Pharmaceutical composition, adsorption method, therapeutic method, and prophylactic method

Abstract

A pharmaceutical composition comprising nano-fibers and / or nano-flakes of a material represented by formula: MQaOb (in the formula, M represents at least one element selected from the group consisting of group 3, 4, 5, 6 and 7 elements, Q represents at least one element selected from the group consisting of group 12, 13, 14, 15, and 16 elements (but excluding O), a is 0-2, and b is more than 0 but not more than 2).

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 to kidney function substitutes for removing disease-causing substances, development is underway of absorbents that are taken orally and absorb toxic substances in the body and then excrete them outside the body.

[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 Rapid 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 for "Kalimate Powder," "Kalimate Dry Syrup 92.59%," and "Kalimate Oral Liquid 20%," Kowa Co., Ltd., revised September 2020 (20th edition); Pharmaceutical interview form for "Phosblock Tablets 250 mg," Kyowa Kirin Co., Ltd., revised November 2020 (1st edition); Hussein O. Badr, et al., "Bottom-up, scalable synthesis of anatase nanofilament-based two-dimensional titanium carbo-oxide flakes," Materials Today (2021) https: / / doi.org / 10.1016 / j.mattod.2021.10.033

[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 compositions of the present disclosure may comprise a compound of the formula: MQ ａ O ｂ(wherein M is at least one element selected from the group consisting of Groups 3, 4, 5, 6 and 7; Q is at least one element selected from the group consisting of Groups 12, 13, 14, 15 and 16 (excluding O); a is 0 or more and 2 or less; and b is 0 or more and 2 or less.

[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 method for adsorption, treatment, or prevention.

[0014] The pharmaceutical compositions of the present disclosure comprise MQ ａ O ｂ The nanofibers and / or nanoflakes of the material represented by the formula (also referred to simply as "MQO" in the present disclosure) are useful for the treatment and / or prevention of various diseases by virtue of their ability to adsorb substances that may cause diseases (disease-causing substances).

[0015] In vivo, disease-causing substances such as metabolites, waste products, toxic substances, and excess electrolytes 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 via the duodenum 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 intended to be limited to any particular theory, MQO contained in the pharmaceutical composition of the present disclosure has the ability to preferentially adsorb these disease-causing substances, etc., and is therefore expected to remain in the intestinal tract upon oral administration, adsorbing disease-causing substances in the blood through the mutual access between the intestinal tract and blood vessels and eliminating them from the blood. Furthermore, by adsorbing substances that may be converted into harmful substances after being absorbed into the blood from the intestinal tract, it is expected to adsorb and eliminate harmful effects on the body before they occur. Furthermore, since MQO that has adsorbed disease-causing substances is not thought to be absorbed by the intestinal tract, it is 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, MQO of the present disclosure is 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 shows the XRD pattern of the material (TiCO) produced in Example 1.

[0018] The pharmaceutical composition of the present disclosure contains a predetermined material (substance). The predetermined material that can be used in this embodiment is a material represented by the following formula (1): MQ ａ O ｂ ... (1) (In the formula, M is at least one element selected from the group consisting of Groups 3, 4, 5, 6 and 7, and may include at least one element selected from the group consisting of so-called early transition metals, for example, Sc, Ti, Zr, Hf, V, Nb, Ta, Cr, Mo and Mn, and preferably at least one element selected from the group consisting of Ti, V, Cr, Mo and Mn; Q is at least one element selected from the group consisting of Groups 12, 13, 14, 15 and 16 (excluding O), and may include at least one element selected from the group consisting of B, C, N, Si, P and S; a is 0 or more and 2 or less; and b is 0 or more and 2 or less.)

[0019] The pharmaceutical compositions of the present disclosure comprise MQａ O ｂ The nanofibers and / or nanoflakes of the material represented by the formula (I) are capable of adsorbing substances that may cause diseases (disease-causing substances), and are therefore useful for the treatment and / or prevention of various diseases.

[0020] The above-mentioned predetermined material will be hereinafter also referred to simply as "MQO." Examples of MQO include TiO ２ , TiCO, TiCON, VO ２ , VCO, VCON, CrO ２ , CrCO, CrCON, MoO ２ , MoCO, MoCON, MnO ２ , MnCO, MnCON, etc. For example, in formula (1), M may be Ti and Q may be C. Also, for example, in formula (1), a may not be 0.

[0021] MQO may typically have a peak in an X-ray diffraction (XRD) pattern where the diffraction angle 2θ is in the range of 2° to 12°. Although the present disclosure is not bound by any theory, the fact that MQO has a peak in an XRD pattern where 2θ is in the range of 2° to 12° is thought to mean that such MQO has a crystal structure different from that of well-known metal oxides.

[0022] In the present disclosure, an XRD pattern is a pattern (vertical axis represents intensity, horizontal axis represents 2θ) obtained by scanning in the θ-axis direction with an XRD analyzer using CuKα radiation (approximately 1.54 Å) as characteristic X-rays, and may also be referred to as an "XRD profile." Peaks in the XRD pattern can be identified visually or using software used with the XRD analyzer. To measure the XRD pattern as accurately as possible in the low 2θ angle range, it is preferable to place a c-axis-oriented MQO film in the XRD analyzer (for example, as in the examples described below, a free-standing film obtained by removing the filter after suction filtration is placed with the surface that was in contact with the filter facing downward).

[0023] Although the present embodiment is not bound by any theory, the crystal structure of MQO is currently thought to be anatase type, lepidocrocite type, or a mixture of these. For example, the crystal structure of MQO may be lepidocrocite type.

[0024] MQO can be produced, for example, using a first raw material and a second raw material as follows: The first raw material contains at least M, and the second raw material contains at least Q, and the first raw material and the second raw material are capable of reacting in a protic solvent to produce MQO.

[0025] As the first raw material, a material represented by the following formula (2) can be used: M ｃ A １ ｄ ... (2) (wherein M is as defined above, A １ is at least one element selected from the group consisting of Groups 12, 13, 14, 15, and 16, and may include, for example, at least one element selected from the group consisting of B, C, N, O, Si, P, and S; and c and d are each independently 1 to 5. However, the material represented by formula (2) must be different from the product MQO. The material represented by formula (2) may typically have no peak in its X-ray diffraction (XRD) pattern in a diffraction angle 2θ range of 2° to 12°.

[0026] Examples of the first raw material represented by formula (2) include TiB ２ , TiB, TiC, TiN, TiO ２ , Ti ５ Si ３ , Ti ２ SbP, VO ２ , V ２ O ４ , NbC, Nb ２ O ５ , MoO ２ , MoO ３ , MoS ２ , MnO ２ , Mn ３ O ４ , MnCO ３ MnO that can be used as the first raw material２ In the XRD pattern, the material has a peak near 2θ=13° and no peak in the 2θ range of 2° or more and 12° or less.

[0027] Alternatively, or in addition to the above, a material represented by the following formula (3) (hereinafter also simply referred to as a "MAX phase" or "MAX raw material") may be used as the first raw material. ｍ A ２ X ｎ ...(3) (wherein M is as defined above, X is at least one element selected from the group consisting of C and N, n is 1 or more and 4 or less, m is greater than n and 5 or less, A ２ is at least one element selected from the group consisting of Groups 12, 13, 14, 15 and 16, and is usually a Group A element, typically Group IIIA and Group IVA, 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, preferably Al). The MAX phase is ｍ X ｎ (which may have a crystal lattice where each X is located in an octahedral array of M), ２ The MAX phase has a crystal structure in which layers composed of atoms are located. When m=n+1, typically, one layer of X atoms is located between each of n+1 layers of M atoms (collectively referred to as "M ｍ X ｎ layer), and the layer next to the n+1-th layer of M atoms is A ２ Atomic layer ("A ２ The MAX phase has repeating units arranged in "atomic layers." However, the MAX phase is not limited to this.

[0028] Examples of the first raw material represented by formula (3) include Ti ３ AlC ２ , Ti ３ GaC ２ , Ti ３ SiC ２ These include:

[0029] As the first raw material, the material represented by formula (2) and the material represented by formula (3) may be used together (for example, as a mixture).

[0030] As the second raw material, an ionically bondable substance having a carbon-containing group can be used. The ionically bondable substance having a carbon-containing group contains C. Examples of the ionically bondable substance include ammonium salts, phosphates, sulfates, etc.

[0031] More specifically, a quaternary ammonium salt may be used as the second raw material. Examples of quaternary ammonium salts include tetramethylammonium hydroxide (TMAH), tetraethylammonium hydroxide (TEAH), tetrapropylammonium hydroxide (TPAH), tetrabutylammonium hydroxide (TBAH or TBAOH), benzyltrimethylammonium hydroxide, tetrabutylammonium fluoride (TBAF), tetrabutylammonium chloride (TBACl), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), benzyltriethylammonium chloride (BTEAC), hexadecyltrimethylammonium bromide, cetyltrimethylammonium bromide (CTAB), benzethonium chloride, benzalkonium chloride, and cetylpyridinium chloride (CPC). Among these, TMAH and TBAOH are preferred.

[0032] Alternatively, or in addition to the above, other ion-binding substances containing P and / or S, etc. may be used as the second raw material.

[0033] The protic solvent may be any solvent capable of at least partially dissolving the first and second raw materials, and may be, in particular, an aqueous solvent. Examples of the protic solvent include water, alcohols (e.g., ethanol, 2-propanol, 2-propanol, isopropanol), and carboxylic acids (e.g., acetic acid and formic acid). The aqueous solvent may be composed of water and, optionally, a liquid substance compatible with water (e.g., a protic solvent other than water), and is preferably water.

[0034] The first raw material and the second raw material are reacted in a protic solvent. The second raw material can be added to the protic solvent in advance. The ratio of the second raw material to the total of the protic solvent and the second raw material can be, for example, 5% by mass or more, particularly 20% by mass or more, and / or, for example, 80% by mass or less, particularly 50% by mass or less. The first raw material can be further added to the protic solvent to which the second raw material has been added, and mixed. In this mixture, the reaction to produce MQO proceeds. The temperature (reaction temperature) of the mixture (which may contain the reaction product) can be, for example, 15°C or more, particularly 40°C or more, and / or, for example, 100°C or less, particularly 80°C or less. The mixing time (reaction time) can be, for example, 1 day or more, particularly 2 days or more, and / or, for example, 10 days or less, particularly 7 days or less. Mixing can be performed, for example, using a hot plate stirrer. However, the treatment operations and conditions (temperature, time, etc.) that can cause the reaction to proceed are not limited to those described above, and may be selected appropriately depending on the first raw material, second raw material, protic solvent, etc. that are used.

[0035] The above reaction produces MQO, which may eventually grow into MQO nanofibers and then MQO nanoflakes. While not limiting the present disclosure, the resulting MQO nanofibers may be in the form of nanoribbons extending two-dimensionally. Alternatively, multiple MQO nanofibers (e.g., nanoribbons) may bond and / or integrate with each other to grow into two-dimensional nanoflakes. Alternatively, multiple MQO nanoflakes may overlap each other (e.g., by van der Waals forces) to form stacks. While the present disclosure is not bound by any theory, the production and growth of MQO may be thought of as a bottom-up synthesis reaction (see, for example, Non-Patent Document 7).

[0036] In the present disclosure, MQO is a solid content. MQO may typically be in the form of particles (or powder).

[0037] The mixture after the reaction (also referred to as a reaction mixture) may be subjected to appropriate post-treatment, such as washing, impact (including shear force), drying (e.g., freeze-drying or heat drying), or pulverization.

[0038] The washing may be carried out using a protic solvent. The same explanation as above may be applied to the protic solvent, and the protic solvent may be washed with, for example, water or alcohol. After washing, a separation operation (centrifugation and / or decantation) may be carried out. The washing and separation operations may be repeated until the pH of the supernatant after centrifugation is, for example, 8 or less.

[0039] Optionally, instead of or in addition to the above washing, washing may be carried out using an aqueous solution of a metal salt. The metal salt may be, for example, a halide (fluoride, chloride, bromide, iodide) of an alkali metal (Li, Na, K, etc.), typically LiCl, NaCl, KCl, etc. Specifically, washing may be carried out using, for example, an aqueous solution of a metal salt having a molar concentration of 1 to 10. After washing, a separation operation (centrifugation and / or decantation) may be carried out. In this case, too, the washing and separation operations may be repeated as necessary until the pH of the supernatant after centrifugation becomes, for example, 8 or less.

[0040] Impact such as vibration and / or ultrasound may be applied during and / or after washing. This can promote the dispersion of MQO particles (e.g., nanofibers / nanoflakes, hereinafter the same). If the MQO particles are aggregated, they can be broken down. This effect is particularly pronounced when impact is applied during washing with an aqueous solution of a metal salt (it is believed that metal cations derived from the metal salt penetrate into the gaps between the aggregates and break them down). Impact can be applied using, for example, one or more of a handshake, an automatic shaker, a mechanical shaker, a vortex mixer, a homogenizer, an ultrasonic bath, etc.

[0041] Since the MQO particles are a solid component, a separation operation can be carried out at any appropriate time to remove unnecessary liquid components, if any. As a final separation operation, for example, a drying operation, typically freeze-drying or thermal drying, may be carried out. Freeze-drying can be carried out, for example, by freezing a mixture containing the MQO particles and a liquid component at any appropriate temperature (e.g., −40° C.) and then drying under reduced pressure. Thermal drying can be carried out, for example, by drying a mixture containing the MQO particles and a liquid component at a temperature of 25° C. or higher (e.g., 200° C. or lower) under atmospheric pressure or under reduced pressure. Pulverization can be carried out using, for example, a mortar and pestle combination, an IKA mill, or the like, without particular limitation. Pulverization may also be carried out after drying.

[0042] As a result, a pharmaceutical composition of the present disclosure containing MQO particles (nanofibers and / or nanoflakes) can be obtained. MQO is represented by formula (1), but the MQO particles do not necessarily consist solely of the constituent elements of formula (1). While not limiting the present disclosure, the MQO particles may optionally have at least one modification or terminal T present on their surface selected from the group consisting of hydroxyl groups, chlorine atoms, oxygen atoms, hydrogen atoms, and nitrogen atoms. Furthermore, the MQO particles may have two or more layers, and at least one cation selected from the group consisting of ammonium ions (e.g., quaternary ammonium cations) and metal cations (e.g., alkali metal ions, alkaline earth metal ions) may be present between these layers.

[0043] The BET specific surface area of ​​the MQO particles is not particularly limited, but is, for example, 10 m ２ / g or more 500m ２ The BET specific surface area is calculated using the BET equation from an isothermal adsorption curve of nitrogen gas or other suitable gas (e.g., krypton (Kr) gas, etc.) at liquid nitrogen temperature (77 K) by an adsorption method using nitrogen gas or other suitable gas.

[0044] The particle size of the MQO particles may be, for example, 0.01 nm or more, in particular 0.1 nm or more, or even 1 nm or more, and / or may be, for example, less than 1000 nm, in particular 100 nm or less, or even 50 nm or less. Such particles may also be referred to as nanoparticles.

[0045] The particle form of the MQO can be at least one selected from the group consisting of nanofibers, nanoflakes, and stacks of nanoflakes. Nanoflakes and stacks of nanoflakes are included in the category of two-dimensional materials.

[0046] Nanofibers may also be referred to as nanowires. A nanofiber refers to a solid object extending in the longitudinal direction, whose cross-sectional dimensions perpendicular to the longitudinal direction are on the nano order (i.e., 1 nm or more and less than 1000 nm) or even smaller, on the sub-nanometer order (less than 1 nm, for example, 0.1 nm or more and less than 1 nm). The cross-sectional dimensions of a nanofiber may be, for example, 0.1 nm or more, particularly 1 nm or more, and for example, 100 nm or less, particularly 50 nm or less, and preferably 15 nm or less.

[0047] Nanoflakes may also be referred to as nanosheets or two-dimensional (nano)sheets. Nanoflakes refer to solid objects having a two-dimensionally extending surface and a thickness that is relatively small compared to the maximum dimension of the surface, with the thickness being on the nano-order or even smaller, sub-nanometer order. The thickness of one layer of nanoflakes may be, for example, 0.01 nm or more, particularly 0.8 nm or more, and for example, 20 nm or less, particularly 3 nm or less. The maximum dimension in a plane parallel to the layer of nanoflakes (the two-dimensional sheet plane) (which may correspond to the "in-plane dimension" of the particle) may be, for example, 0.1 μm or more, particularly 1 μm or more, and for example, 200 μm or less, particularly 40 μm or less. Nanoflakes may be formed by the aggregation of nanofibers.

[0048] The stack of nanoflakes may also be referred to as a multi-layer MQO. The distance (interlayer distance or gap size) between two adjacent nanoflakes (or two adjacent layers of MQO) is not particularly limited.

[0049] Each of the above dimensions can be determined as a number-average dimension (number average of at least 40 dimensions) based on a photograph observed with a scanning electron microscope (SEM), a transmission electron microscope (TEM), or an atomic force microscope (AFM) (after processing by a method such as focused ion beam (FIB) if necessary), or as a distance in real space calculated from the position in reciprocal lattice space of the (002) plane measured by X-ray diffraction (XRD).

[0050] However, it should be noted that in the present disclosure, the MQO is not limited to the above forms and may have any suitable form.

[0051] The pharmaceutical composition (including MQO particles) of the present disclosure may contain unreacted first and / or second raw materials as impurities, and may also contain substances derived from the first, second, and / or protic solvents. For example, when a quaternary ammonium salt is used as the second raw material, N may be present (residual) in any form in the MQO particles. Furthermore, when a MAX raw material is used as the first raw material, the MQO particles of the present disclosure may contain a relatively small amount of residual A atoms, for example, 10% by mass or less relative to the original A atoms. The amount of residual A atoms may be preferably 8% by mass or less, more preferably 6% by mass or less. However, even if the amount of residual A atoms exceeds 10% by mass, this may not be a problem depending on the conditions of use, etc.

[0052] To obtain MQO particles with higher purity, it is preferable to repeat washing and centrifugation multiple times and recover the supernatant after the final centrifugation. The supernatant can be used as is, or after being appropriately diluted with a liquid medium, or after being dried and then mixed with a liquid medium to form a slurry containing MQO particles.

[0053] 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.

[0054] In an adsorption test using human plasma, for example, MQO (e.g., MQO particles) exhibits the ability to adsorb disease-causing substances such as electrolytes, medium-molecular-weight proteins, and particularly uremic substances. In other words, a pharmaceutical composition containing MQO can be used to adsorb disease-causing substances in vivo. The disease-causing substances may include electrolytes, more specifically, at least one selected from the group consisting of Na and K. Alternatively or in addition, the disease-causing substances may include uremic substances with a molecular weight of 100 or more, more specifically, β2-microglobulin, etc. Examples of disease-causing substances include parathyroid hormone, uremic proteins (specifically, medium-molecular-weight uremic substances) such as the aforementioned β2-microglobulin, and other proteins such as albumin and M protein. Alternatively or in addition, the disease-causing substances may include cytokines such as interleukins, interferons, chemokines, hematopoietic factors, growth factors, and tumor necrosis factors (in one embodiment, inflammatory cytokines such as interleukin-18, interleukin-6 (IL-6), interferon-γ (INF-γ), and tumor necrosis factor (TNF-α)). The above-mentioned inflammatory cytokines can cause various inflammatory symptoms in vivo, and adsorption of these cytokines is expected to have an inflammation-preventing effect. The disease-causing substances may include enzymes such as α-amylase, whose blood concentration increases due to decreased renal function.

[0055] Therefore, pharmaceutical compositions containing MQO are useful for treating or preventing diseases. Examples of such diseases include symptoms associated with kidney diseases (also referred to as kidney disease or renal dysfunction), such as acute kidney disease (including acute renal failure) and chronic kidney disease (including chronic renal failure and end-stage renal failure), particularly symptoms associated with renal failure. In other words, a method for treating or preventing symptoms associated with kidney disease can be carried out, which includes administering an effective amount of MQO to a subject. Specific examples of symptoms associated with kidney disease include electrolyte metabolism disorders such as hypernatremia and / or hyperkalemia.

[0056] Furthermore, because MQO can preferentially adsorb the above-mentioned disease-causing substances, administering MQO to a subject is expected to adsorb the disease-causing substances in vivo and reduce the disease-causing substances in the blood. In other words, an adsorption method can be carried out, comprising administering an effective amount of MQO to a subject to adsorb the disease-causing substances in vivo. In particular, it is expected that MQO, 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 treatment required for dialysis therapy and the burden on organs such as the kidneys.

[0057] 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.

[0058] The pharmaceutical composition according to this embodiment can be formulated as a pharmaceutical composition further comprising MQO as an active ingredient and pharmacologically acceptable additives by known methods depending on the dosage form. Such additives include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, etc. The pharmaceutical composition of the present disclosure can be prepared by appropriately mixing MQO with the additives, or by diluting and dissolving MQO with the additives.

[0059] 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.

[0060] When the pharmaceutical composition of the present disclosure is used for treatment, the dosage of MQO, which is the active ingredient, is determined appropriately depending on the patient's age, sex, body 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.

[0061] In addition, pharmaceutical compositions containing MQO can be used to manufacture medicaments for treating or preventing diseases.

[0062] The present disclosure includes: [1] a compound of the formula: MQ ａ O ｂ (wherein M is at least one element selected from the group consisting of Groups 3, 4, 5, 6 and 7, Q is at least one element selected from the group consisting of Groups 12, 13, 14, 15 and 16 (excluding O), a is 0 to 2, and b is 0 to 2). [2] The pharmaceutical composition according to [1], wherein the material has a peak in an X-ray diffraction pattern at a diffraction angle 2θ in the range of 2° to 12°. [3] The pharmaceutical composition according to [1] or [2], wherein M is Ti, Q is C, and a is not 0. [4] The pharmaceutical composition according to any of [1] to [3], which is used for adsorbing a disease-causing substance in a living body. [5] The pharmaceutical composition according to claim [4], wherein the disease-causing substance includes a uremic substance having a molecular weight of 100 or more. [6] The pharmaceutical composition according to [5], wherein the uremic substance having a molecular weight of 100 or more includes β2-microglobulin. [7] The pharmaceutical composition according to any one of [4] to [6], wherein the disease-causing substance includes an electrolyte. [8] The pharmaceutical composition according to [7], wherein the electrolyte includes at least one selected from the group consisting of Na and K. [9] The pharmaceutical composition according to any one of claims [1] to [8], which is for oral administration.

[10] A pharmaceutical composition according to the following formula: MQ ａ O ｂ(wherein M is at least one element selected from the group consisting of groups 3, 4, 5, 6 and 7, Q is at least one element selected from the group consisting of groups 12, 13, 14, 15 and 16 (excluding O), a is 0 or more and 2 or less, and b is 0 or more and 2 or less) to a subject, thereby adsorbing disease-causing substances in vivo.

[11] The adsorption method according to

[10] , wherein the material has a peak in the range of diffraction angle 2θ of 2° or more and 12° or less in an X-ray diffraction pattern.

[12] A method for adsorption according to the following formula: MQ ａ O ｂ A method for treating or preventing symptoms associated with kidney disease, comprising administering to a subject an effective amount of nanofibers and / or nanoflakes of a material represented by the formula: (wherein M is at least one element selected from the group consisting of Groups 3, 4, 5, 6 and 7; Q is at least one element (excluding O) selected from the group consisting of Groups 12, 13, 14, 15 and 16; a is 0 or more and 2 or less; and b is 0 or more and 2 or less).

[13] The method according to

[12] , wherein the material has a peak in an X-ray diffraction pattern with a diffraction angle 2θ in the range of 2° or more and 12° or less.

[14] The method according to

[12] or

[13] , wherein the symptoms associated with kidney disease are at least one selected from the group consisting of hypernatremia and hyperkalemia.

[0063] The present disclosure will be explained in more detail with reference to the following examples, but the present disclosure is not limited thereto.

[0064] Example 1 [Preparation of TiCO] First, 10 g of titanium carbide (TiC, manufactured by Kojundo Chemical Laboratory Co., Ltd.) and 30 mL of 25% by mass tetramethylammonium hydroxide (TMAH) aqueous solution (manufactured by Tokyo Chemical Industry Co., Ltd.) were placed in a container (100 mL Eye Boy). A stirrer tip with a length (35 mm) approximately equal to the inner diameter of the circular bottom of the container was placed therein. While the container was maintained at 50°C in a water bath, the mixture in the container was stirred with the stirrer tip and maintained for 120 hours, thereby allowing the reaction to proceed. Next, the reaction mixture in the container (without adding a liquid medium such as ethanol or water) was transferred to a 50 mL centrifuge tube using a stainless steel spatula. The solids were precipitated by centrifugation at 3500 G for 5 minutes using a centrifuge. (i) After centrifugation, the supernatant was discarded; (ii) 40 mL of ethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the remaining sediment in the centrifuge tube and the mixture was hand-shaken for 5 minutes (reslurry); and (iii) centrifugation was performed under the same conditions as above. These steps (i) to (iii) were repeated until the pH of the supernatant reached 8 or below. After three repetitions, the pH of the supernatant reached 8 or below, so the supernatant was discarded and the repetition process was terminated. 40 mL of pure water was added to the remaining sediment in the centrifuge tube and the mixture was shaken and stirred for 15 minutes using an automatic shaker. The mixture was then centrifuged at 3500 G for 30 minutes using a centrifuge, and the supernatant was collected as a sample slurry. The resulting sample slurry corresponds to a slurry containing TiCO (which may have the form of nanofibers and / or nanoflakes) (see the analysis results below).

[0065] Analysis: The sample slurry prepared above was suction filtered overnight using a Nutsche filter. A membrane filter (Durapore, pore size 0.45 μm, manufactured by Merck Ltd.) was used for the suction filtration. After suction filtration, the precursor film on the filter was dried overnight at 80°C in a vacuum oven, and the filter was removed to obtain a free-standing film. The free-standing film obtained in this manner was analyzed by X-ray photoelectron spectroscopy (XPS). Peaks corresponding to Ti 2p, C 1s, O 1s, and N 1s were observed in the resulting XPS spectrum, thus detecting Ti, C, O, and N. Since N is believed to be a residual component of the raw material TMAH, the material of the free-standing film is believed to be composed of Ti, C, and O. Furthermore, the XRD profile of the free-standing film obtained in the same manner as above was measured using an XRD device (MiniFlex, manufactured by Rigaku Corporation) (characteristic X-rays: CuKα = 1.54 Å). The obtained XRD pattern is shown in Figure 1. As can be seen from FIG. 1, this material had a peak at 2θ=7.26°.

[0066] The sample slurry prepared above was freeze-dried (freezed in a freezer at −40° C., and then vacuum-dried) to form a dry powder. The obtained dry powder (corresponding to TiCO powder) was subjected to adsorption evaluation.

[0067] Example 2 [Preparation of TiCO] First, titanium boride (TiB ２1.16 g of ethanol (manufactured by Kojundo Chemical Laboratory Co., Ltd.) and 30 mL of 25% by weight tetramethylammonium hydroxide (TMAH) aqueous solution (manufactured by Tokyo Chemical Industry Co., Ltd.) were added. A stirrer tip with a length (35 mm) approximately equal to the inner diameter of the circular bottom of the container was placed therein. The container was kept at 50 °C in a water bath and the mixture in the container was stirred with the stirrer tip for 72 hours, allowing the reaction to proceed. Next, the reaction mixture in the container was transferred to a 50 mL centrifuge tube using a stainless steel spatula (without adding a liquid medium such as ethanol or water). The solids were sedimented by centrifugation at 3500 G for 5 minutes. (i) After centrifugation, the supernatant was discarded, (ii) 40 mL of ethanol (manufactured by Fujifilm Wako Pure Chemical Industries Co., Ltd.) was added to the remaining sediment in the centrifuge tube, and the mixture was shaken for 5 minutes (reslurry), and (iii) the centrifugation was carried out under the same conditions as above. These steps (i) to (iii) were repeated until the pH of the supernatant reached 8 or less. After three repetitions, the supernatant was discarded and the repetition process was terminated. 40 mL of pure water was added to the remaining sediment in the centrifuge tube, and the mixture was shaken and stirred for 15 minutes using an automatic shaker. The mixture was then centrifuged at 3500 G for 30 minutes using a centrifuge, and the supernatant was collected as a sample slurry.

[0068] The analysis and preparation of the dry powder were carried out in the same manner as in Example 1.

[0069] Example 3 [Preparation of TiCO] First, 10 g of titanium carbide (TiC, manufactured by Kojundo Chemical Laboratory Co., Ltd.) and 30 mL of 25% by mass tetramethylammonium hydroxide (TMAH) aqueous solution (manufactured by Tokyo Chemical Industry Co., Ltd.) were placed in a container (100 mL Eye Boy). A stirrer tip with a length (35 mm) approximately equal to the inner diameter of the circular bottom of the container was placed therein. While the container was maintained at 50°C in a water bath, the mixture in the container was stirred with the stirrer tip and maintained for 24 hours, thereby allowing the reaction to proceed. Next, the reaction mixture in the container (without adding a liquid medium such as ethanol or water) was transferred to a 50 mL centrifuge tube using a stainless steel spatula. The solids were precipitated by centrifugation at 3500 G for 5 minutes using a centrifuge. (i) After centrifugation, the supernatant was discarded; (ii) 40 mL of ethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the remaining sediment in the centrifuge tube, followed by handshaking for 5 minutes (reslurry); and (iii) centrifugation was performed under the same conditions as above. These steps (i) to (iii) were repeated until the pH of the supernatant reached 8 or below. After three repetitions, the pH of the supernatant reached 8 or below, so the supernatant was discarded and the repetition process was terminated. 40 mL of pure water was added to the remaining sediment in the centrifuge tube, and the mixture was shaken and stirred for 15 minutes using an automatic shaker. Then, the mixture was centrifuged at 3500 G for 30 minutes using a centrifuge, and the supernatant was collected as a sample slurry.

[0070] The analysis and preparation of the dry powder were carried out in the same manner as in Example 1.

[0071] 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.

[0072] Comparative Example 2 An adsorption-type blood purifier ("Rixel", manufactured by Kaneka Corporation) was disassembled, and the removed adsorbent was subjected to adsorption evaluation.

[0073] Comparative Example 3 Medicinal charcoal (manufactured by Nichi-Iko Pharmaceutical Co., Ltd.) was subjected to adsorption evaluation.

[0074] Evaluation of adsorption performance [adsorption of Na, P, K, β2-microglobulin, interleukin-18, α-amylase, and albumin]

[0075] Adsorption Evaluation Method 10 mL of human plasma collected from a healthy subject and 0.6 g of adsorbent were weighed into a 50 mL centrifuge tube and shaken and stirred for 15 minutes using a thermostatic shaker (Tytec BR-43FM) set to 37°C. The tube was then centrifuged in a centrifuge (TOMY AX-521) at 3200 rpm for 10 minutes at 20°C, and several mL of the supernatant was sampled for component analysis.

[0076] Component analysis was performed for Na, P, K, β2-microglobulin, interleukin-18 (IL-18), α-amylase, and albumin. Measurements of Na and K were performed by electrode method; P and α-amylase were performed by enzymatic method; β2-microglobulin was measured by latex agglutination method; interleukin-18 was measured by EIA method; and albumin was measured by colorimetric method (BGC method).

[0077] 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: Adsorption and removal rate (mass%) = (C Ａ０ -C Ａ１ ) / C Ａ０ ×100

[0078] The results are shown in Table 1.

[0079]

[0080] It was confirmed that the dry powders of Examples 1 to 3 exhibited the ability to adsorb disease-causing substances, particularly Na and K (electrolytes) and β2-microglobulin (a uremic substance). Therefore, pharmaceutical compositions containing MQO (TiCO in Example 1) may be useful for the treatment of diseases.

[0081] [Adsorption of cytokines other than interleukin-18] As cytokine reagents, 10 ng of interferon-γ (INF-γ) (manufactured by FUJIFILM Wako Pure Chemical Corporation), 10 ng of interleukin-1β (IL-1β) (manufactured by FUJIFILM Wako Pure Chemical Corporation), 10 ng of interleukin-6 (IL-6) (manufactured by FUJIFILM Wako Pure Chemical Corporation), and 10 ng of tumor necrosis factor (TNF-α) (manufactured by FUJIFILM Wako Pure Chemical Corporation), 0.5 mg of the adsorbent (the dried powder of Example 2), and 20 mL of pure water were added to a 50 mL centrifuge tube, and the mixture was shaken and stirred for 15 minutes using a thermostatic shaker (Tytec BR-43FM) set at 37°C. Thereafter, the mixture was centrifuged at 4500 rpm for 5 minutes at 20° C. using a centrifuge (TOMY AX-521), and several mL of the supernatant was sampled and analyzed for components.

[0082] For the component analysis, absorbance was measured using the ELISA method (sandwich method) for each of INF-γ, IL-1β, IL-6, and TNF-α, and the amount of cytokine adsorption (cytokine + adsorbent concentration) was determined using a calibration curve of absorbance and cytokine adsorption amount obtained in advance.

[0083] The same treatment was also carried out on centrifuge tubes containing only each cytokine reagent and water, without the adsorbent, and these were used as baselines for the component concentrations. The concentration of component A (the concentration of cytokines plus adsorbent) in the cytokine reagent-containing water after the adsorption test was measured. Ａ１ , the baseline concentration of component A (concentration of cytokines only) is C Ａ０ The adsorption and removal rate was calculated based on the following formula: Adsorption and removal rate (mass%) = (C Ａ０ -C Ａ１ ) / C Ａ０ ×100

[0084] The results are shown in Table 2.

[0085]

[0086] From Table 2, it was confirmed that MQO exhibits the ability to adsorb INF-γ, IL-6, and TNF-α. On the other hand, no ability to adsorb IL-1β was observed. From these results, it can be said that MQO also has the effect of adsorbing the cytokines INF-γ, IL-6, and TNF-α, and that pharmaceutical compositions containing MQO may be useful in the treatment of diseases.

[0087] This application claims priority to U.S. Application No. 63 / 423608, filed November 8, 2022, the entire contents of which are incorporated herein by reference.

[0088] The pharmaceutical compositions of the present disclosure can be used for a wide variety of purposes, including, but not limited to, for adsorbing disease-causing substances in vivo.

Claims

1. The following formula: MQ ａ O ｂ (wherein M is at least one element selected from the group consisting of Groups 3, 4, 5, 6 and 7, Q is at least one element selected from the group consisting of Groups 12, 13, 14, 15 and 16 (excluding O), a is 0 or more and 2 or less, b is greater than 0 and 2 or less) A pharmaceutical composition comprising nanofibers and / or nanoflakes of a material represented by the formula, wherein the crystal structure of the material is of the lepidocrocite type.

2. The pharmaceutical composition according to Claim 1, wherein Q is C and a is 1 or more and 2 or less.

3. The pharmaceutical composition according to Claim 1 or 2, wherein the material has a peak in the range of diffraction angle 2θ of 2° or more and 12° or less in the X-ray diffraction pattern.

4. The pharmaceutical composition according to Claim 1 or 2, wherein M is Ti, Q is C, and a is not 0.

5. The pharmaceutical composition according to Claim 1 or 2, which is used for adsorbing disease-causing substances in vivo.

6. The pharmaceutical composition according to Claim 5, wherein the disease-causing substances include uremic substances having a molecular weight of 100 or more.

7. The pharmaceutical composition according to Claim 6, wherein the uremic substances having a molecular weight of 100 or more include β2-microglobulin.

8. The pharmaceutical composition according to Claim 5, wherein the disease-causing substances include electrolytes.

9. The pharmaceutical composition according to Claim 8, wherein the electrolyte includes at least one selected from the group consisting of Na and K.

10. The pharmaceutical composition according to Claim 5, wherein the disease-causing substances include cytokines.

11. The pharmaceutical composition according to Claim 10, wherein the cytokine includes at least one selected from the group consisting of interleukins, interferons, chemokines, hematopoietic factors, cell growth factors and tumor necrosis factors.

12. The pharmaceutical composition according to Claim 1 or 2, which is for oral administration.

13. The following formula: MQ ａ O ｂ (wherein M is at least one element selected from the group consisting of Groups 3, 4, 5, 6 and 7, Q is at least one element selected from the group consisting of Groups 12, 13, 14, 15 and 16 (excluding O), a is 0 or more and 2 or less, b is greater than 0 and 2 or less) An adsorption method that includes administering an effective amount of nanofibers and / or nanoflakes of a material represented by to adsorb disease-causing substances in vivo.

14. The adsorption method according to claim 13, wherein the material has a peak in a range where the diffraction angle 2θ is 2° or more and 12° or less in the X-ray diffraction pattern.