought to be due to compensatory hypertrophy, and as shown in Figure 3(e), more significant renal hypertrophy was observed in the high-dose and low-dose MXene-administered groups. The sham group was used to assess the effect of stress during laparotomy on renal function, but no significant effect was observed.

[0124] As shown in Figures 3(c) and 3(d), serum creatinine (Cr) levels decreased at day 15 in both the 5 / 6 nephrectomy group, the high-dose group, and the low-dose group, and remained low even after several days of treatment. Furthermore, the high-dose and low-dose MXene-treated groups showed a more pronounced decrease in serum creatinine (Cr). The decrease in serum creatinine (Cr) levels was likely due to compensatory hypertrophy, and as shown in Figure 3(e), more pronounced renal hypertrophy was observed in the high-dose and low-dose MXene-treated groups. The sham group was used to assess the effect of stress during laparotomy on renal function, but no significant effect was observed.

[0125] From this, it can be said that administration of MXene removed uremic substances from the body, alleviated symptoms associated with renal damage, and restored renal function.

[0126] Animal Experiment 2: Administration Experiment on Hypertensive Mice Hypertension causes inflammation of cerebral capillaries, resulting in chronic hypoperfusion. This leads to a decline in cognitive function, a condition known as vascular dementia. In Animal Experiment 2, MXene was administered to mice with genetic hypertension to remove inflammatory substances from the body and confirm whether cognitive function could be restored. The administration period was 56 days, and the administration amount was 8% of the food intake. After the administration period, blood pressure fluctuations and cognitive behavior analysis (Novel Object Recognition Test) were performed. As a comparative example, a Ctl group that was not administered MXene was also prepared.

[0127] For cognitive behavior analysis (Novel Object Recognition Test), a black box measuring 400 mm in length, width, and height was used. On days 1 and 2, mice were left in the box for 10 minutes for habituation. On day 3, two identical substances (old substances) were placed in the cage and the mice were left for 10 minutes. On day 4, one of the objects was replaced with a novel substance and the mice were left for 10 minutes. The time spent exploring both objects was measured, and the ratio of the time spent exploring the novel substance to the total exploration time (Times of Entries Discrimination Index) was calculated using the following formula: Times of Entries Discrimination Index = [n / (n+f)] - 0.5 (where n represents the number of times the mouse touched the novel object and f represents the number of times the mouse touched the conventional object). This was used as an index of memory and learning ability. The mouse's behavioral area is shown in Figure 4, and the Times of Entries Discrimination Index is shown in Figure 5.

[0128] Although MXene administration did not result in a decrease in blood pressure, the Novel Object Recognition Test confirmed that the Times of Entries Discrimination Index was higher in the MXene group, with a positive number. This indicates that the subjects were interested in and approached the new substance more frequently than the old substance. In other words, the new substance was recognized as new, suggesting that cognitive function had recovered.

[0129] This indicates that administration of MXene removed inflammatory substances and alleviated symptoms associated with vascular disorders.

[0130] The present disclosure includes: [1] a two-dimensional particle having one or more layers, wherein the layers are represented by the following formula: M ｍ X ｎ(wherein M is at least one Group 3, 4, 5, 6 or 7 metal; X is a carbon atom, a nitrogen atom or a combination thereof; n is 1 or more and 4 or less; and m is greater than n and 5 or less), and a modified or terminal T (T is at least one selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom and a hydrogen atom) present on the surface of the layer body, the pharmaceutical composition being used for adsorbing a disease-causing substance in a living body by oral administration. [2] The pharmaceutical composition according to [1], wherein the disease-causing substance comprises a uremic substance having a molecular weight of 100 or more. [3] The pharmaceutical composition according to [2], wherein the uremic substance having a molecular weight of 100 or more comprises β2-microglobulin. [4] The pharmaceutical composition according to any one of [1] to [3], wherein the disease-causing substance comprises a cytokine. [5] The pharmaceutical composition according to any one of [1] to [4], wherein the cytokine comprises at least one selected from the group consisting of interleukins, interferons, chemokines, hematopoietic factors, cell growth factors, and tumor necrosis factors. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the disease-causing substance comprises an electrolyte. [7] The pharmaceutical composition according to any one of [1] to [5], wherein the disease-causing substance comprises Na ＋ , K. ＋ , Mg ２＋ , Ca ２＋ and P.O. ４ ３－ [8] The pharmaceutical composition according to any one of [1] to [6], which comprises at least one selected from the group consisting of:

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[10] The pharmaceutical composition according to any one of [1] to [6], which comprises administering to a subject an effective amount of two-dimensional particles having one or more layers to adsorb disease-causing substances ｍ X ｎ(wherein M is at least one metal of Group 3, 4, 5, 6, or 7; X is a carbon atom, a nitrogen atom, or a combination thereof; n is 1 or more and 4 or less; and m is greater than n and 5 or less), and a modification or termination T (T is at least one selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom, and a hydrogen atom) present on the surface of the layer body. [9] An adsorption method comprising administering to a subject an effective amount of two-dimensional particles having one or more layers, wherein the layer is represented by the following formula: M ｍ X ｎ (wherein M is at least one Group 3, 4, 5, 6 or 7 metal; X is a carbon atom, a nitrogen atom or a combination thereof; n is 1 or more and 4 or less; and m is greater than n and 5 or less), and a modified or terminal T (T is at least one selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom and a hydrogen atom) present on the surface of the layer body.

[10] The method according to [9], wherein the symptoms associated with renal failure are uremia, hypernatremia, hyperkalemia, hypermagnesemia, hypercalcemia or hyperphosphatemia.

[11] A method for treating or preventing an inflammatory disease, comprising administering to a subject an effective amount of two-dimensional particles having one or more layers, wherein the layer comprises a layer body represented by the following formula: MmXn (wherein M is at least one Group 3, 4, 5, 6, or 7 metal, X is a carbon atom, a nitrogen atom, or a combination thereof, n is 1 or more and 4 or less, and m is greater than n and 5 or less), and a modified or terminal T present on the surface of the layer body (T is at least one selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom, and a hydrogen atom).

[12] The method according to

[11] , wherein the inflammatory disease includes inflammatory bowel disease, vascular dementia, hepatitis, myocarditis, etc.

[0131] 1a, 1b Layer body (M ｍ X ｎLayer) 3a, 5a, 3b, 5b Modified or terminated T 7a, 7b MXene layer 10, 10a, 10b MXene particle (2D particle of layered material)

Claims

1. two-dimensional particles having one or more layers, The layer has the following formula: M ｍ X ｎ wherein M is at least one Group 3, 4, 5, 6, or 7 metal; X is a carbon atom, a nitrogen atom, or a combination thereof; n is 1 or more and 4 or less, m is greater than n and is equal to or less than 5. and a modification or terminal T (T is at least one selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom and a hydrogen atom) present on the surface of the layer body.

2. The pharmaceutical composition according to claim 1 , wherein the disease-causing substance comprises a uremic substance having a molecular weight of 100 or more.

3. The pharmaceutical composition according to claim 2, wherein the uremic substance having a molecular weight of 100 or more includes β2-microglobulin.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disease-causing substance comprises a cytokine.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cytokine comprises at least one selected from the group consisting of interleukins, interferons, chemokines, hematopoietic factors, cell growth factors, and tumor necrosis factors.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disease-causing substance comprises an electrolyte.

7. The disease-causing substance is Na ＋ , K ＋ , Mg ２＋ , Ca ２＋ and P.O. ４ ３－ The pharmaceutical composition according to any one of claims 1 to 3, comprising at least one selected from the group consisting of:

8. administering to a subject an effective amount of two-dimensional particles having one or more layers to adsorb disease-causing agents in vivo; The layer has the following formula: M ｍ X ｎ wherein M is at least one Group 3, 4, 5, 6, or 7 metal; X is a carbon atom, a nitrogen atom, or a combination thereof; n is 1 or more and 4 or less, m is greater than n and is equal to or less than 5. and a modification or termination T (T is at least one selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom and a hydrogen atom) present on the surface of the layer body.

9. A pharmaceutical composition for adsorbing disease-causing substances by oral administration, comprising MXene.