Pharmaceutical composition, method for improving intestinal flora, method for treating intestinal flora, and method for preventing intestinal flora

Abstract

The present invention provides a pharmaceutical composition, a method for improving intestinal flora, a method for treating the intestinal flora, and a method for preventing the intestinal flora. One purpose of the present invention is to provide a novel pharmaceutical composition, preferably a pharmaceutical composition capable of improving intestinal flora in a living body or increasing short-chain fatty acids in a living body. The pharmaceutical composition comprises MXene and is used for improving intestinal flora in a living body or increasing short-chain fatty acid in the living body.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, a method for improving the intestinal flora, a treatment method, and a prevention method. Background Art

[0002] In recent years, the association between the intestinal environment and various diseases has been pointed out, and therapeutic effects for these diseases can be expected by improving the intestinal environment.

[0003] Patent Document 1 describes a pharmaceutical composition for improving the intestinal flora, which contains 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0004] Non-Patent Document 1 describes that by administering genetically engineered Escherichia coli to dextran sulfate sodium-induced colitis (DSS) mice, which are model animals for inflammatory bowel disease (IBD), the diversity of the intestinal flora is promoted, and Ruminococcaceae proliferates. As a result, the production of butyric acid can be enhanced.

[0005] Non-Patent Document 2 describes that the diversity of intestinal bacteria promotes the expression of Cldn and can reduce the permeability of the blood-brain barrier (BBB).

[0006] Non-Patent Document 3 describes that butyrate can significantly correct hypertensive symptoms in pregnant women.

[0007] Prior Art Documents

[0008] Patent Documents

[0009] Patent Document 1: Japanese Patent Application Laid-Open No. 2023-12558

[0010] Non-Patent Documents

[0011] Non-Patent Document 1: Lifu Wang et al., An engineered probiotic secreting Sj16 ameliorates colitis via Ruminococcaceae / butyrate / retinoic acid axis, BIOENGINEERING & TRANSLATIONAL MEDICINE, volume 6, Issue 3 September 2021

[0012] Non-Patent Document 2: V. Braniste et al., The gut microbiota influences blood-brain barrier permeability in mice, 2014, Science Translational Meddicine, 6:263ra158

[0013] Non-Patent Document 3: Luisa F. Gomez-Arango et al., Increased Systolic andDiastolic Blood Pressure Is Associated With Altered Gut MicrobiotaComposition and Butyrate Production in Early Pregnancy, Hyperteinsion October2016 Vol 68, Issue 4 Summary of the Invention

[0014] Problems to be Solved by the Invention

[0015] In Patent Document 1, it is described that the intestinal flora can be improved by administering a specified compound. In Non-Patent Documents 1 to 3, it is described that by directly administering Escherichia coli, Ruminococcaceae, which is one kind of intestinal bacteria, can be proliferated. In addition, butyric acid that can be produced therefrom can help inhibit the enhancement of blood-brain barrier (BBB) permeability and improve hypertensive symptoms, etc., but there is no description of the action of MXene.

[0016] One object of the present invention is to provide a novel pharmaceutical composition, preferably a pharmaceutical composition capable of improving the intestinal flora in a living body or increasing short-chain fatty acids in a living body.

[0017] Means for Solving the Problems

[0018] The pharmaceutical composition of the present invention contains MXene and can be used to improve the intestinal flora in a living body.

[0019] Effects of the Invention

[0020] The present invention can provide a novel pharmaceutical composition, preferably a pharmaceutical composition capable of improving the intestinal flora in a living body or increasing short-chain fatty acids in a living body. In addition, the present invention can provide a treatment method or a prevention method.

[0021] The pharmaceutical composition of the present invention contains MXene and can promote the proliferation of intestinal bacteria, thereby improving the intestinal flora or increasing short-chain fatty acids in the organism. Therefore, it is useful for the treatment and / or prevention of various diseases.

[0022] Without being limited by a specific theory, it is considered that MXene contained in the pharmaceutical composition of the present invention has the ability to promote the proliferation of intestinal bacteria in the intestine, and it can be expected that intestinal bacteria can actually proliferate. In addition, through the proliferation of these intestinal bacteria, it is expected that the increase in short-chain fatty acids that can be produced by the metabolism of these intestinal bacteria will also be promoted. As a result, through the action of these short-chain fatty acids, it is expected that the repair of the vascular barrier will be promoted. In addition, by the ingestion of MXene, a decrease in blood pressure can also be expected. And it is considered that the above-mentioned MXene is not absorbed from the intestine, so it can be expected to be directly excreted together with feces and urine through the digestive tract. As described above, although initially having two excretion functions of bile excretion and urine excretion in the organism, the metabolic pathway of the pharmaceutical composition of the present invention can also be said to be a third metabolic pathway, and it can be expected to be related to, for example, the treatment related to dialysis therapy for patients with renal failure. In addition, for pathogenic substances contained in the content of food, etc., it can also be expected that the MXene of the present invention adsorbs them in the digestive tract so that they are not absorbed by the intestine. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is a schematic cross-sectional view showing MXene particles of a layered material in one embodiment of the present invention. Figure 1 (a) shows single-layer MXene particles. Figure 1 (b) shows multi-layer (exemplarily bilayer) MXene particles.

[0024] Figure 2 It is a schematic cross-sectional view showing the material in one embodiment of the present invention.

[0025] Figure 3 It shows the results of an experiment in which MXene was administered to hypertensive mice. Figure 3 (a) thereof shows the change in systolic blood pressure (SBP). Figure 3 (b) thereof shows the change in diastolic blood pressure (DBP).

[0026] Figure 4 It shows the results of an experiment in which MXene was administered to hypertensive mice, showing the behavior area of the mice in the cognitive behavior analysis.

[0027] Figure 5 It shows the results of an experiment in which MXene was administered to hypertensive mice, showing the Time of Entries Discrimination Index in the cognitive behavior analysis.

[0028] Figure 6 Shows the results of the experiment of administering MXene to hypertensive mice. In the 16S-rRNA analysis, Figure 6 (a) shows the relative abundance of Ignavibacteriaceae in the class Ignavibacteria of the phylum Actinobacteria, Figure 6 (b) shows the relative abundance of Ruminococcaceae in the order Oscillospirales of the class Clostridia of the phylum Firmicutes, Figure 6 (c) shows the relative abundance of Lachnospiraceae in the order Lachnospirales of the class Clostridia of the phylum Firmicutes, Figure 6 (d) shows the relative abundance of Butyricicoccaceae in the order Oscillospirales of the class Clostridia of the phylum Firmicutes.

[0029] Figure 7 Shows the results of the experiment of administering MXene to hypertensive mice. In the 16S-rRNA analysis, Figure 7 (a) shows the α-diversity of the gut microbiota, Figure 7 (b) shows the β-diversity depicted by PCoA.

[0030] Figure 8 Shows the results of the experiment of administering MXene to hypertensive mice, showing the changes in the amounts of (a) butyric acid, (b) acetic acid, and (c) propionic acid in CE-MS.

[0031] Figure 9 Shows the results of the experiment of administering MXene to hypertensive mice, showing the change in Cldn5 in the RNA seq of corpus callosum cells.

[0032] Figure 10 Shows the results of the experiment of administering MXene to hypertensive mice, showing the fluorescence microscope observation images of myelin staining.

[0033] Figure 11 Shows the results of the experiment of administering MXene to hypertensive mice, showing the amount of MBP measured by the WB method. The amount of MBP (a) shows the photo of the membrane after transfer, and (b) shows the ratio of the amount of MBP based on the amount of β-actin. Detailed implementation mode

[0034] The pharmaceutical composition of the present invention contains Mxene. Mxene is typically a layered material having one or more layers. Generally, MXene has the form of particles (which may include powders, flakes, nanosheets, etc.) of this layered material.

[0035] The above-mentioned Mxene preferably contains two-dimensional particles of a layered material having one or more layers. The layer preferably contains at least one metal selected from Group 3, 4, 5, 6, and 7 metals, and at least one selected from carbon atoms and nitrogen atoms.

[0036] The Group 3, 4, 5, 6, and 7 metals described above are preferably at least one selected from Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, Sc, W, and Mn, and more preferably at least one selected from Ti, V, Cr, and Mo.

[0037] The layer described above preferably has the following compositional formula: M m X n for the layer main body shown,

[0038] (wherein M is at least one Group 3, 4, 5, 6, and 7 metal,

[0039] X is a carbon atom, a nitrogen atom, or a combination thereof,

[0040] n is 1 or more and 4 or less,

[0041] m is greater than n and 5 or less).

[0042] The layer described above preferably further includes a modification or terminal T (T is at least one selected from a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom, and a hydrogen atom) present on the surface of the layer main body.

[0043] The pharmaceutical composition of the present invention includes two-dimensional particles having a Mxene, preferably a layer main body of M m X n shown and T, and is useful for the treatment and / or prevention of various diseases by being able to adsorb disease-causing substances (pathogenic substances).

[0044] In the present invention, the above-mentioned layered material can be understood as a layered compound, and the above-mentioned layer can also be expressed as "M m X n T s ". s is an arbitrary number, and in the past, x or z has sometimes been used instead of s. Hereinafter, the above-mentioned layered material is sometimes referred to as MXene, the above-mentioned layer is sometimes referred to as the MXene layer, and the above-mentioned two-dimensional particles are sometimes referred to as MXene two-dimensional particles or MXene particles.

[0045] In the present invention, when a certain element is referred to as an "atom", the oxidation number of the element is not limited to 0 and can be any number within the range of oxidation numbers that the element can take.

[0046] In addition, regarding the symbols in the general formulas shown in the present invention, as long as there is no special mention, the definitions of the same symbol are common among the general formulas including the symbol.

[0047] In the above formula: M m X nAmong them, m can typically be 2, 3, 4, or 5, but is not limited thereto. Additionally, n can be 1, 2, 3, or 4, but is not limited thereto. In one embodiment, m can be 3 and n can be 2.

[0048] In the above formula: M m X n M is preferably at least one selected from Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, Sc, W, and Mn, and more preferably at least one selected from Ti, V, Cr, and Mo.

[0049] As M m X n substances as shown below are known.

[0050] Sc2C, Ti2C, Ti2N, Zr2C, Zr2N, Hf2C, Hf2N, V2C, V2N, Nb2C, Ta2C, Cr2C, Cr2N, Mo2C, Mo 1.3 C, Cr 1.3 C, (Ti, V)2C, (Ti, Nb)2C, W2C, W 1.3 C, Mo2N, Nb 1.3 C, Mo 1.3 Y 0.6 C (in the above formula, "1.3" and "0.6" respectively refer to approximately 1.3 (= 4 / 3) and approximately 0.6 (= 2 / 3).)

[0051] Ti3C2, Ti3N2, Ti3(CN), Zr3C2, (Ti, V)3C2, (Ti2Nb)C2, (Ti2Ta)C2, (Ti2Mn)C2, Hf3C2, (Hf2V)C2, (Hf2Mn)C2, (V2Ti)C2, (Cr2Ti)C2, (Cr2V)C2, (Cr2Nb)C2, (Cr2Ta)C2, (Mo2Sc)C2, (Mo2Ti)C2, (Mo2Zr)C2, (Mo2Hf)C2, (Mo2V)C2, (Mo2Nb)C2, (Mo2Ta)C2, (W2Ti)C2, (W2Zr)C2, (W2Hf)C2,

[0052] Ti4N3, V4C3, Nb4C3, Ta4C3, (Ti, Nb)4C3, (Nb, Zr)4C3, (Ti2Nb2)C3, (Ti2Ta2)C3, (V2Ti2)C3, (V2Nb2)C3, (V2Ta2)C3, (Nb2Ta2)C3, (Cr2Ti2)C3, (Cr2V2)C3, (Cr2Nb2)C3, (Cr2Ta2)C3, (Mo2Ti2)C3, (Mo2Zr2)C3, (Mo2Hf2)C3, (Mo2V2)C3, (Mo2Nb2)C3, (Mo2Ta2)C3, (W2Ti2)C3, (W2Zr2)C3, (W2Hf2)C3, (Mo 2.7 V 1.3 )C3 (In the above formulae, "2.7" and "1.3" respectively refer to approximately 2.7 (= 8 / 3) and approximately 1.3 (= 4 / 3).)

[0053] Typically, in the above formula: M m X n M may be Ti or V, and X may be a carbon atom or a nitrogen atom; M may be Ti and X may be a carbon atom. In one embodiment, the MXene may be Ti3C2T s (In other words, M is Ti, X is C, n is 2, and m is 3). In this case, the precursor of this MXene (also referred to as the "MAX phase") may be Ti3AlC2.

[0054] MXene can be produced by removing the A atoms contained in the MAX phase of the precursor (in one embodiment, represented by M m AX n , where the meanings of M, m, X, and n are the same as above, and A is at least one element from Group 12, 13, 14, 15, or 16), but MXene may also contain the A atoms. In one embodiment, the residual amount of the A atoms contained in the MXene may preferably be 10 mass% or less, more preferably 8 mass% or less, and further preferably 6 mass% or less, relative to the content of the A atoms in the precursor.

[0055] In another embodiment, the residual amount of the A atoms may exceed 10 mass%. For example, a substance obtained by removing only a part of the A atoms from the MAX phase is also included in the technical scope of the above MXene. As such MXene, for example, there can be cited MXene obtained by removing the A atoms only from the vicinity of the ends in the plane direction of the MAX phase (the direction parallel to the plane of the M m X n layer contained in the MAX phase). In this embodiment, the residual amount of the A atoms can be, for example, 50 mass% or more, further 80 mass% or more, and particularly 90 mass% or more.

[0056] The lithium content in the above-mentioned MXene 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 still more preferably 0% by mass or more and 0.002% by mass or less. By making the lithium content within the above range, biocompatibility can be improved.

[0057] The lithium content in MXene can be measured by inductively coupled plasma atomic emission spectrometry (ICP-AES).

[0058] The above-mentioned MXene contains Figure 1 an aggregate of particles of MXene having 1 layer schematically illustrated in (a) (hereinafter simply referred to as "MXene particles") 10a (single-layer MXene particles). More specifically, the MXene particles 10a are typically the MXene layer 7a, and the MXene layer 7a has M m X n the shown layer main body (M m X n layer) 1a and the modification or terminal T3a, 5a present on the surface of the layer main body 1a (more specifically, at least one of the two surfaces facing each other in each layer). Therefore, the MXene layer 7a is also expressed as "M m X n T s ", and s is an arbitrary number.

[0059] The above-mentioned MXene may contain one or more layers. As the MXene particles having multiple layers (multi-layer MXene particles), as schematically shown in Figure 1 (b), MXene particles 10b having 2 layers can be cited, but are not limited to these examples. Figure 1 1b, 3b, 5b, 7b in (b) are the same as 1a, 3a, 5a, 7a in the above-mentioned Figure 1 (a). The two adjacent MXene layers (for example, 7a and 7b) of the multi-layer MXene particles do not have to be completely spaced apart and may be in partial contact. The above-mentioned single-layer MXene particles 10a are particles in which the above-mentioned multi-layer MXene particles 10b are each separated and exist as a single layer. Sometimes, unseparated multi-layer MXene particles 10b remain in the MXene, and it is a mixture of the above-mentioned single-layer MXene particles 10a and multi-layer MXene particles 10b.

[0060] Typically, at least one of the surfaces of the layer main body 1a shown by M m X n can be planar (two-dimensional), and the surfaces of the layer main body 1a can all be planar (two-dimensional).

[0061] Although the present embodiment is not limited thereto, the thickness of each layer (corresponding to the above-mentioned MXene layers 7a and 7b) contained in the MXene particles is, for example, 0.8 nm or more and 5 nm or less, particularly 0.8 nm or more and 3 nm or less (which mainly varies depending on the number of M atomic layers contained in each layer).

[0062] The thickness of each layer can be determined in the form of a number-average size (e.g., number-average of at least 40) based on atomic force microscopy (AFM) images or transmission electron microscopy (TEM) images.

[0063] For each stack of MXene (especially the multi-layer MXene particles that can be included), the interlayer distance (or void size, Figure 1 represented by Δd in (b)) can be, for example, 0.8 nm or more and 10 nm or less, particularly 0.8 nm or more and 5 nm or less, and more particularly about 1 nm, and the total number of layers can be 2 or more and 20,000 or less.

[0064] Regarding the interlayer distance in MXene, in the X-ray diffraction measurement of MXene, the interplanar distance (the sum of the interlayer distance and the thickness of each layer) can be determined from the position of the peak corresponding to the (002) plane of MXene existing at 2θ = 10° (deg) or less, and the interlayer distance can be measured by subtracting the thickness of each layer from the interplanar distance.

[0065] The above-mentioned MXene can contain MXene particles with a small number of layers. The above "small number of layers" means, for example, that the number of stacked MXene layers is 6 or less. In addition, the thickness in the stacking direction of the multi-layer MXene particles with a small number of layers is preferably 15 nm or less, and more preferably 10 nm or less. Hereinafter, this "multi-layer MXene particle with a small number of layers" is sometimes referred to as a "few-layer MXene particle". In addition, single-layer MXene particles and few-layer MXene particles are sometimes collectively referred to as "single-layer and few-layer MXene particles".

[0066] In the above-mentioned MXene, the proportion of single-layer and few-layer MXene particles with a thickness of 15 nm or less can be 0 vol% or more and 100 vol% or less, further 0 vol% or more and 99 vol% or less, still further 0 vol% or more and 50 vol% or less, and particularly 0 vol% or more and 30 vol% or less.

[0067] (Average value of the major axis of the two-dimensional plane of MXene)

[0068] The major axis of the above-mentioned MXene in a plane parallel to each layer (hereinafter, also referred to as the "two-dimensional plane") is preferably 1 μm or more and 20 μm or less. Hereinafter, the average value of the major axis of the two-dimensional plane is sometimes referred to as the "average flake size".

[0069] The larger the above-average flake size, the better the orientation of MXene in the material containing MXene. The average value of the major axis of the two-dimensional plane is preferably 1.5 μm or more, more preferably 2.5 μm or more. In the case where delamination of MXene is carried out by subjecting MXene to ultrasonic treatment, most of the MXene is miniaturized to about several hundred nm in terms of the major axis due to the ultrasonic treatment. Therefore, it is considered that the orientation of MXene in the film formed of single-layer MXene delaminated by ultrasonic treatment is low.

[0070] From the viewpoint of dispersibility in the dispersion medium, the average value of the major axis of the two-dimensional plane is 20 μm or less, preferably 15 μm or less, more preferably 10 μm or less.

[0071] The above-mentioned major axis of the two-dimensional plane refers to the major axis when each MXene particle is approximated as an elliptical shape in a transmission electron microscope photograph of MXene observed from a direction substantially orthogonal to the plane parallel to each layer. The average value of the major axis of the two-dimensional plane refers to the number average of the above-mentioned major axes of 80 particles or more. As the electron microscope, a scanning electron microscope (SEM) or a transmission electron microscope (TEM) photograph can be used.

[0072] The average value of the major axis of MXene in this embodiment can be measured by dissolving the material containing the MXene in a solvent and dispersing the MXene in the solvent. Alternatively, it can also be measured based on the SEM image of the above material.

[0073] (Average value of the thickness of MXene)

[0074] The average value of the thickness of MXene in this embodiment is preferably 1 nm or more and 100 μm or less. The above thickness is preferably 50 μm or less, more preferably 20 μm or less. On the other hand, considering the thickness of single-layer MXene particles, the lower limit of the thickness of MXene can be 1 nm.

[0075] The above-mentioned thickness of MXene can be understood as the length in a direction substantially orthogonal to the plane parallel to each layer. The average value of the thickness of MXene can be obtained in the form of a number average size (for example, digital average of at least 40) based on an atomic force microscope (AFM) photograph or a transmission electron microscope (TEM) photograph.

[0076] The above-mentioned MXene can be manufactured by the following manufacturing method, but the MXene in the present invention is not limited to being manufactured by the following manufacturing method.

[0077] In one mode, the manufacturing method of the above-mentioned MXene includes:

[0078] (a)Prepare the following formula: Mm AX n The step of the precursor shown

[0079] (wherein M is at least one metal of Groups 3, 4, 5, 6, and 7,

[0080] X is a carbon atom, a nitrogen atom, or a combination thereof,

[0081] A is at least one element of Groups 12, 13, 14, 15, and 16,

[0082] n is 1 or more and 4 or less,

[0083] m is greater than n and 5 or less);

[0084] (b) The step of using an etching solution to remove at least a part of the A atoms from the above precursor by etching to obtain the above etch-treated product;

[0085] (c) The step of cleaning the above etch-treated product to obtain a cleaned product,

[0086] The above method may further include:

[0087] (d) The step of using a metal-containing compound to perform an intercalation treatment on the above etch-treated product in a dispersion medium to obtain an intercalated product; and

[0088] (e) The step of performing an exfoliation treatment on the above intercalated product to obtain an exfoliated product.

[0089] In one mode, the above etch-treated product and exfoliated product can be used as the above MXene, and preferably the above cleaned product can be used as the above MXene.

[0090] Hereinafter, each step will be described.

[0091] · Step (a)

[0092] First, a specified precursor is prepared. The specified precursor that can be used in the present embodiment is the MAX phase as the precursor of MXene,

[0093] represented by the following formula: M m AX n as shown,

[0094] (wherein M is at least one metal of Groups 3, 4, 5, 6, and 7,

[0095] X is a carbon atom, a nitrogen atom, or a combination thereof,

[0096] A is at least one element of Groups 12, 13, 14, 15, and 16,

[0097] n is 1 or more and 4 or less,

[0098] m is greater than n and less than 5).

[0099] The meanings of M, X, n, and m are the same as described above.

[0100] A is at least one element selected from Group 12, 13, 14, 15, and 16 elements, usually a Group A element, typically a Group IIIA element and a Group IVA element. More specifically, it may include at least one selected from Al, Ga, In, Tl, Si, Ge, Sn, Pb, P, As, S, and Cd, preferably Al or Si.

[0101] The MAX phase has a crystal structure in which the layer composed of A atoms is located between the two layers shown by M m X n (It may have a lattice in which each X is within the octahedral array of M). The MAX phase typically has the following repeating unit when m = n + 1: that is, one layer of X atom layer is arranged between each layer of the n + 1 layers of M atom layers (collectively referred to as "M m X n layer"), and a layer of A atoms ("A atom layer") is arranged as the next layer of the (n + 1)-th M atom layer, but it is not limited thereto.

[0102] The above MAX phase can be manufactured by known methods. For example, TiC powder, Ti powder, and Al powder are mixed with a ball mill, and the obtained mixed powder is fired in an Ar atmosphere to obtain a fired body (block-shaped MAX phase). Then, the obtained fired body is crushed with a end mill to obtain a powdery MAX phase for the next process.

[0103] · Step (b)

[0104] In step (b), an etching process is performed to remove at least a part of the A atoms from the precursor (MAX phase) shown by the above M m AX n . Thus, an etched product in which at least a part of the layer composed of A atoms is removed while maintaining the state of the M m X n layer in the precursor can be obtained.

[0105] The conditions of the etching process are not particularly limited, and known conditions can be adopted. The etching can be carried out using an etching solution containing F - . This etching solution may contain hydrofluoric acid, hydrochloric acid, phosphoric acid, etc. as acids. In one embodiment, as the etching solution, hydrofluoric acid; a mixed solution of hydrofluoric acid and hydrochloric acid; a mixed solution of lithium fluoride and hydrochloric acid, etc. can be cited, and all of them may further contain phosphoric acid. As the solvent in the etching solution, water can be used, for example, pure water can be used.

[0106] The etching treatment can be carried out in the form of a slurry by mixing the above-mentioned precursor and the above-mentioned etching solution.

[0107] In one mode, the intercalation treatment can be carried out simultaneously in step (b). By making the metal-containing compound described below coexist in the etching solution, the etching treatment and the intercalation treatment can be carried out simultaneously. In this case, the subsequent step (e) can be further carried out.

[0108] In step (b), when the intercalation treatment is carried out simultaneously, the content ratio 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, and particularly 0.1% by mass or more and 1% by mass or less.

[0109] · Step (c)

[0110] In step (c), the treated product obtained by the etching treatment is washed to obtain a washed treated product. By washing, acids and the like used in the etching treatment can be sufficiently removed.

[0111] The washing is preferably carried out using water. The amount of water mixed with the etched product and the washing method are not particularly limited. For example, adding water and stirring, centrifugation, etc. can be cited. As the stirring method, stirring methods using hand shaking, automatic shaker, shear mixer, jar mill, etc. can be cited. The stirring degree such as the stirring speed and the stirring time is adjusted according to the amount, concentration, etc. of the etched product to be treated. The above washing with water can be carried out 1 time or more, and preferably multiple times of washing with water are carried out. For example, specifically, the above washing with water can be carried out by successively carrying out the following steps: step (i) adding water to the treated product or the remaining precipitate obtained in the following (iii) and stirring, step (ii) centrifuging the stirred product, and step (iii) discarding the supernatant after centrifugation. It can be cited that steps (i) to (iii) are repeated within a range of 2 times or more, for example, 15 times or less.

[0112] · Step (d)

[0113] In step (d), an intercalation treatment is carried out, that is, a metal-containing compound containing metal ions is used to carry out an intercalation treatment on the above-mentioned etched product in a dispersion medium to obtain an intercalated product. Thus, an intercalated product in which metal ions contained in the metal-containing compound are intercalated between two adjacent M m X n layers can be obtained.

[0114] The above metal ions may include monovalent metal ions. Examples of the monovalent metal ions include alkali metal ions such as lithium ions, sodium ions, and potassium ions, copper ions, silver ions, gold ions, and the like.

[0115] Examples of the above metal-containing compound include ionic compounds formed by combining the above metal ions and anions. For example, iodides, phosphates, sulfide salts including sulfates, nitrates, acetates, and carboxylates of the above metal ions can be cited. As the above metal ions, lithium ions are preferred. As the metal-containing compound, a metal-containing compound containing lithium ions is preferred, an ionic compound of lithium ions is more preferred, and one or more of iodides, phosphates, and sulfide salts of lithium ions are further preferred. It is considered that if lithium ions are used as metal ions, the water hydrated with lithium ions has the most negative dielectric constant, so monolayer formation is easy.

[0116] The content ratio of the metal-containing compound in the total of the above etch-treated material, metal-containing compound, and dispersion medium can be, for example, 0.001 mass% or more and 10 mass% or less, further can be 0.01 mass% or more and 1 mass% or less, and particularly can be 0.1 mass% or more and 1 mass% or less. If the content ratio of the metal-containing compound is within the above range, the dispersibility in the dispersion medium is good.

[0117] The specific method of the intercalation treatment is not particularly limited. For example, the dispersion medium, etch-treated material, and metal-containing compound can be mixed and stirred, or left standing. For example, stirring at room temperature can be cited. Examples of the above stirring method include methods using stirrers such as stirring rods, methods using stirring blades, methods using mixers, and methods using centrifugal devices. The stirring time can be set according to the production scale of monolayer / few-layer MXene particles. For example, it can be set between 12 and 24 hours. The mixing order of the dispersion medium, etch-treated material, and metal-containing compound is not particularly limited. In one mode, the dispersion medium and the etch-treated material can be mixed and then the metal-containing compound can be mixed. Representatively, the etch solution after the etch treatment can be used as the dispersion medium.

[0118] · Step (e)

[0119] In step (e), delamination treatment is performed on the intercalation-treated material obtained by the intercalation treatment to obtain a delamination-treated material. The delamination treatment includes applying shear stress to the intercalation-treated material to peel off at least a part of the two adjacent M m X n layers. Through the delamination treatment, MXene particles can be made into monolayer / few-layer.

[0120] The conditions for delamination treatment are not particularly limited and can be carried out by known methods. For example, as a method of applying shear stress to the intercalated material, a method of dispersing the intercalated material in a dispersion medium and stirring it can be cited. As the stirring method, stirring using ultrasonic treatment, handshake, an automatic shaker, etc. can be cited. The degree of stirring such as the stirring speed and stirring time can be adjusted according to the amount, concentration, etc. of the material to be treated. For example, it can be cited that after centrifuging the slurry after the above intercalation and discarding the supernatant, pure water is added to the remaining precipitate, and stirring is carried out, for example, by handshake or using an automatic shaker for delamination. The removal of undelaminated material can be cited as a process of centrifuging and discarding the supernatant, and then washing the remaining precipitate with water. For example, it can be cited that (i) pure water is added to the remaining precipitate after discarding the supernatant and stirred, (ii) centrifuged, and (iii) the supernatant is recovered. The operations of (i) to (iii) are repeated 1 or more times, preferably 2 or more times and 10 or less times, and as the delaminated material, a supernatant containing single-layer and few-layer MXene particles can be obtained. Alternatively, the supernatant can also be centrifuged, and the supernatant after centrifugation can be discarded to obtain clay containing single-layer and few-layer MXene particles as the delaminated material.

[0121] In the above method for manufacturing MXene, in the case of carrying out intercalation treatment, a washing treatment can be further carried out at any stage after the intercalation treatment, preferably at a stage after the delamination treatment. By carrying out this washing treatment, metal ions and metal-containing compounds used in the intercalation can be sufficiently removed. Representatively, this washing treatment is carried out after step (e).

[0122] In one mode, the washing treatment after the intercalation treatment can be carried out in the same manner as the above step (c). In addition, in another mode, after acid-treating the delaminated material, the acid-treated material can be washed in the same manner as the above step (c). In these cases, the etched material in the above step (c) can be replaced with the delaminated material or the acid-treated material respectively to carry out the washing treatment.

[0123] The above acid treatment can be carried out by mixing and stirring the delaminated material and an acid solution. As the acid, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydroiodic acid, hydrobromic acid, hydrofluoric acid, etc.; organic acids such as acetic acid, citric acid, oxalic acid, benzoic acid, sorbic acid, etc. can be appropriately used, and the concentration of the acid in the acid solution can be appropriately adjusted according to the delaminated material. The above stirring can be carried out using handshake, an automatic shaker, a shear mixer, a jar mill, etc. The acid treatment is carried out 1 or more times, and if necessary, an operation of mixing and stirring with a fresh acid solution (an acid solution not used in the acid treatment) can be carried out within a range of 2 or more times, for example, 10 or less times.

[0124] The intermediates and target substances in the manufacturing method described above can be separated by common purification methods. As such purification methods, examples include suction filtration; drying such as heat drying, freeze drying, vacuum drying, etc.

[0125] The above-mentioned MXene can have the effect of improving the intestinal flora in vivo. Especially in vivo, it can promote the generation of intestinal bacteria. The intestinal bacteria preferably include intestinal bacteria that increase short-chain fatty acids (intestinal bacteria that produce short-chain fatty acids through metabolism). The intestinal bacteria that increase short-chain fatty acids preferably include Clostridia of the phylum Firmicutes, more preferably include Euzebya of the order Rhodospirillales, family Euzebyaceae, of the class Rhodospirillaceae, phylum Actinobacteria, Ruminococcaceae of the order Oscillospirales, class Clostridia, phylum Firmicutes, and Lachnospiraceae of the order Lachnospirales, class Clostridia, phylum Firmicutes. Further preferably, it includes Butyricoccus of the order Oscillospirales, class Clostridia, phylum Firmicutes.

[0126] As the above-mentioned short-chain fatty acids, fatty acids having 1 to 4 carbon atoms can be mentioned, and preferably butyric acid, acetic acid, and propionic acid can be mentioned. The above-mentioned short-chain fatty acids can have the effect of repairing the vascular barrier. As such vascular barriers, an intestinal barrier and a cerebrovascular barrier can be mentioned.

[0127] In addition, the above-mentioned MXene can have the effect of reducing blood pressure in vivo.

[0128] Although the present invention should not be construed as being limited to a specific theory, as the effects of short-chain fatty acids, the following (i) to (iii) can be considered:

[0129] (i) Repairing the vascular barrier and / or inhibiting the repair of the vascular barrier;

[0130] (ii) Enhancing the anti-inflammatory effect;

[0131] (iii) Improving hypertension.

[0132] Regarding (i), short-chain fatty acids contribute to the maintenance of the homeostasis of the blood barrier (especially the cerebrovascular endothelial cell-blood-brain barrier), and can inhibit the excessive enhancement of permeability and play a protective role on the brain tissue. This can be confirmed by the enhancement of Cldn, which is an RNA encoding Claudin, and Claudin is a protein that forms the blood barrier (especially the blood-brain barrier). As such vascular barriers, an intestinal barrier and a blood-brain barrier can be mentioned.

[0133] Regarding (ii), short-chain fatty acids act as ligands for G protein-coupled receptors (GPRs) and have anti-inflammatory effects throughout the body via the immune system. In the central nervous system, short-chain fatty acids, especially those with high permeability through the blood-brain barrier, have anti-inflammatory effects due to the inhibitory effect on histone deacetylase (HDAC) activated at the injury site. The effect of butyric acid on the white matter of the brain can be confirmed based on the significant enrichment of the GPR signaling pathway in the white matter of the brain by MFT administration in RNA-sequencing data (functional enrichment analysis of the Database for Annotation, Visualization and Integrated Discovery (DAVID)) using hypertensive mice.

[0134] Regarding (iii), short-chain fatty acids can have a blood pressure-lowering effect. It is a known fact that the white matter of the brain (nerve axons and myelin [complementary]) is damaged by hypertension. This blood pressure-lowering effect can be confirmed in terms of the protective effect on the central component (myelin) of the white matter and the reduction in blood pressure in the white matter of hypertensive mice.

[0135] That is, the MXene of the present invention can be used for one or more of the following (i) to (iii):

[0136] (i) Repairing the vascular barrier and / or inhibiting the repair of the vascular barrier;

[0137] (ii) Enhancing the anti-inflammatory effect;

[0138] (iii) Improving hypertension.

[0139] The above improvement of hypertension also includes lowering blood pressure in vivo.

[0140] The above MXene can be used for the treatment or prevention of diseases in which symptom improvement can be expected through the repair of the vascular barrier in vivo. Examples of such diseases include one or more selected from vascular dementia, Parkinson's disease, inflammatory bowel disease, chronic renal failure, irritable bowel syndrome, and ischemic and demyelinating central nervous system diseases.

[0141] The above MXene and pharmaceutical composition can be administered orally.

[0142] The pharmaceutical composition of the present embodiment can be made into various dosage forms according to the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, liquids, sublingual tablets, etc. In addition, injections, ointments, suppositories, patches, etc. can also be mentioned.

[0143] The pharmaceutical composition of the present embodiment can be configured, according to its dosage form, by a known method, to further comprise MXene as an active ingredient and a pharmaceutically acceptable additive. As such an additive, excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizing aids, etc. can be cited. The pharmaceutical composition of the present invention can be prepared by appropriately mixing the above-mentioned MXene and the above-mentioned additives, or by diluting and dissolving the above-mentioned MXene with an additive.

[0144] The pharmaceutical composition of the present embodiment can be administered systemically or locally via oral or parenteral (nasal, pulmonary, intravenous, enteral, subcutaneous, intramuscular, transdermal) routes. In one mode, the pharmaceutical composition of the present embodiment can be administered orally.

[0145] When the pharmaceutical composition of the present invention is used for treatment, the dosage of the above-mentioned MXene as its active ingredient is appropriately determined according to the age, sex, weight, disease, and degree of treatment of the patient. For example, in the case of oral administration, regarding the dosage, it can be appropriately administered once or in several divided doses within the range of an effective amount of approximately 100 mg to 10 g per day per adult (body weight is set at 60 kg).

[0146] In addition, the pharmaceutical composition containing the above-mentioned MXene can be used to manufacture a drug for treating or preventing diseases.

[0147]

Examples

[0148] The present invention will be described more specifically by the following examples, but the present invention is not limited to these examples.

[0149] Example 1

[0150] 〔Production of MXene〕

[0151] In Examples 1 and 2, MXene two-dimensional particles were produced by successively performing (1) preparation of a precursor (MAX), (2) etching of the precursor, and (3) washing and drying, which are detailed below.

[0152] (1)Preparation of precursor (MAX)

[0153] TiC powder, Ti powder, and Al powder (all manufactured by High Purity Chemical Research Institute Co., Ltd.) were put into a ball mill equipped with zirconia balls and mixed for 24 hours at a molar ratio of 2:1:1. The obtained mixed powder was fired in an Ar atmosphere at 1,350 °C for 2 hours. The fired body (block) thus obtained was crushed with a vertical milling cutter to a maximum size of 40 μm or less. Thus, Ti3AlC2 particles as a precursor (MAX) were obtained.

[0154] (2)Etching of the precursor

[0155] Using the Ti3AlC2 particles (powder) prepared by the above method, etching was carried out under the following etching conditions to obtain a solid-liquid mixture (slurry) containing the solid components from the Ti3AlC2 powder.

[0156] (Etching conditions)

[0157] ·Precursor: Ti3AlC2 (passed through a sieve with a mesh of 45 μm)

[0158] ·Composition of the etching solution: 6 mL of 50 mass% HF,

[0159] 18 mL of H2O

[0160] 36 mL of HCl (12 M)

[0161] ·Amount of precursor charged: 3.0 g

[0162] ·Etching container: 100 mL IBOY

[0163] ·Etching temperature: 35 °C

[0164] ·Etching time: 24 h

[0165] ·Stirrer rotation speed: 400 rpm

[0166] (3)Washing and drying

[0167] The above slurry was divided into two portions and inserted into two 50 mL centrifuge tubes respectively. After centrifugation at 3,500 G using a centrifuge, the supernatant was discarded. 40 mL of pure water was added to each centrifuge tube, and centrifugation was carried out again at 3,500 G to separate and remove the supernatant. This operation was repeated 11 times. After the final centrifugation, the supernatant was discarded to obtain Ti3C2T s - water-medium clay. The obtained clay was made into dry powder by freeze-drying to obtain the dry powder of MXene.

[0168] Animal experiment 1 Administration experiment on hypertensive mice

[0169] Hypertension causes inflammation of cerebral capillaries, resulting in chronic hypoperfusion. The symptoms of cognitive decline caused by this are called vascular dementia. In Animal Experiment 2, MXene was administered to genetically hypertensive mice to remove inflammatory substances in the body, and it was confirmed whether there was hope of restoring cognitive function. The administration period was set to 56 days, and the administration amount was set to 8% of the food intake. After the administration period ended, blood pressure changes and cognitive behavior analysis (Novel Object Recognition Test) were performed. It should be noted that as a comparison example, a control group (Ctl group) without MXene administration was also prepared.

[0170] (Blood pressure changes)

[0171] The changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the MXene group and the control group were measured. The difference based on the blood pressure value on the first day was taken for comparison. The results are shown in Figure 3 . From around the fourth week onwards, a decrease in blood pressure was confirmed in the MXene group.

[0172] (Behavioral analysis)

[0173] In the behavioral analysis (Novel Object Recognition Test), a black box with a vertical width of 400 mm, a horizontal width of 400 mm, and a height of 400 mm was used. On the first and second days, the mice were placed in the box for 10 minutes for acclimation. On the third day, two identical substances (old substances) were placed in the cage, and the mice were placed for 10 minutes. On the fourth day, one object was changed to a new substance, and the mice were placed for 10 minutes. The time spent exploring the two objects was measured, and the ratio of the exploration time of the new substance to the total exploration time (Times of Entries Discrimination Index) was calculated based on the following formula:

[0174] Exploration time discrimination index = [n / (n + f)] - 0.5

[0175] [In the formula, n represents the number of times of contacting the new object, and f represents the number of times of contacting the previous object.], as an index of memory learning ability. The behavioral areas of the mice are shown in Figure 4 , and the exploration time discrimination index is shown in Figure 5 .

[0176] As Figure 5 shown, in the novel object recognition test, the exploration time discrimination index was higher and positive in the MXene group. This indicates that the number of times of being interested in and approaching the new substance is higher than that of the old substance. That is, it can be recognized that the new substance is new, suggesting that cognitive function has been restored.

[0177] (Confirmation of gut microbiota)

[0178] As Figure 6 shown in (a) - (d) below, the presence ratios of the gut microbiota of mice were compared between groups by 16s-rRNA analysis. It was confirmed that the Actinobacteria, Coriobacteriia, Coriobacteriales, Eggerthellaceae, Firmicutes, Clostridia, Oscillospirales, Ruminococcaceae, Firmicutes, Clostridia, Lachnospirales, Lachnospiraceae, and Firmicutes, Clostridia, Oscillospirales, Butyricicoccaceae proliferated.

[0179] (Confirmation of gut microbiota diversity)

[0180] As Figure 7 shown in (a) and (b) below, the diversity of the gut microbiota of mice obtained by 16s-rRNA analysis was compared. For α-diversity, the Shannon Index was used, and for β-diversity, after analysis based on Bray-Curtis distance, visualization was performed by PCoA (Principal Coordinates Analysis). It was confirmed that the diversity of the bacterial microbiota changed between the two groups by the administration of MXene.

[0181] (Confirmation of short-chain fatty acids)

[0182] Metabolome analysis using CE-MS (capillary electrophoresis mass spectrometer) was performed on mouse serum to confirm the changes in biological components caused by MXene. As Figure 8 shown in (a) - (c) below, an increase in butyric acid, acetic acid, and propionic acid, which are short-chain fatty acids, was confirmed in the MXene group.

[0183] (Confirmation of RNA changes)

[0184] RNA_seq of corpus callosum cells was performed using a next-generation sequencer. As Figure 9 shown below, an increase in Cldn5, which is a gene encoding the protein (Claudin) that forms the blood-brain barrier, was confirmed.

[0185] (Confirmation of brain tissue damage)

[0186] Corpus callosum staining evaluation of the sample was performed. By staining myelin sheaths that functionalize axons, the damage condition can be confirmed. The more myelin sheaths remain, the greater the brightness during staining, and it can be judged that the damage is smaller. For image analysis, to correct the deviation during shooting, the brightness of the white matter part based on a part called the cortex was compared. As Figure 10 shown below, it was confirmed that the brightness of the MXene group was significantly higher and the damage to the white matter was suppressed.

[0187] Based on the above results, for the determination of myelin quality, WB assay of MBP was performed. The method was the usual WB method. Proteins were extracted from the corpus callosum tissue, transferred to a membrane after gel electrophoresis, and the bands were detected by antibody reaction. During the determination, as the total protein amount, the amount of MBP based on the amount of β-actin was compared among the samples.

[0188] Quantification based on image processing was performed based on the markers emerging on the membrane. As shown in (a) and (b) of Figure 11 , an increase in MBP was confirmed in the MXene application group.

[0189] It was observed that due to MXene, Actinobacteria, Rhodospirillales, Ignavibacteriaceae, Firmicutes, Clostridia, Oscillospirales, Ruminococcaceae, Firmicutes, Clostridia, Lachnospirales, Lachnospiraceae, Firmicutes, Clostridia, Oscillospirales, Butyricicoccaceae, which are short-chain fatty acid-producing bacteria, increased in the intestine. It is considered that the increased short-chain fatty acids promoted blood pressure reduction, blood-brain barrier repair, and contributed to the improvement of cognitive function.

[0190] In addition, in the examples, it was confirmed that MXene adjusted the intestinal bacteria and proliferated short-chain fatty acid (SCFA)-producing bacteria, especially butyrate-producing bacteria. Here, the effects of SCFAs (especially butyrate) can be roughly divided into three.

[0191] The first is to contribute to the maintenance of homeostasis of cerebrovascular endothelial cells and the blood-brain barrier, inhibit the excessive enhancement of permeability, and play a protective role on the brain tissue. This can be confirmed by the enhancement of Cldn5, which is an RNA encoding Claudin, a protein that forms the blood-brain barrier.

[0192] The second is to act as a ligand for G protein-coupled receptors (GPRs) and have an anti-inflammatory effect systemically via the immune system. In the central nervous system, short-chain fatty acids, especially those with high blood-brain barrier permeability, have an anti-inflammatory effect due to the inhibitory effect on histone deacetylase (HDAC) activated at the injury site. In fact, in the above examples, in the RNA sequencing data (functional enrichment analysis of Database for Annotation, Visualization and Integrated Discovery (DAVID)) of hypertensive mice, it was also confirmed that the GPR signaling pathway in the white matter of the brain was significantly enriched due to MFT application, and butyrate acted on the white matter of the brain.

[0193] The third is the effect of reducing blood pressure. It is a known fact that the white matter of the brain (nerve axons and myelin sheaths [complementary]) is damaged by high blood pressure. This time, from the aspects of confirming the protective effect on the central component (myelin sheath) of white matter and the reduction of blood pressure in the white matter of hypertensive mice, it can be definitely considered that it has the effect of reducing blood pressure.

[0194] Based on the above points, it was confirmed that MXene has a multi-targeted protective effect on damaged white matter by adjusting gut bacteria to proliferate short-chain fatty acid (SCFA)-producing bacteria, especially butyrate-producing bacteria.

[0195] The present invention includes the following.

[0196] [1]

[0197] A pharmaceutical composition comprising MXene,

[0198] for improving the gut microbiota in a living body or increasing short-chain fatty acids in a living body.

[0199] [2]

[0200] The pharmaceutical composition according to [1], wherein the above-mentioned Mxene comprises two-dimensional particles having one or more layers,

[0201] The above-mentioned layer comprises at least one metal selected from Group 3, 4, 5, 6, 7 metals, and at least one selected from carbon atoms and nitrogen atoms.

[0202] [3]

[0203] The pharmaceutical composition according to [2], wherein the above-mentioned layer comprises the following formula: M m X n the shown layer main body,

[0204] (wherein, M is at least one Group 3, 4, 5, 6, 7 metal,

[0205] X is a carbon atom, a nitrogen atom or a combination thereof,

[0206] n is 1 or more and 4 or less,

[0207] m is greater than n and 5 or less).

[0208] [4]

[0209] The pharmaceutical composition according to [3], wherein the above-mentioned layer further comprises a modification or terminal T (T is at least one selected from a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom and a hydrogen atom) present on the surface of the above-mentioned layer main body.

[0210] [5]

[0211] According to the pharmaceutical composition described in [1], wherein the above-mentioned Mxene contains Ti3C2.

[0212] [6]

[0213] According to the pharmaceutical composition described in any one of [1] to [5], wherein the improvement of the above-mentioned gut microbiota includes the proliferation of gut bacteria that increase short-chain fatty acids.

[0214] [7]

[0215] According to the pharmaceutical composition described in any one of [1] to [6], wherein the gut bacteria that metabolize the above-mentioned short-chain fatty acids include Clostridia of the phylum Firmicutes.

[0216] [8]

[0217] According to the pharmaceutical composition described in any one of [1] to [7], wherein the gut bacteria that metabolize the above-mentioned short-chain fatty acids include Rhodospirillales of the phylum Actinobacteria, Ruminococcaceae of the order Oscillospirales of the phylum Firmicutes, Lachnospiraceae of the order Lachnospirales of the phylum Firmicutes, or Butyricicoccaceae of the order Oscillospirales of the phylum Firmicutes.

[0218] [9]

[0219] According to the pharmaceutical composition described in any one of [1] to [8], wherein the above-mentioned short-chain fatty acids include butyric acid.

[0220]

[10]

[0221] According to the pharmaceutical composition described in any one of [1] to [9], it is also used for one or more of the following (i) to (iii):

[0222] (i) Repairing the vascular barrier and / or inhibiting the repair of the vascular barrier;

[0223] (ii) Enhancing the anti-inflammatory effect;

[0224] (iii) Improving hypertension.

[0225]

[11]

[0226] According to the pharmaceutical composition described in any one of [1] to

[10] , wherein the above-mentioned vascular barrier is an intestinal barrier or a blood-brain barrier.

[0227]

[12]

[0228] According to the pharmaceutical composition described in any one of [1] to

[11] , it is also used for reducing blood pressure.

[0229]

[13]

[0230] The pharmaceutical composition according to any one of [1] to

[12] is for oral administration.

[0231]

[14]

[0232] A method for improving gut microbiota or increasing short-chain fatty acids in a living body, comprising the step of administering an effective amount of MXene to a subject.

[0233]

[15]

[0234] According to the method described in

[14] , wherein the MXene is administered orally.

[0235]

[16]

[0236] A method for treating or preventing a disease, comprising the step of administering an effective amount of MXene to a subject, and

[0237] Improvement of symptoms can be expected through the repair of the vascular barrier.

[0238]

[17]

[0239] According to the method described in

[16] , wherein the disease includes one or more selected from the group consisting of vascular dementia, Parkinson's disease, inflammatory bowel disease, chronic renal failure, irritable bowel syndrome, and ischemic and demyelinating central nervous system diseases.

[0240]

[18]

[0241] According to the treatment or prevention method described in

[16] or

[17] , wherein the MXene is administered orally.

[0242] Explanation of reference numerals

[0243] 1a, 1b: layer body (M m X n layer)

[0244] 3a, 5a, 3b, 5b: modification or terminal T

[0245] 7a, 7b: MXene layer

[0246] 10, 10a, 10b: MXene particles (two-dimensional particles of layered materials)

Claims

1. A pharmaceutical composition comprising MXene for improving gut microbiota or increasing short-chain fatty acids in an organism.

2. The pharmaceutical composition according to claim 1, wherein, The Mxene comprises two-dimensional particles having one or more layers, The layer comprises at least one metal selected from Group 3, 4, 5, 6, 7 metals, and at least one selected from carbon atoms and nitrogen atoms.

3. The pharmaceutical composition according to claim 2, wherein The layer contains the following formula: M m X n The layer body shown Formula M m X n wherein M is at least one metal of Groups 3, 4, 5, 6, and 7 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 5 or less.

4. The pharmaceutical composition according to claim 3, wherein, The layer further comprises a modification or terminus T present on the surface of the layer body, and T is at least one selected from a hydroxyl group, a fluorine atom, a chlorine atom, an oxygen atom, and a hydrogen atom.

5. The pharmaceutical composition according to claim 1, wherein, The Mxene comprises Ti3C2.

6. The pharmaceutical composition according to claim 1, wherein, The improvement of the gut microbiota includes the proliferation of gut bacteria that increase short-chain fatty acids.

7. The pharmaceutical composition according to claim 1, wherein, The gut bacteria that metabolize the short-chain fatty acids include Clostridia of the phylum Firmicutes.

8. The pharmaceutical composition according to claim 1, wherein, The gut bacteria that metabolize the short-chain fatty acids include the family Ignavibacteriaceae of the order Rhodospirillales of the class Rhodospirillaceae of the phylum Actinobacteria, the family Ruminococcaceae of the order Oscillospirales of the class Clostridia of the phylum Firmicutes, the family Lachnospiraceae of the order Lachnospirales of the class Clostridia of the phylum Firmicutes, or the family Butyricicoccaceae of the order Oscillospirales of the class Clostridia of the phylum Firmicutes.

9. The pharmaceutical composition according to claim 1, wherein, The short-chain fatty acids include butyric acid.

10. The pharmaceutical composition according to claim 1, which is further used for one or more of the following (i) to (iii): (i) Repairing the vascular barrier and / or inhibiting the repair of the vascular barrier; (ii) Enhancing the anti-inflammatory effect; (iii) Improving hypertension.

11. The pharmaceutical composition according to claim 1, wherein, The vascular barrier is an intestinal barrier or a blood-brain barrier.

12. The pharmaceutical composition according to claim 1, which is further used for reducing blood pressure.

13. The pharmaceutical composition according to any one of claims 1 to 12, which is for oral administration.

14. A method for improving gut microbiota or increasing short-chain fatty acids in an organism, which comprises the step of administering an effective amount of MXene to a subject.

15. The method according to claim 14, wherein, The MXene is administered orally.

16. A method for treating or preventing a disease, which comprises the step of administering an effective amount of MXene to a subject, and Improvement of symptoms can be expected through the repair of the vascular barrier.

17. The method according to claim 16, wherein, The disease includes one or more selected from vascular dementia, Parkinson's disease, inflammatory bowel disease, chronic renal failure, irritable bowel syndrome, and ischemic and demyelinating central nervous system diseases.

18. The treatment or prevention method according to claim 16, wherein, The MXene is administered orally.

Images