Use of manganese-containing compounds for reducing uric acid levels in mammalian individuals

Abstract

Use of a manganese-containing compound for reducing uric acid levels in a mammalian subject, the invention relates to a pharmaceutical composition, in particular to application of an insoluble manganese-containing compound in preparation of a medicine for preventing and / or treating uric acid level rise in blood and / or digestive tract of a mammal individual or diseases or symptoms related to the uric acid level rise in the blood and / or digestive tract and a pharmaceutical composition for the application. The invention relates to a kit and a method for preventing and / or treating related diseases or conditions.

Description

Use of manganese-containing compounds for reducing uric acid levels in mammalian subjects Technical Field

[0001] The present application generally relates to the use of manganese-containing compounds in lowering uric acid levels in mammalian individuals, and more particularly to the use of insoluble manganese-containing compounds in the preparation of medicaments for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of mammalian individuals or diseases or conditions associated with elevated uric acid levels in the blood and / or digestive tract, as well as pharmaceutical compositions, kits, and methods for preventing and / or treating related diseases or conditions for such use. Background Art

[0002] Uric acid is a nitrogen- and oxygen-containing heterocyclic compound with a molecular formula of C5H4N4O3 and is the final metabolic product of purine in the body. Conditions associated with abnormally elevated uric acid levels in the blood and / or serum primarily include hyperuricemia, gout, and its complications, such as gouty arthritis (with or without tophi), gouty urinary stones (i.e., gouty urolithiasis), gouty nephropathy (i.e., urate nephropathy), and the sequelae of these diseases. Hyperuricemia is associated with an increased risk of developing gout. The more severe and prolonged an individual's hyperuricemia, the higher the risk of developing gout. In addition to gouty arthritis, chronic hyperuricemia can lead to the deposition of urate crystals in the urinary tract, renal parenchyma, and soft tissues, resulting in gouty urolithiasis, gouty nephropathy, and soft tissue tophi, respectively.

[0003] At present, the clinical treatment of hyperuricemia or gout mainly includes the use of drugs that reduce the blood concentration of uric acid. In addition, the symptoms of acute gout can be controlled by using anti-inflammatory drugs. Such drugs are mainly used for anti-inflammatory, but can not provide the effect of reducing uric acid levels. Lowering the uric acid level in individual blood and / or serum to a normal range can reduce the recurrence rate of acute gout and prevent other diseases or conditions related to the increase in uric acid levels. So far, many patients still cannot effectively control uric acid levels after receiving the standard treatment of existing drugs. In addition, many currently available hyperuricemia or gout treatment drugs are associated with multiple harmful side effects.

[0004] The level of uric acid in an individual's blood and / or serum depends on the balance between the amount of purine obtained through food or drink intake, the amount of uric acid produced in the body, and the amount of uric acid excreted through urine or the digestive tract. Regarding the production of uric acid in the body, about 80% of uric acid comes from the body's own synthesis, while about 20% of uric acid still enters the body through intestinal intake (Current hypertension reports, 2016, 18 (10): 1-6.). Some patients with hyperuricemia have increased intestinal uric acid intake due to factors such as dietary habits and intestinal lesions. On the other hand, regarding the excretion of uric acid in the body, in normal people, about 70% of uric acid is excreted through the kidneys, while about 30% of uric acid is still excreted through the intestines. For patients with chronic kidney disease, due to the decreased ability of the kidneys to clear uric acid, excretion of uric acid through the intestine has become the main route of uric acid excretion (Mini Reviews in Medicinal Chemistry, 2020, 20 (18): 1857-1866.). It can be seen that by clearing uric acid in the digestive tract, it may help to reduce the uric acid content in an individual's body. On the other hand, drugs that only work locally in the digestive tract (such as Veltassa and Lokelma, drugs for treating hyperkalemia, etc.) are not absorbed into the blood and do not cause systemic side effects, thus having a good safety profile. Therefore, the development of a uric acid-lowering drug based on the mechanism of clearing uric acid in the digestive tract is of great significance and will become a good supplement to existing uric acid-lowering drugs.

[0005] Summary of the Invention

[0006] The present application is at least partly based on the inventor's unexpected discovery that manganese-containing compounds have excellent absorption and / or the favorable properties of removing uric acid (including its salts, such as monosodium urate), and compared with materials with adsorption properties known in the prior art, this manganese-containing compound's absorption and / or removal of uric acid (including its salts, such as monosodium urate) is not subject to, is substantially not subject to, or is less subject to the influence of various substances (including but not limited to digestive juices such as gastric juice, small intestinal juice and chyme) present in the digestive tract of mammals. In addition, the inventor has also unexpectedly found that manganese-containing compounds can be used with very high oral safety doses without causing unacceptable side effects, thereby having a desirable safety profile. Based on the above discovery, a technical solution that meets the above and other needs is provided hereinafter.

[0007] In one aspect, the present disclosure provides use of an insoluble manganese-containing compound in the preparation of a medicament for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian subject, or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract.

[0008] In another aspect, the present disclosure provides use of a manganese-containing compound in the preparation of a medicament for adsorbing uric acid in the digestive tract of a mammal.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian individual, or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract, wherein the pharmaceutical composition comprises an insoluble manganese-containing compound and a pharmaceutically acceptable excipient.

[0010] In another aspect, the present disclosure provides a kit comprising: (i) any one of the pharmaceutical compositions according to the present disclosure; and (ii) a pharmaceutical insert and / or a pharmaceutical label.

[0011] In another aspect, the present disclosure provides a method for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian individual, or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract, comprising administering to the individual in need thereof an effective amount of an insoluble manganese-containing compound.

[0012] In another aspect, the present disclosure provides a method for preventing and / or treating elevated blood uric acid levels or a disease or condition associated with elevated blood uric acid levels in a mammalian subject, comprising administering to the subject in need thereof an effective amount of an insoluble manganese-containing compound over an extended period of time.

[0013] In another aspect, the present disclosure provides a method for maintaining blood uric acid levels in a mammalian subject, comprising administering to the subject in need thereof an effective amount of an insoluble manganese-containing compound over an extended period of time.

[0014] In another aspect, the present disclosure provides a pharmaceutical composition comprising manganese oxide, wherein the amount of manganese oxide is sufficient to reduce the blood and / or serum uric acid levels in at least about 10% of mammalian subjects having blood and / or serum uric acid levels above 360 ​​μmol / L or 420 μmol / L by at least about 5% within 24 hours after administration of the pharmaceutical composition.

[0015] In another aspect, the present disclosure provides a pharmaceutical composition formulated as at least one solid dosage unit for oral administration to a mammalian subject, wherein the solid dosage unit comprises manganese oxide, and wherein the manganese oxide has a uric acid clearance capacity as measured in a simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay that is at least about 100 mg / g higher than the uric acid clearance capacity of activated carbon under equivalent conditions.

[0016] The illustrative embodiments of the present disclosure are shown and described in detail below, from which other aspects and advantages of the present disclosure will be apparent to those skilled in the art. As will be appreciated by those skilled in the art, the accompanying drawings and descriptions are illustrative, not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The features and advantages of the inventions of this application will be better understood by referring to the exemplary embodiments and accompanying drawings described in detail below. The following is a brief description of the information in the various drawings attached to the specification. It should be understood that the drawings are illustrative and do not constitute any limitation of the inventions of this application.

[0018] FIG1 shows the uric acid clearance capacity (mg / g) and uric acid clearance rate (%) of each test substance measured in the simulated intestinal fluid (SIF) assay described in Section 2.1 of Example 2.

[0019] FIG. 2 shows the uric acid clearance (%) of each test substance measured in the simulated intestinal fluid (SIF) assay described in Section 2.2 of Example 2.

[0020] FIG3 shows a graph showing the uric acid clearance (%) of each test substance as a function of mixing time as measured in the simulated intestinal fluid (SIF) assay described in Section 2.3 of Example 2.

[0021] FIG4 shows the uric acid clearance capacity (mg / g) of each test substance measured in the simulated intestinal fluid (SIF) assay described in Section 2.4 of Example 2.

[0022] FIG5 shows the uric acid clearance capacity (mg / g) of each test substance at different uric acid concentrations (μM) measured in the simulated intestinal fluid (SIF) assay described in the first part of Section 2.5 of Example 2.

[0023] FIG6 shows the uric acid clearance capacity (mg / g) of each test substance at different uric acid concentrations (μM) measured in the simulated fasting small intestinal fluid (FaSSIF) assay described in the first part of Section 2.5 of Example 2.

[0024] FIG7 shows the uric acid clearance capacity (mg / g) of each test substance at different uric acid concentrations (μM) measured in the simulated fed small intestinal fluid (FeSSIF) assay described in the first part of Section 2.5 of Example 2.

[0025] FIG8 shows the uric acid clearance capacity (mg / g) of each test substance at different uric acid concentrations (μM) measured in the simulated intestinal fluid (SIF) assay described in the second part of Section 2.5 of Example 2.

[0026] FIG9 shows the uric acid clearance (%) of each test substance at different uric acid concentrations (μM) measured in the simulated intestinal fluid (SIF) assay described in the second part of Section 2.5 of Example 2.

[0027] FIG10 shows the uric acid clearance capacity (mg / g) of each test substance at different uric acid concentrations (μM) measured in the simulated fasting small intestinal fluid (FaSSIF) assay described in the second part of Section 2.5 of Example 2.

[0028] FIG11 shows the uric acid clearance (%) of each test substance at different uric acid concentrations (μM) measured in the simulated fasting small intestinal fluid (FaSSIF) assay as described in the second part of Section 2.5 of Example 2.

[0029] FIG12 shows the uric acid clearance capacity (mg / g) of each test substance at different uric acid concentrations (μM) measured in the simulated fed small intestinal fluid (FeSSIF) assay described in the second part of Section 2.5 of Example 2.

[0030] FIG. 13 shows the uric acid clearance (%) of each test substance at different uric acid concentrations (μM) measured in the simulated fed small intestinal fluid (FeSSIF) assay described in the second part of Section 2.5 of Example 2.

[0031] FIG. 14 shows the uric acid clearance capacity (mg / g) of each test substance measured in the pork enzymatic hydrolysate assay described in Section 2.6 of Example 2.

[0032] FIG. 15 shows the uric acid clearance capacity (mg / g) of each test substance measured in the food enzymatic solution assay described in Section 2.7 of Example 2.

[0033] FIG. 16 shows the uric acid clearance capacity (mg / g) of each test substance measured in the simulated intestinal fluid (SIF) assay described in Section 2.8 of Example 2.

[0034] FIG. 17 shows the uric acid clearance capacity (mg / g) of each test substance measured in the simulated intestinal fluid (SIF) assay described in Section 2.9 of Example 2.

[0035] FIG. 18 shows the uric acid clearance (%) of each test substance measured in the simulated intestinal fluid (SIF) assay described in Section 2.9 of Example 2.

[0036] Figure 19 shows the measured values ​​of the uric acid clearance capacity (mg / g) of each test substance measured in the 12 simulated intestinal fluid (SIF) assays described in Section 2.10 of Example 2 and the 12 cumulative uric acid clearance capacity (mg / g).

[0037] FIG20 shows the amount of uric acid excreted via urine within 24 hours (mg / day) of each group of mice measured in the hyperuricemia model mouse experiment induced by potassium oxonate and adenine as described in Section 4.4.2 of Example 4.

[0038] FIG21 shows a curve showing the change in serum uric acid levels (μM) over time in each group of mice measured in the uric acid-induced hyperuricemia model mouse experiment described in Section 4.4.3 of Example 4.

[0039] FIG22 shows the serum uric acid levels (μM) of each group of mice measured in the hyperuricemia model mouse experiment induced by potassium oxonate and hypoxanthine as described in Section 4.4.4 of Example 4.

[0040] FIG23 shows the serum uric acid levels (μM) of each group of mice measured in the hyperuricemia model mouse experiment induced by potassium oxonate and uric acid as described in Section 4.4.5 of Example 4. DETAILED DESCRIPTION

[0041] Various exemplary embodiments or examples of the invention to which this application relates are disclosed below. It should be understood that these embodiments or examples are merely illustrative and are not intended to limit the scope of protection of the invention to which this application relates. Without departing from the spirit of the present disclosure, those skilled in the art will appreciate many variations, changes, and substitutions of these exemplary embodiments or examples. It should be understood that the embodiments or examples obtained through these variations, changes, or substitutions also fall within the scope of protection of this application.

[0042] To the extent that publications, patents, and patent applications are cited in the specification, all such cited publications, patents, and patent applications are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. To the extent such incorporated by reference publications, patents, and patent applications conflict with the disclosure contained in the specification, the interpretation and / or description in the specification shall control.

[0043] Where the specification mentions a numerical range, it should be understood that all numerical ranges mentioned in this disclosure are intended to include the two endpoints of the range (i.e., the upper limit and the lower limit), all numerical values ​​within the range (especially integers), and sub-ranges formed by these numerical values ​​(especially integers).

[0044] definition

[0045] As used throughout this document, the singular forms "a," "an," "the," and "the" include plural referents unless the context clearly indicates otherwise. In addition, unless it is not specifically stated whether a certain referent is singular or plural, this application includes both the singular and the plural.

[0046] As used throughout this document, the term "plurality" refers to more than one, including but not limited to two, three, four, five, six, etc.

[0047] As used throughout this document, the terms "comprises," "comprising," "having," "containing," and variations thereof are intended to represent open-ended transitional phrases, terms, or words that do not exclude the possibility of additional steps, substances, or structures. When such terms are used to describe a drug, pharmaceutical composition, kit, use, or method, etc., of the present disclosure, they also encompass situations where the drug, pharmaceutical composition, kit, use, or method, etc., consists of the enumerated elements or elements. In the context of the present disclosure, the term "consisting of" means that, in addition to the enumerated elements or elements, no unenumerated elements or elements (e.g., steps, substances, or structures, etc.) are present in the subject matter or method.

[0048] As used throughout this document, the term "optionally" means that the subsequently described element or event may or may not exist / occur, and includes both the presence / occurrence and absence / occurrence of the element or event.

[0049] As used throughout this document, the term "about" means approximately, in the region of, roughly, or around, and is used to indicate that the characteristic being described is within an acceptable error range for a person of ordinary skill in the art for a given value. When the term "about" is used in reference to a numerical value, it is used to indicate any numerical value within a range of ±20% of the recited numerical value. In some embodiments, the term "about" can be used to encompass any numerical value within a range of ±10%, ±5%, ±1%, ±0.5%, or ±0.1% of a particular value.

[0050] As used throughout this document, the term "manganese-containing compound" refers to a chemical substance composed of manganese and any other element or elements (usually in a fixed mass ratio) bonded together by chemical bonds (i.e., forces binding the atoms or ions constituting the compound, including but not limited to covalent bonds and ionic bonds).

[0051] As used herein, the term "insoluble manganese-containing compound" refers to a manganese-containing compound that is insoluble in water and / or digestive tract fluids (including but not limited to gastric juice, small intestinal juice, large intestinal juice, pancreatic juice and / or bile) under physiological conditions, or has very low solubility therein. The insoluble manganese-containing compound of the present disclosure can be identified by measuring the mass of the manganese-containing compound dissolved in 1 mL of water or a simulant of digestive tract fluid (including but not limited to simulated intestinal fluid (SIF), simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF)) at about 37° C. and about 1 atmosphere of pressure when saturated. When the mass of the manganese-containing compound dissolved under the above conditions is less than about 100 μg, for example, less than about 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng, it can be considered as an "insoluble manganese-containing compound" as described in the present disclosure. On the other hand, an "insoluble manganese-containing compound" can also be characterized by its physiological inertness, that is, it is substantially unable to be absorbed into the blood circulation through the gastrointestinal tract (i.e., the digestive tract) and / or does not substantially react chemically with surrounding substances or tissues in the body after administration. For example, an "insoluble manganese-containing compound" can be a manganese-containing compound that enters the blood circulation through absorption in the gastrointestinal tract in an amount less than about 20% of the administered dose, such as less than about 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose and / or does not chemically react with surrounding substances or tissues in the body after administration or only less than about 20% of the administered dose, such as less than about 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose chemically reacts with surrounding substances or tissues in the body. Without being limited by theory, due to its physiological inertness and insolubility, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the administered amount of the insoluble manganese-containing compound of the present application is excreted from the body. As non-limiting examples, the insoluble manganese-containing compound is selected from one or more of manganese oxide, manganese sulfide, manganese carbonate, manganese silicate, manganese borate, manganese ferrocyanide, manganese oxalate, manganese selenite, manganese iodate, manganese tungstate and manganese phosphate, and solvates thereof (e.g., hydrates).

[0052] As used herein, the terms "particle size" and "particle size" are used interchangeably and refer to a measure of the size (or dimensions) of a particle population (e.g., a particle population of an insoluble manganese-containing compound in the context of the present disclosure). Methods for measuring particle size are known in the art. For example, the particle size of a particle population can be measured using a method of dynamic image analysis (DIA). For another example, the particle size of a particle population can be measured using a method of dynamic light scattering. For another example, the particle size of a particle population can be measured using a method of a laser particle size analyzer (or laser diffraction particle size analyzer). When referring to the particle size range of a certain particle group in the context of the present disclosure, it should be understood that there may still be a small amount of particles in the particle group that do not meet the particle size range (for example, the particles that do not meet the particle size range account for ≤5%, ≤4%, ≤3%, ≤2%, ≤1%, ≤0.9%, ≤0.8%, ≤0.7%, ≤0.6%, ≤0.5%, ≤0.4%, ≤0.5%, ≤0.4%, ≤0.3%, ≤0.2% or ≤0.1% of the total amount of the particle group), but the presence of this part of the particles will not substantially affect the overall properties of the particle group.

[0053] As used throughout this document, the term "manganese oxide" refers to a chemical substance composed of at least one manganese (Mn) atom, at least one oxygen (O) atom, and optionally other metal (including atomic groups with metal-like properties, such as ammonia) or hydrogen (represented by M; M = H, K, Na, Li, Ba, Pb, Ca, Zn, etc.) atoms bonded together by chemical bonds (Note: "atom" as described herein also includes charged ions formed by losing or gaining one or more electrons, and for the purposes of this disclosure, metal ions also include ammonium ions). Manganese oxide is typically a black or brown solid, and its basic structural unit is typically an octahedral unit [MnO6] formed by one manganese atom coordinated with six oxygen atoms and stacked to form different crystalline structures by sharing edges or corners. In the stacked structure, each atomic layer forms tetrahedral and octahedral cavities. In manganese oxide, manganese can exhibit oxidation states of +2, +3, +4, +6, and +7, so that manganese oxide can exist in a variety of different forms or mixtures of these forms. In addition, various cations can be doped into the cavities between the atoms in the structure of manganese oxide; in this article, the manganese oxide doped with impurity cations is referred to as "salt-type manganese oxide". In some embodiments of the present disclosure, the manganese oxide is: (1) manganese oxide composed only of manganese atoms and oxygen atoms, such as manganese monoxide (MnO), manganese dioxide (MnO2), manganese trioxide (MnO3), manganese dioxide (Mn2O3), manganese pentaoxide (Mn5O8), manganese tetraoxide (Mn3O4), manganese heptoxide (Mn2O7), manganese dodecaoxide (Mn7O8), manganese octaoxide (Mn7O8), manganese sesquioxide (Mn3O4), manganese octaoxide (Mn2O7), manganese octaoxide (Mn7O8), manganese sesquioxide (Mn3O4), manganese sesquioxide (Mn2O7), manganese octaoxide (Mn7O8 ...monoxide (MnO2), manganese sesquioxide (MnO3), manganese sesquioxide (Mn2O3), manganese octaoxide (Mn5O8), manganese sesquioxide (Mn3O4), manganese sesquioxide (Mn2O7), manganese octaoxide (Mn7O8), manganese sesquioxide (Mn7O8), manganese sesquioxide (Mn7O8), manganese sesquioxide (Mn7O8), manganese sesquioxide (Mn7O8), manganese sesquioxide (Mn7O8), man 12 ), heptadroxide (Mn7O 13) etc.; (2) manganese oxide composed only of manganese atoms, hydrogen atoms and oxygen atoms, such as manganese oxyhydroxide (MnOOH), manganese hydroxide (Mn(OH)2), etc.; or (3) manganese oxide composed of manganese atoms, oxygen atoms, metal atoms and optionally hydrogen atoms, such as various types of salt-type manganese oxides, such as potassium-type manganese oxide, hydrogen-type manganese oxide, ammonium-type manganese oxide, sodium-type manganese oxide, calcium-type manganese oxide, magnesium-type manganese oxide, iron-type manganese oxide, ferrous-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide and silver-type manganese oxide, etc. In the above embodiments, the various atoms mentioned, including manganese, oxygen, hydrogen and metal atoms, may be in their ionic forms as needed. Manganese oxide can be generally obtained from natural minerals, such as ramsonite, cryptomalusite, pyrolusite, hexagonite, birnessite, busel ore, rehydrated manganese, ramsdellite, barium psilomelane, barium magnesium manganite, manganite, sphene, hexagonite, hydrinomanganite, pyrolusite, pyrolusite, pyrolusite and sphene. Accordingly, in some embodiments, the manganese oxide is a manganese oxide in the form of natural minerals. Manganese oxide and their solvates (such as hydrates) can also exist in polymorphic forms. In some embodiments, manganese oxide is in the form of crystalline forms such as α, β, γ, δ, λ, ε or R type or in amorphous form. In some embodiments, in the preparation process of the polymorph of manganese oxide, the formation of a specific phase is driven by structure-directed impurity ions. Depending on the type of ions in the solution used to prepare the polymorph of manganese oxide, various cations may be incorporated into the cavities between the atoms in the structure of the resulting polymorph of manganese oxide, thereby forming a "salt-type polymorph" of manganese oxide. In some embodiments, the cations are potassium, sodium, ammonium, calcium, magnesium, ferric, ferrous, zinc, lanthanum, bismuth, lithium, or hydrogen ions; accordingly, the polymorph of manganese oxide with potassium, sodium, ammonium, calcium, magnesium, ferric, ferrous, zinc, lanthanum, bismuth, lithium, or hydrogen ions incorporated into these cavities is referred to as "potassium-type," "sodium-type," "ammonium-type," "calcium-type," "magnesium-type," "ferrous-type," "ferrous-type," "zinc-type," "lanthanum-type," "bismuth-type," "lithium-type," or "hydrogen-type" polymorph of manganese oxide, respectively.

[0054] As used throughout this document, the terms "disease," "disorder," "condition," "(medical) condition," and the like are used interchangeably and refer to any deviation from a normal state of an individual. For example, these terms may refer to physical discomfort or distress in an individual, or to any change in the state of certain organs or tissues that prevents or disrupts the normal performance of their functions.

[0055] As used throughout this document, the term "adsorption" refers to the attachment of uric acid (also including urate salts such as monosodium urate) to the surface of a manganese-containing compound.

[0056] As used throughout this article, the term "uric acid" refers to 7,9-dihydro-1H-purine-2,6,8(3H)-trione. Uric acid is a heterocyclic compound containing carbon, nitrogen, oxygen, and hydrogen with the molecular formula C5H4N4O3. In humans and most other primates, uric acid is the end product of purine metabolism. At the pH of body fluids, uric acid exists primarily in its ionic form, urate. Therefore, the term "uric acid" also includes urate salts (e.g., monosodium urate).

[0057] As used herein, the term "elevated uric acid levels" or "elevated uric acid levels" refers to blood and / or serum uric acid levels that are greater than normal. For humans, the upper limit of normal levels is typically about 420 μmol / L for men and about 360 μmol / L for women. In some embodiments, the blood and / or serum uric acid levels of an individual with "elevated uric acid levels" or "elevated uric acid levels" are at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 240 μmol / L, 260 μmol / L, 280 μmol / L, 300 μmol / L, 320 μmol / L, 340 μmol / L, 360 μmol / L, 380 μmol / L, 400 μmol / L, or 420 μmol / L. Inappropriate elevation of blood and / or serum uric acid levels can be associated with a variety of diseases or conditions. In some embodiments, the disease or condition can be at least one disease or condition selected from the group consisting of gout, gout complications, hyperuricemia, elevated uric acid levels that do not reach levels typically diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related conditions, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle spasms, localized swelling, joint pain, malignancy, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, nonalcoholic fatty liver disease, stroke, hemolytic anemia, inborn errors of metabolism, poisoning, carbuncle, and transplantation of blood, bone marrow, or solid organs.

[0058] As used throughout this document, the term "hyperuricemia (HUA)" refers to abnormally high uric acid levels in the blood and / or serum. Under the pH conditions of body fluids, uric acid exists primarily in its ionic form, urate. The body's urate content is determined by the balance between the amount of purines consumed in the diet, the amount of urate synthesized by the body, and the amount of urate excreted in the urine and digestive system. Hyperuricemia can be caused by excessive uric acid production, decreased uric acid excretion, or a combination of both. Clinically, hyperuricemia can be divided into two major categories: primary hyperuricemia and secondary hyperuricemia. Primary hyperuricemia is typically caused by a congenital abnormality in purine metabolism. Secondary hyperuricemia can be caused by taking certain medications that inhibit uric acid excretion (e.g., thiazide diuretics, aspirin, pyrazinamide, levodopa, ethambutol, etc.) or by certain other medical conditions (e.g., hematological malignancies, chronic kidney disease, etc.).

[0059] As used herein throughout, the term "higher uric acid levels that do not reach the level typically diagnosed as hyperuricemia" refers to blood and / or serum uric acid levels greater than those in a given population (such as those with a specific sex, age, and / or disease or condition), but not yet reaching the blood and / or serum uric acid levels typically diagnosed as the blood and / or serum uric acid levels required for hyperuricemia. In the context of the present disclosure, for some given population, appropriate blood and / or serum uric acid levels can be less than or equal to 240 μmol / L, 260 μmol / L, 280 μmol / L, 300 μmol / L, 320 μmol / L, 340 μmol / L, 360 μmol / L, 380 μmol / L, or 400 μmol / L.

[0060] As used herein, the term "gout" refers to a recurrent inflammatory disease caused by increased purine biosynthesis metabolism, excessive uric acid production, or poor uric acid excretion, resulting in elevated uric acid in the blood, and deposition of urate crystals in the synovium, bursa, cartilage, and other tissues. In the context of the present disclosure, gout includes, but is not limited to, acute gout, chronic gout, and refractory gout. The term "acute gout" refers to gout present in individuals with at least one acute attack of gout symptom (e.g., podoconiosis). The term "chronic gout" refers to gout that is present in individuals with recurrent or persistent acute attacks of gout, tophi formation, chronic inflammatory arthritis, or joint degeneration associated with gout, and includes the period after recovery from acute gout and the period between acute gout attacks (i.e., gout interictal period). The term "refractory gout" refers to gout that is unresponsive or poorly responded to one or more oral uric acid-lowering drugs (e.g., xanthine oxidase inhibitors), making it difficult for the individual's blood uric acid level to return to normal.

[0061] As used herein, the term "gout complication" refers to a disease or condition caused by a secondary reaction during the development of gout. For example, gout can cause complications such as gouty arthritis due to the deposition of urate (e.g., monosodium urate) crystals in the joints. In the context of this disclosure, the gout complication of interest can be at least one of gouty arthritis, gouty urinary stones, and gouty nephropathy.

[0062] As used throughout this article, the term "effective amount" refers to an amount sufficient to achieve or at least partially achieve the desired effect. In the context of the present disclosure, a "therapeutically effective amount" of a drug, pharmaceutical composition, or therapeutic agent (e.g., a manganese-containing compound of the present disclosure, including insoluble manganese-containing compounds such as manganese oxide) refers to any amount that promotes regression of a disease or condition (which can be demonstrated by a reduction in the severity of the symptoms of the disease or condition, an increase in the frequency and duration of asymptomatic periods of the disease or condition, or prevention of damage or disability caused by the disease or condition). A "prophylactically effective amount" of a drug, pharmaceutical composition, or therapeutic agent refers to any amount that, when administered to an individual at risk of disease or condition development or disease or condition recurrence, inhibits the development or recurrence of a disease or condition. The "effective amount" of a drug, pharmaceutical composition, or therapeutic agent can be evaluated using a variety of methods known to those skilled in the art, such as by evaluating human subjects during clinical trials, by predicting efficacy in humans using animal model systems, or by measuring the activity of the drug, pharmaceutical composition, or therapeutic agent in in vitro assays. In general, the exact amount of a drug, pharmaceutical composition, or therapeutic agent required to achieve an effective amount will vary with factors such as the species, age and general condition of the individual, the severity of the disease or condition, the nature of the substance being administered, and the mode of administration. In some embodiments, an effective amount is achieved by delivering a drug, pharmaceutical composition, or therapeutic agent described herein once daily, twice daily, three times daily, every other day, every three days, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, an effective amount is obtained by administering a manganese-containing compound of the present disclosure, including an insoluble manganese-containing compound such as manganese oxide, once, twice, or more daily at a dosage level sufficient to deliver about 0.001 mg to about 10 g, e.g., about 0.005 mg to about 5000 mg, about 0.01 mg to about 2500 mg, about 0.05 mg to about 1000 mg, about 0.1 mg to about 750 mg, about 0.2 mg to about 500 mg, about 0.5 mg to about 250 mg, about 0.5 mg to about 100 mg, about 0.5 mg to about 75 mg, or about 1 mg to about 50 mg per kilogram of body weight of the individual per day. In some embodiments, an effective amount is achieved by administering a manganese-containing compound of the present disclosure, including insoluble manganese-containing compounds such as manganese oxide, once, twice, or more daily at a dosage level sufficient to deliver about 3 mg to about 3000 mg of manganese oxide per day (e.g., about 100 mg to about 3000 mg of manganese oxide per day, about 200 mg to about 3000 mg of manganese oxide per day, or about 500 mg to about 3000 mg of manganese oxide per day).In some embodiments, it is also possible to obtain an effective amount by administering a manganese-containing compound of the present disclosure, including an insoluble manganese-containing compound such as manganese oxide, once, twice, or more daily at a higher dosage level, i.e., from about 3 g to about 50 g of manganese oxide per day (e.g., from about 3 g to about 5 g, 10 g, 15 g, 20 g, 25 g, 30 g, 35 g, 40 g, 45 g of manganese oxide per day), provided that administration of such high dosage levels does not cause unacceptable side effects to the individual. Determination of an effective amount of a drug, pharmaceutical composition, or therapeutic agent appropriate for a particular disease or condition is within the skill of one skilled in the art.

[0063] As used throughout this article, the term "administer" refers to the process of introducing a drug, pharmaceutical composition or therapeutic agent of the present disclosure into an individual's body by any route of introduction or delivery. Any method known to those skilled in the art for contacting a cell, tissue or organ with the drug, pharmaceutical composition or therapeutic agent can be used. The route of administration may include, but is not limited to, parenteral administration, topical administration or oral administration. In the context of the present disclosure, the term "parenteral administration" refers to a mode of administration other than through the gastrointestinal tract and topical administration, typically administered by injection. The means of parenteral administration include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardial, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In the context of the present disclosure, topical administration routes may include, but are not limited to, epidermal or mucosal administration routes, such as intranasal, vaginal, rectal or sublingual administration. A daily dose of a drug, pharmaceutical composition or therapeutic agent may be divided into one, two or more doses in an appropriately formatted manner for administration at one, two or more time points during a certain period of time.

[0064] As used throughout this document, the term "prevention" refers to preventing the onset of a disease or condition in an individual at risk of the disease or the recurrence of a disease or condition that has disappeared, and "treatment" refers to controlling, alleviating or relieving the pathological progression of a disease or condition and prolonging the survival of an individual with the disease. Therefore, in the context of the present disclosure, the terms "prevention and / or treatment" encompass preventing the onset or further increase in severity of a disease or condition or one or more symptoms associated therewith; reducing and / or alleviating the severity and / or duration of a disease or condition or one or more symptoms associated therewith; slowing or reversing the progression of a disease or condition or one or more symptoms associated therewith; preventing, reducing or reversing any physiological damage caused by a disease or condition or one or more symptoms associated therewith; any pharmacological effect that is generally beneficial to the individual being treated, etc.

[0065] As used throughout this document, the term "subject" refers to a human or non-human mammal in need of diagnosis, amelioration, prevention and / or treatment of a disease or condition, such as humans (including neonates, infants, adolescents and adult subjects), non-human primates (e.g., apes (e.g., gibbons), orangutans (e.g., gorillas, chimpanzees), macaques, cynomolgus monkeys, rhesus monkeys), companion animals (e.g., dogs and cats), farm animals (e.g., poultry, such as chickens and ducks, horses, cows, goats, sheep, pigs), and experimental animals (e.g., mice, rats, rabbits, guinea pigs).

[0066] As used throughout this document, the term "pharmaceutically acceptable" refers to those substances that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammalian subjects without excessive toxicity, irritation, allergic response, or other problems, and are commensurate with a reasonable benefit / risk ratio.

[0067] As used throughout this document, the term "pharmaceutically acceptable excipient" refers to an excipient (or carrier) that does not cause excessive irritation to the tissues or organs of a mammalian subject and does not abrogate the pharmacological activity and properties of the administered drug, pharmaceutical composition, or therapeutic agent. In the context of this disclosure, the term "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, stabilizers, fillers, binders, disintegrants, lubricants, glidants, sweeteners, flavorings, dyes, and the like, as well as one or more combinations thereof. As non-limiting examples, pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum oxide; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulosic substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; polyethylene glycol; and lanolin. Examples of suitable pharmaceutically acceptable excipients can be found, for example, in Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pages 1289-1329, which are hereby incorporated by reference herein. Unless incompatible with the active ingredient, any conventional excipient will be considered for use in the present disclosure.

[0068] As used herein, the term "drug" refers to a substance that can produce a beneficial biological effect on humans or other mammals. In the context of this disclosure, "drug" may refer only to active pharmaceutical ingredients (drug substances), but also encompasses pharmaceutical compositions (including formulations thereof).

[0069] As used throughout this document, the term "pharmaceutical composition" refers to a substance or material composed of an active pharmaceutical ingredient (e.g., a manganese-containing compound, optionally in combination with an additional therapeutic agent) and a pharmaceutically acceptable excipient mixed in a certain proportion and having a specific medical use (e.g., for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian individual or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract).

[0070] As used herein, the terms "preparation" and "pharmaceutical preparation" or "dosage form" are used interchangeably and refer to a pharmaceutical composition that is formulated in accordance with certain dosage form requirements to meet the needs of treatment or prevention and is in a form that can be directly administered to an individual. As non-limiting examples, the preparation can be a preparation for parenteral administration, topical administration, or oral administration. As oral preparations, solid oral preparations or liquid oral preparations can be mentioned, wherein the solid oral preparation can be any of powders, granules, tablets, capsules, pills, and lozenges.

[0071] As used throughout this document, the terms "crystalline form" and "crystal" are used interchangeably to refer to a solid with a regular geometric shape formed by the periodic arrangement of atoms, ions, or molecules that make up a substance during the crystallization process. Depending on the different periodic arrangements of atoms, ions, or molecules, a substance may exist in two or more different crystalline forms, a phenomenon known as polymorphism.

[0072] As used throughout this document, the term "amorphous" or "amorphous" refers to a solid in which the atoms, ions or molecules that constitute the substance are not arranged periodically in a certain spatial order (i.e., they are distributed in a disordered state), as opposed to a crystal.

[0073] As used throughout this document, the term "polymorph" refers to various different forms of a solid material that exists in more than one form. In the context of this disclosure, the term "polymorph" encompasses both "crystalline forms" and "amorphous forms."

[0074] As used herein, the term "solvate" refers to a complex formed by the combination of a solute molecule and one or more pharmaceutically acceptable solvent molecules. When the solvent is water, the "solvate" is specifically a "hydrate."

[0075] As used throughout this document, the term "simulated intestinal fluid (SIF)" refers to a solution that simulates the main inorganic salt components and pH value of intestinal fluid in the human small intestine. Simulated intestinal fluid can be commercially obtained or prepared by methods well known to those skilled in the art. For example, in some embodiments, simulated intestinal fluid is prepared as follows: 6.8 g of potassium dihydrogen phosphate is taken and dissolved in 500 mL of water; the pH value is adjusted to 6.8 with 0.1 mol / L sodium hydroxide solution; 10 g of pancreatic enzyme is taken and dissolved in an appropriate amount of water; the two liquids are mixed and the volume is made up to 1000 mL with water.

[0076] As used throughout this document, the term "Fasted State Simulated Intestinal Fluid (FaSSIF)" refers to a solution that simulates the intestinal fluid in the small intestine of humans in a hungry state before a meal. The components and corresponding concentrations of the simulated fasting intestinal fluid are: taurocholate 3mM, phospholipids 0.75mM, sodium 148mM, chloride 106mM, and phosphate 29mM. The simulated fasting intestinal fluid can be purchased commercially or prepared by methods well known to those skilled in the art. For example, in some embodiments, the simulated fasting intestinal fluid is prepared as follows: (1) Prepare a buffer solution: Mix 37.48g of FaSSIF buffer concentrate and 865.0g of purified water; (2) Add FaSSIF powder to the buffer solution: Add 2.016g of FaSSIF powder to the buffer solution; (3) Stir the resulting mixture until all solids are dissolved; (4) Allow (equilibrate) the resulting solution for at least 2 hours. FaSSIF buffer concentrate and FaSSIF powder are commercially available, for example from Biorelevant.com Ltd.

[0077] As used throughout this document, the term "Fed State Simulated Intestinal Fluid (FeSSIF)" refers to a solution that simulates the intestinal fluid in the small intestine of humans in a full state after a meal. The components and corresponding concentrations of the simulated fed intestinal fluid are: 15mM taurocholate, 3.75mM phospholipids, 319mM sodium, 203mM chloride, and 144mM acetic acid. The simulated fed intestinal fluid can be commercially obtained or prepared by methods well known to those skilled in the art. For example, in some embodiments, the simulated fed intestinal fluid is prepared as follows: (1) Prepare a buffer solution by mixing 73.27g of FeSSIF buffer concentrate and 827.5g of purified water; (2) Add FeSSIF powder to the buffer solution by adding 10.08g of FeSSIF powder to the buffer solution; (3) Stir the resulting mixture until all solids are dissolved. FeSSIF buffer concentrate and FeSSIF powder are commercially available, for example, from Biorelevant.com Ltd.

[0078] Detailed description of the implementation plan

[0079] As far as the inventors know, there is currently no drug based on the mechanism of clearing uric acid in the digestive tract that has been approved for lowering uric acid levels in patients with hyperuricemia. Known adsorbents such as activated carbon do have a large specific surface area and have been shown to adsorb various substances, but this type of adsorption often does not have good selectivity. Therefore, in the complex physiological environment of the gastrointestinal tract, the adsorption of uric acid by activated carbon will face interference from a large number of other components of the intestine, and thus it will not be possible to achieve efficient adsorption of uric acid. Therefore, how to achieve efficient adsorption of uric acid in a complex gastrointestinal environment is an important challenge in the development of drugs based on the mechanism of clearing uric acid in the digestive tract.

[0080] The present disclosure describes the use of manganese-containing compounds in reducing uric acid levels in mammalian individuals, and particularly relates to the use of insoluble manganese-containing compounds in the preparation of medicaments for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of mammalian individuals or diseases or conditions associated with elevated uric acid levels in the blood and / or digestive tract, as well as pharmaceutical compositions, kits, and methods for preventing and / or treating related diseases or conditions for such use.

[0081] The manganese-containing compounds described in the present disclosure have special utility and / or benefits in preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian individual or diseases or conditions associated with elevated uric acid levels in the blood and / or digestive tract, adsorbing uric acid in the digestive tract of a mammal, and / or maintaining (normal or appropriate) uric acid levels in the blood of a mammalian individual. In some embodiments of the present disclosure, the manganese-containing compounds described in the present disclosure exhibit excellent adsorption and / or scavenging effects on uric acid (including salts thereof, such as monosodium urate) in the digestive tract of a mammalian individual. In some embodiments, the manganese-containing compounds described in the present disclosure have superior adsorption and / or scavenging effects on uric acid (including salts thereof, such as monosodium urate) in the digestive tract of a mammalian individual compared to materials known to have adsorption properties, such as zeolite molecular sieves, Prussian blue, activated carbon, montmorillonite, ion exchange resins (e.g., sevelamer hydrochloride), metal-organic framework materials, and the like. In some embodiments, the adsorption and / or scavenging effect of the manganese-containing compounds of the present disclosure on uric acid (including its salts, such as monosodium urate) in the digestive tract of a mammalian individual is not, substantially not, or is less affected by the various substances present in the digestive tract of the mammal (including but not limited to digestive juices such as gastric juice, small intestinal juice, and chyme). In some embodiments, the manganese-containing compounds of the present disclosure have the ability to continuously adsorb uric acid (including its salts, such as monosodium urate) at low uric acid (including its salts, such as monosodium urate) concentrations, and can still maintain the ability to effectively adsorb uric acid (including its salts, such as monosodium urate) after multiple adsorptions. In some embodiments, the manganese-containing compounds of the present disclosure can be administered at very high oral safety doses (e.g., about 50 grams / day or even higher) without causing unacceptable side effects, thereby having a desirable safety profile. In some embodiments, the manganese-containing compounds of the present disclosure have extremely low systemic absorption and in vivo accumulation effects after administration to a mammal, and do not significantly affect the blood biochemical indicators of the mammalian individual.

[0082] In some embodiments, the manganese-containing compound is an insoluble manganese-containing compound. The insoluble manganese-containing compound described in the present disclosure is characterized in that it is insoluble in water and / or digestive tract fluids (including but not limited to gastric juice, small intestinal fluid, large intestinal fluid, pancreatic juice and / or bile) under physiological conditions or has extremely low solubility therein, and / or has physiological inertness (i.e., it is substantially unable to enter the blood circulation through absorption in the gastrointestinal tract (i.e., digestive tract) and / or does not substantially react chemically with surrounding substances or tissues in the body after administration).

[0083] Thus, in a first aspect, the present disclosure provides the use of an insoluble manganese-containing compound in the preparation of a medicament for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian subject, or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract.

[0084] In some embodiments, the insoluble manganese-containing compound refers to a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved in 1 mL of water at saturation as measured at about 37° C. and about 1 atmosphere.

[0085] In some embodiments, the insoluble manganese-containing compound refers to a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved in 1 mL of simulated intestinal fluid (SIF) at saturation as measured at about 37° C. and about 1 atmosphere of pressure.

[0086] In some embodiments, the insoluble manganese-containing compound refers to a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved at saturation in 1 mL of simulated fasting small intestinal fluid (FaSSIF) measured at about 37° C. and about 1 atmosphere of pressure.

[0087] In some embodiments, the insoluble manganese-containing compound refers to a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved at saturation in 1 mL of simulated fed small intestinal fluid (FeSSIF) measured at about 37°C and about 1 atmosphere of pressure.

[0088] In some embodiments, the insoluble manganese-containing compound is a manganese-containing compound that is absorbed into the blood circulation via the gastrointestinal tract in an amount less than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose.

[0089] In some embodiments, the insoluble manganese-containing compound is a manganese-containing compound that does not chemically interact with surrounding substances or tissues in the body after administration or only has less than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose chemically interacting with surrounding substances or tissues in the body.

[0090] In some embodiments, the particle size of the insoluble manganese-containing compound is ≥ 1 μm, for example, from 1 μm to 1 mm.

[0091] In some embodiments, the insoluble manganese-containing compound is selected from one or more of manganese oxide, manganese sulfide, manganese carbonate, manganese silicate, manganese borate, manganese ferrocyanide, manganese oxalate, manganese selenite, manganese iodate, manganese tungstate and manganese phosphate, and solvates thereof (e.g., hydrates).

[0092] In some embodiments, the insoluble manganese-containing compound is a manganese oxide or a solvate thereof (e.g., a hydrate). In some embodiments, the manganese oxide is selected from one or more of the following: (1) a manganese oxide consisting solely of manganese atoms and oxygen atoms; (2) a manganese oxide consisting solely of manganese atoms, hydrogen atoms, and oxygen atoms; and (3) a manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms, and optional hydrogen atoms. In some embodiments, the manganese oxide is a manganese oxide consisting solely of manganese atoms and oxygen atoms. In some embodiments, the manganese oxide is a manganese oxide consisting solely of manganese atoms, hydrogen atoms, and oxygen atoms. In some embodiments, the manganese oxide is a manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms, and optional hydrogen atoms.

[0093] In some embodiments, the manganese oxide is a manganese oxide in the form of a natural mineral. In some embodiments, the manganese oxide in the form of a natural mineral is selected from one or more of hollandite, cryptomelane, pyrolusite, nsutit, birnessite, buserite, vernadite, ramsdellite, romanechite, todorokite, manganite, groutite, feitknechtite, hydrohausmannite, lithiophorite, chalcophanite, hausmannite, bixbyite, pyrochroite, and manganosite. In some embodiments, the manganese oxide in the form of a natural mineral is hollandite. In some embodiments, the manganese oxide in the form of a natural mineral is cryptomelane. In some embodiments, the manganese oxide in the form of a natural mineral is pyrolusite. In some embodiments, the manganese oxide in the form of a natural mineral is nsutit. In some embodiments, the manganese oxide in the form of a natural mineral is birnessite. In some embodiments, the manganese oxide in the form of a natural mineral is buserite. In some embodiments, the manganese oxide in the form of a natural mineral is vernadite. In some embodiments, the manganese oxide in the form of a natural mineral is ramsdellite. In some embodiments, the manganese oxide in the form of a natural mineral is romanechite. In some embodiments, the manganese oxide in the form of a natural mineral is todorokite. In some embodiments, the manganese oxide in the form of a natural mineral is manganite. In some embodiments, the manganese oxide in the form of a natural mineral is groutite. In some embodiments, the manganese oxide in the form of a natural mineral is feitknechtite. In some embodiments, the manganese oxide in the form of a natural mineral is hydrohausmannite.In some embodiments, the manganese oxide in the form of a natural mineral is lithiophorite. In some embodiments, the manganese oxide in the form of a natural mineral is chalcophanite. In some embodiments, the manganese oxide in the form of a natural mineral is hausmannite. In some embodiments, the manganese oxide in the form of a natural mineral is bixbyite. In some embodiments, the manganese oxide in the form of a natural mineral is pyrochroite. In some embodiments, the manganese oxide in the form of a natural mineral is manganosite.

[0094] In some embodiments, the manganese oxide is a manganese oxide consisting only of manganese atoms and oxygen atoms. In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is selected from manganese monoxide (MnO), manganese dioxide (MnO2), manganese trioxide (MnO3), manganese dioxide (Mn2O3), manganese pentaoxide (Mn5O8), manganese tetraoxide (Mn3O4), manganese heptoxide (Mn2O7), manganese dodecaoxide (Mn7O8), and manganese octaoxide (Mn7O8). 12 ) and Mn7O 13 ). In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is manganese monoxide (MnO). In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is manganese dioxide (MnO2). In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is manganese trioxide (MnO3). In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is manganese trioxide (Mn2O3). In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is manganese pentaoxide (Mn5O8). In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is manganese tetraoxide (Mn3O4). In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is manganese heptoxide (Mn2O7). In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is manganese dodecaoxide (Mn7O 12 In some embodiments, the manganese oxide consisting only of manganese atoms and oxygen atoms is heptadodecanomanganese (Mn7O 13 ).

[0095] In some embodiments, the manganese oxide is a manganese oxide consisting only of manganese atoms, hydrogen atoms, and oxygen atoms. In some embodiments, the manganese oxide consisting only of manganese atoms, hydrogen atoms, and oxygen atoms is selected from one or both of manganese oxide hydroxide (MnOOH) and manganese hydroxide (Mn(OH)2). In some embodiments, the manganese oxide consisting only of manganese atoms, hydrogen atoms, and oxygen atoms is manganese oxide hydroxide. In some embodiments, the manganese oxide hydroxide is a manganese oxide hydroxide in the form of a polymorph. In some embodiments, the manganese oxide hydroxide in the form of a polymorph is selected from one or more of α-type crystalline manganese oxide hydroxide, β-type crystalline manganese oxide hydroxide, and γ-type crystalline manganese oxide hydroxide. In some embodiments, the manganese oxide hydroxide in the form of a polymorph is α-type crystalline manganese oxide hydroxide. In some embodiments, the α-type crystalline manganese oxide hydroxide is an α-type crystalline manganese oxide hydroxide in the form of groutite. In some embodiments, the manganese oxide hydroxide in the form of a polymorph is β-type crystalline manganese oxide hydroxide. In some embodiments, the beta-type crystalline manganese oxyhydroxide is a beta-type crystalline manganese oxyhydroxide in the form of one or both of feitknechtite and hydrohausmannite. In some embodiments, the manganese oxyhydroxide in the form of a polymorph is a gamma-type crystalline manganese oxyhydroxide. In some embodiments, the gamma-type crystalline manganese oxyhydroxide is a gamma-type crystalline manganese oxyhydroxide in the form of manganite. In some embodiments, the manganese oxide consisting only of manganese atoms, hydrogen atoms, and oxygen atoms is manganese hydroxide. In some embodiments, the manganese hydroxide is a manganese hydroxide in the form of a polymorph.

[0096] In some embodiments, the manganese oxide is a manganese oxide composed of manganese atoms, oxygen atoms, metal atoms, and optional hydrogen atoms. In some embodiments, the manganese oxide composed of manganese atoms, oxygen atoms, metal atoms, and optional hydrogen atoms is a salt-type manganese oxide. In some embodiments, the salt-type manganese oxide is selected from one or more of potassium-type manganese oxide, hydrogen-type manganese oxide, ammonium-type manganese oxide, sodium-type manganese oxide, calcium-type manganese oxide, magnesium-type manganese oxide, iron-type manganese oxide, ferrous-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide. In some embodiments, the salt-type manganese oxide is potassium-type manganese oxide. In some embodiments, the salt-type manganese oxide is hydrogen-type manganese oxide. In some embodiments, the salt-type manganese oxide is ammonium-type manganese oxide. In some embodiments, the salt-type manganese oxide is sodium-type manganese oxide. In some embodiments, the salt-type manganese oxide is calcium-type manganese oxide. In some embodiments, the salt-type manganese oxide is magnesium-type manganese oxide. In some embodiments, the salt-type manganese oxide is iron-type manganese oxide. In some embodiments, the salt-type manganese oxide is ferrous manganese oxide. In some embodiments, the salt-type manganese oxide is zinc manganese oxide. In some embodiments, the salt-type manganese oxide is lanthanum manganese oxide. In some embodiments, the salt-type manganese oxide is bismuth manganese oxide. In some embodiments, the salt-type manganese oxide is lithium manganese oxide. In some embodiments, the salt-type manganese oxide is silver manganese oxide.

[0097] In some embodiments, the manganese oxide is manganese oxide in the form of a polymorph, for example, manganese oxide in the form of a salt polymorph.

[0098] In some embodiments, the manganese oxide in the form of a polymorph is selected from one or more of α-type crystalline manganese oxide (e.g., salt-type α-type crystalline manganese oxide), β-type crystalline manganese oxide (e.g., salt-type β-type crystalline manganese oxide), γ-type crystalline manganese oxide (e.g., salt-type γ-type crystalline manganese oxide), δ-type crystalline manganese oxide (e.g., salt-type δ-type crystalline manganese oxide), λ-type crystalline manganese oxide (e.g., salt-type λ-type crystalline manganese oxide), ε-type crystalline manganese oxide (e.g., salt-type ε-type crystalline manganese oxide), R-type crystalline manganese oxide (e.g., salt-type R-type crystalline manganese oxide), amorphous manganese oxide (e.g., salt-type amorphous manganese oxide), α-type crystalline manganese oxyhydroxide (e.g., salt-type α-type crystalline manganese oxyhydroxide), β-type crystalline manganese oxyhydroxide (e.g., salt-type β-type crystalline manganese oxyhydroxide), and γ-type crystalline manganese oxyhydroxide (e.g., salt-type γ-type crystalline manganese oxyhydroxide).

[0099] In some embodiments, the manganese oxide in the form of a polymorph is an α-type crystalline manganese oxide. In some embodiments, the α-type crystalline manganese oxide is an α-type crystalline manganese oxide in the form of hollandite or cryptomelane.

[0100] In some embodiments, the manganese oxide in the form of a polymorph is a beta-type crystalline manganese oxide. In some embodiments, the beta-type crystalline manganese oxide is a beta-type crystalline manganese oxide in the form of pyrolusite.

[0101] In some embodiments, the manganese oxide in the form of a polymorph is a gamma-type crystalline manganese oxide. In some embodiments, the gamma-type crystalline manganese oxide is a gamma-type crystalline manganese oxide in the form of nsutit.

[0102] In some embodiments, the manganese oxide in the form of a polymorph is a delta crystalline manganese oxide. In some embodiments, the delta crystalline manganese oxide is a delta crystalline manganese oxide in the form of one or more of birnessite, buserite, and vernadite.

[0103] In some embodiments, the manganese oxide in the form of a polymorph is lambda crystalline manganese oxide.

[0104] In some embodiments, the manganese oxide in the form of a polymorph is epsilon-form manganese oxide.

[0105] In some embodiments, the manganese oxide in the form of a polymorph is an R-type crystalline manganese oxide. In some embodiments, the R-type crystalline manganese oxide is an R-type crystalline manganese oxide in the form of ramsdellite.

[0106] In some embodiments, the manganese oxide in the form of a polymorph is amorphous manganese oxide.

[0107] In some embodiments, the manganese oxide in the form of a polymorph is alpha-type crystalline manganese oxyhydroxide. In some embodiments, the alpha-type crystalline manganese oxyhydroxide is alpha-type crystalline manganese oxyhydroxide in the form of groutite.

[0108] In some embodiments, the manganese oxide in the form of a polymorph is a β-type crystalline manganese oxyhydroxide. In some embodiments, the β-type crystalline manganese oxyhydroxide is a β-type crystalline manganese oxyhydroxide in the form of one or both of feitknechtite and hydrohausmannite.

[0109] In some embodiments, the manganese oxide in the form of a polymorph is gamma crystalline manganese oxyhydroxide. In some embodiments, the gamma crystalline manganese oxyhydroxide is gamma crystalline manganese oxyhydroxide in the form of manganite.

[0110] In some embodiments, the manganese oxide is a manganese oxide in the form of a salt polymorph.

[0111] In some embodiments, the manganese oxide in the form of a salt polymorph is selected from one or more of a salt α-type crystalline manganese oxide, a salt β-type crystalline manganese oxide, a salt γ-type crystalline manganese oxide, a salt δ-type crystalline manganese oxide, a salt λ-type crystalline manganese oxide, a salt ε-type crystalline manganese oxide, a salt R-type crystalline manganese oxide, and a salt amorphous manganese oxide.

[0112] In some embodiments, the manganese oxide in the form of a salt polymorph is a salt α-type crystalline manganese oxide. In some embodiments, the salt α-type crystalline manganese oxide is selected from one or both of potassium α-type crystalline manganese oxide and hydrogen α-type crystalline manganese oxide. In some embodiments, the salt α-type crystalline manganese oxide is potassium α-type crystalline manganese oxide. In some embodiments, the potassium α-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.8±0.2°, 18.1±0.2°, 25.5±0.2°, 28.7±0.2°, 39.0±0.2°, 42.0±0.2°, 49.9±0.2°, 56.4±0.2°, 60.2±0.2°, 65.1±0.2°, 70.0±0.2° and 72.5±0.2°. In some embodiments, the potassium-type α-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.7±0.2°, 18.0±0.2°, 25.4±0.2°, 28.7±0.2°, 39.1±0.2°, 42.0±0.2°, 50.0±0.2°, 56.5±0.2°, 60.1±0.2°, 65.2±0.2°, 70.1±0.2° and 72.5±0.2°. In some embodiments, the potassium-type α-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.7±0.2°, 18.0±0.2°, 25.4±0.2°, 28.7±0.2°, 39.2±0.2°, 42.0±0.2°, 50.0±0.2°, 56.4±0.2°, 60.1±0.2°, 65.2±0.2°, 70.1±0.2°, and 72.5±0.2°. In some embodiments, the salt-type α-type crystalline manganese oxide is hydrogen-type α-type crystalline manganese oxide. In some embodiments, the hydrogen α-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.8±0.2°, 18.1±0.2°, 25.7±0.2°, 28.8±0.2°, 36.7±0.2°, 39.0±0.2°, 41.9±0.2°, 49.8±0.2°, 56.4±0.2°, 60.1±0.2°, 65.2±0.2°, 70.1±0.2° and 72.7±0.2°.In some embodiments, the hydrogen α-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.7±0.2°, 18.0±0.2°, 25.5±0.2°, 28.7±0.2°, 39.1±0.2°, 42.0±0.2°, 50.0±0.2°, 56.5±0.2°, 60.1±0.2°, 65.2±0.2°, 70.1±0.2° and 72.5±0.2°. In some embodiments, the hydrogen α-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.7±0.2°, 18.1±0.2°, 25.4±0.2°, 28.8±0.2°, 39.1±0.2°, 42.0±0.2°, 50.0±0.2°, 56.5±0.2°, 60.0±0.2°, 65.2±0.2°, 70.1±0.2° and 72.5±0.2°.

[0113] In some embodiments, the manganese oxide in the form of a salt polymorph is a salt β-type crystalline manganese oxide. In some embodiments, the salt β-type crystalline manganese oxide is selected from one or both of potassium β-type crystalline manganese oxide and hydrogen β-type crystalline manganese oxide. In some embodiments, the salt β-type crystalline manganese oxide is potassium β-type crystalline manganese oxide. In some embodiments, the potassium β-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 28.7±0.2°, 37.4±0.2°, 41.1±0.2°, 42.9±0.2°, 46.2±0.2°, 56.8±0.2°, 59.5±0.2°, 65.0±0.2°, 67.5±0.2° and 72.6±0.2°. In some embodiments, the salt-type β-type crystalline manganese oxide is hydrogen-type β-type crystalline manganese oxide. In some embodiments, the hydrogen-type β-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 28.7±0.2°, 37.4±0.2°, 41.1±0.2°, 42.9±0.2°, 46.2±0.2°, 56.8±0.2°, 59.5±0.2°, 65.0±0.2°, 67.5±0.2°, and 72.6±0.2°. In some embodiments, the hydrogen form β-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 28.7±0.2°, 37.4±0.2°, 41.1±0.2°, 42.9±0.2°, 46.2±0.2°, 56.8±0.2°, 59.5±0.2°, 65.0±0.2°, 67.5±0.2° and 72.6±0.2°.

[0114] In some embodiments, the manganese oxide in the form of a salt polymorph is a salt γ-type crystalline manganese oxide. In some embodiments, the salt γ-type crystalline manganese oxide is selected from one or both of ammonium γ-type crystalline manganese oxide and hydrogen γ-type crystalline manganese oxide. In some embodiments, the salt γ-type crystalline manganese oxide is ammonium γ-type crystalline manganese oxide. In some embodiments, the ammonium γ-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 23.0±0.2°, 26.7±0.2°, 34.0±0.2°, 37.1±0.2°, 42.5±0.2°, 50.0±0.2°, 56.3±0.2°, 65.5±0.2° and 69.4±0.2°. In some embodiments, the salt γ-type crystalline manganese oxide is hydrogen γ-type crystalline manganese oxide. In some embodiments, the hydrogenated gamma-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 23.0±0.2°, 26.7±0.2°, 34.0±0.2°, 37.3±0.2°, 42.5±0.2°, 56.3±0.2°, and 65.5±0.2°. In some embodiments, the hydrogenated gamma-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 23.0±0.2°, 26.7±0.2°, 34.0±0.2°, 37.1±0.2°, 42.5±0.2°, 50.0±0.2°, 56.4±0.2°, 65.5±0.2°, and 69.6±0.2°.

[0115] In some embodiments, the manganese oxide in the form of a salt polymorph is a salt δ-type crystalline manganese oxide. In some embodiments, the salt δ-type crystalline manganese oxide is selected from one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) of potassium δ-type crystalline manganese oxide, hydrogen δ-type crystalline manganese oxide, sodium δ-type crystalline manganese oxide, ammonium δ-type crystalline manganese oxide, calcium δ-type crystalline manganese oxide, magnesium δ-type crystalline manganese oxide, iron δ-type crystalline manganese oxide, ferrous δ-type crystalline manganese oxide, zinc δ-type crystalline manganese oxide, lanthanum δ-type crystalline manganese oxide, bismuth δ-type crystalline manganese oxide, lithium δ-type crystalline manganese oxide, and silver δ-type crystalline manganese oxide. In some embodiments, the salt δ-type crystalline manganese oxide is potassium δ-type crystalline manganese oxide. In some embodiments, the potassium-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.2±0.2°, 24.9±0.2°, 37.0±0.2°, 56.4±0.2°, and 65.8±0.2°. In some embodiments, the potassium-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.4±0.2°, 25.0±0.2°, 36.9±0.2°, 56.0±0.2°, and 66.1±0.2°. In some embodiments, the potassium-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.7±0.2°, 37.2±0.2°, 56.9±0.2°, and 66.4±0.2°. In some embodiments, the potassium-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.5±0.2°, 24.5±0.2°, 37.1±0.2°, and 66.0±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is hydrogen-type delta-type crystalline manganese oxide. In some embodiments, the hydrogen form delta crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.5±0.2°, 25.1±0.2°, 36.8±0.2°, 56.9±0.2°, and 66.0±0.2°. In some embodiments, the hydrogen form delta crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.6±0.2°, 24.8±0.2°, 36.5±0.2°, 55.7±0.2°, and 66.3±0.2°.In some embodiments, the hydrogen-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.6±0.2°, 37.5±0.2°, 57.0±0.2°, and 66.2±0.2°. In some embodiments, the hydrogen-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.8±0.2°, 37.3±0.2°, 56.7±0.2°, and 66.8±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is sodium-type delta-type crystalline manganese oxide. In some embodiments, the sodium-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.7±0.2°, 37.1±0.2°, 57.2±0.2°, and 66.3±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is ammonium-type delta-type crystalline manganese oxide. In some embodiments, the ammonium-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.6±0.2°, 24.9±0.2°, 36.9±0.2°, 56.9±0.2°, and 66.1±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is calcium-type delta-type crystalline manganese oxide. In some embodiments, the calcium-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 8.9±0.2°, 12.6±0.2°, 18.5±0.2°, and 37.0±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is a magnesium-type delta-type crystalline manganese oxide. In some embodiments, the magnesium-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 9.0±0.2°, 18.5±0.2°, and 28.1±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is an iron-type delta-type crystalline manganese oxide. In some embodiments, the iron-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.3±0.2°, 25.0±0.2°, 36.8±0.2°, 56.7±0.2°, and 66.2±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is ferrous-type delta-type crystalline manganese oxide.In some embodiments, the ferrous δ-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.6±0.2°, 24.9±0.2°, 36.8±0.2°, 56.5±0.2°, and 66.7±0.2°. In some embodiments, the salt-type δ-type crystalline manganese oxide is zinc-type δ-type crystalline manganese oxide. In some embodiments, the zinc-type δ-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.5±0.2°, 25.2±0.2°, 36.9±0.2°, 56.7±0.2°, and 66.9±0.2°. In some embodiments, the salt-type δ-type crystalline manganese oxide is lanthanum-type δ-type crystalline manganese oxide. In some embodiments, the lanthanum-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 9.2±0.2°, 12.5±0.2°, 18.3±0.2°, 25.0±0.2°, and 37.0±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is a bismuth-type delta-type crystalline manganese oxide. In some embodiments, the bismuth-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 12.6±0.2°, 25.2±0.2°, 37.1±0.2°, 56.7±0.2°, and 67.0±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is a lithium-type delta-type crystalline manganese oxide. In some embodiments, the lithium-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.6±0.2°, 25.0±0.2°, 36.9±0.2°, 56.5±0.2°, and 66.8±0.2°. In some embodiments, the salt-type delta-type crystalline manganese oxide is a silver-type delta-type crystalline manganese oxide. In some embodiments, the silver-type delta-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern exhibits characteristic X-ray diffraction peaks at the following 2θ angles: 12.5±0.2°, 24.9±0.2°, 36.8±0.2°, 56.7±0.2°, and 66.9±0.2°.

[0116] In some embodiments, the manganese oxide in the form of a salt polymorph is a salt λ-type crystalline manganese oxide. In some embodiments, the salt λ-type crystalline manganese oxide is selected from one or both of lithium λ-type crystalline manganese oxide and hydrogen λ-type crystalline manganese oxide. In some embodiments, the salt λ-type crystalline manganese oxide is lithium λ-type crystalline manganese oxide. In some embodiments, the salt λ-type crystalline manganese oxide is hydrogen λ-type crystalline manganese oxide. In some embodiments, the hydrogen λ-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 19.0±0.2°, 37.1±0.2°, 45.1±0.2°, 49.5±0.2°, 59.7±0.2°, 65.6±0.2°, and 69.1±0.2°.

[0117] In some embodiments, the manganese oxide in the form of a salt polymorph is a salt epsilon crystalline manganese oxide. In some embodiments, the salt epsilon crystalline manganese oxide is selected from one or both of potassium epsilon crystalline manganese oxide and hydrogen epsilon crystalline manganese oxide. In some embodiments, the salt epsilon crystalline manganese oxide is potassium epsilon crystalline manganese oxide. In some embodiments, the potassium epsilon crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 21.0 ± 0.2°, 37.1 ± 0.2°, 42.5 ± 0.2°, 56.0 ± 0.2°, and 66.8 ± 0.2°. In some embodiments, the salt epsilon crystalline manganese oxide is hydrogen epsilon crystalline manganese oxide. In some embodiments, the hydrogen-form epsilon-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 21.0±0.2°, 37.1±0.2°, 42.5±0.2°, 56.0±0.2° and 66.8±0.2°.

[0118] In some embodiments, the manganese oxide in the form of a salt polymorph is a salt R-type crystalline manganese oxide. In some embodiments, the salt R-type crystalline manganese oxide is a hydrogen R-type crystalline manganese oxide. In some embodiments, the hydrogen R-type crystalline manganese oxide is characterized in that its powder X-ray diffraction pattern shows characteristic X-ray diffraction peaks at the following 2θ angles: 22.0±0.2°, 35.0±0.2°, 36.9±0.2°, 38.5±0.2°, 41.2±0.2°, 46.8±0.2°, and 54.0±0.2°.

[0119] In some embodiments, the manganese oxide in the form of a salt polymorph is a salt amorphous manganese oxide. In some embodiments, the salt amorphous manganese oxide is selected from one or both of potassium amorphous manganese oxide and hydrogen amorphous manganese oxide. In some embodiments, the salt amorphous manganese oxide is potassium amorphous manganese oxide. In some embodiments, the potassium amorphous manganese oxide is characterized in that its powder X-ray diffraction pattern does not show obvious characteristic X-ray diffraction peaks. In some embodiments, the salt amorphous manganese oxide is hydrogen amorphous manganese oxide. In some embodiments, the hydrogen amorphous manganese oxide is characterized in that its powder X-ray diffraction pattern does not show obvious characteristic X-ray diffraction peaks.

[0120] Insoluble manganese-containing compounds (e.g., manganese oxide) described in the present disclosure show high uric acid clearance capacity in simulated intestinal fluid (SIF) determination. The simulated intestinal fluid (SIF) determination can be measured using methods well known to those skilled in the art. For example, in some embodiments, the simulated intestinal fluid (SIF) determination is to measure in the SIF at a concentration of about 8.4 ± 0.2 mg / dL, such as 8.2 mg / dL, 8.3 mg / dL, 8.4 mg / dL, 8.5 mg / dL or 8.6 mg / dL. In some embodiments, the pH value of the SIF is about 6.8 ± 0.2, such as about 6.6, 6.7, 6.8, 6.9 or 7.0. In some embodiments, the phosphate content of the SIF is about 10 mM to 100 mM, such as about 10 mM to 100 mM, about 20 mM to 90 mM, about 30 mM to 80 mM, about 40 mM to 60 mM or about 50 mM. In some embodiments, the simulated intestinal fluid (SIF) assay is measured in SIF having a uric acid concentration of about 8.4 ± 0.2 mg / dL, a pH of about 6.8 ± 0.2, and containing about 10 mM to 100 mM phosphate. In some embodiments, the simulated intestinal fluid (SIF) assay is performed at a temperature between about 25°C and 37°C, such as about 25°C to 26°C, 25°C to 27°C, 25°C to 28°C, 25°C to 29°C, 25°C to 30°C, 25°C to 31°C, 25°C to 32°C, 25°C to 33°C, 25°C to 34°C, 25°C to 35°C, 25°C to 36°C, 26°C to 37°C, 27°C to 37°C, 28°C to 37°C, 29°C to 37°C, 30°C to 37°C, 31°C to 37°C, 32°C to 37°C, 33°C to 37°C, 34°C to 37°C, 35°C to 37°C, or 36°C to 37°C.In some embodiments, the simulated intestinal fluid (SIF) assay is performed when the concentration of insoluble manganese-containing compounds is about 0.1 g / L to 2 g / L, such as about 0.1 g / L to 0.2 g / L, 0.1 g / L to 0.3 g / L, 0.1 g / L to 0.4 g / L, 0.1 g / L to 0.5 g / L, 0.1 g / L to 0.6 g / L, 0.1 g / L to 0. 7g / L, 0.1g / L to 0.8g / L, 0.1g / L to 0.9g / L, 0.1g / L to 1.0g / L, 0.1g / L to 1.1g / L, 0.1g / L to 1.2g / L, 0.1g / L to 1.3g / L, 0.1g / L to 1.4g / L, 0.1g / L to 1.5g / L, 0.1g / L to 1.6g / L, 0. 1g / L to 1.7g / L, 0.1g / L to 1.8g / L, 0.1g / L to 1.9g / L, 0.2g / L to 2g / L, 0.3g / L to 2g / L, 0.4g / L to 2g / L, 0.5g / L to 2g / L, 0.6g / L to 2g / L, 0.7g / L to 2g / L, 0.8g / L to 2g / L, 0.9g / L to 2 In some embodiments, the simulated intestinal fluid (SIF) assay is performed under conditions of oscillation. The frequency of oscillation can be, for example, ≥50 rpm, ≥100 rpm, ≥150 rpm, ≥200 rpm, ≥250 rpm, ≥300 rpm or higher. In some embodiments, the simulated intestinal fluid (SIF) assay is performed using simulated intestinal fluid (SIF) having a uric acid concentration of about 8.4 ± 0.2 mg / dL, at a temperature between about 25 ° C and 37 ° C, and a manganese oxide concentration of about 0.1 g / L to 2 g / L, and under shaking conditions. In some embodiments, the duration of the simulated intestinal fluid (SIF) assay is ≥ 5 min, such as ≥ 10 min, ≥ 15 min, ≥ 20 min, ≥ 25 min, ≥ 30 min, ≥ 35 min, ≥ 40 min, ≥ 45 min, ≥ 50 min, ≥ 55 min, ≥ 60 min, ≥ 90 min, ≥ 120 min, ≥ 180 min, ≥ 240 min, ≥ 300 min, ≥ 360 min, ≥ 420 min, ≥ 480 min, ≥ 520 min, or ≥ 600 min.

[0121] In some embodiments, the insoluble manganese-containing compound (eg, manganese oxide) has a uric acid clearance capacity of about 50 mg / g to about 1000 mg / g as measured in a simulated intestinal fluid (SIF) assay.

[0122] In some embodiments, the insoluble manganese-containing compound (eg, manganese oxide) has a uric acid clearance capacity of about 100 mg / g to about 900 mg / g as measured in a simulated intestinal fluid (SIF) assay.

[0123] In some embodiments, the insoluble manganese-containing compound (eg, manganese oxide) has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated intestinal fluid (SIF) assay.

[0124] For example, in some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) has a uric acid clearance capacity as measured in a simulated intestinal fluid (SIF) assay of about 100 mg / g to about 1000 mg / g, about 150 mg / g to about 1000 mg / g, about 200 mg / g to about 1000 mg / g, about 250 mg / g to about 1000 mg / g, about 300 mg / g to about 1000 mg / g, about 350 mg / g to about 1000 mg / g, about 400 mg / g to about 1000 mg / g, about 450 mg / g to about 1000 mg / g, about 500 mg / g to about 1000 mg / g, about 550 mg / g to about 1000 mg / g, about 60 ... 0 mg / g to about 1000 mg / g, about 650 mg / g to about 1000 mg / g, about 700 mg / g to about 1000 mg / g, about 750 mg / g to about 1000 mg / g, about 800 mg / g to about 1000 mg / g, about 850 mg / g to about 1000 mg / g, about 900 mg / g to about 1000 mg / g, about 950 mg / g to about 1000 mg / g, about 100 mg / g to about 900 mg / g, about 150 mg / g to about 900 mg / g, about 200 mg / g to about 900 mg / g, about 250 mg / g to about 900 mg / g, about 300 mg / g to about 900 mg / g, about 350 mg / g to about 1000 mg / g about 900 mg / g, about 400 mg / g to about 900 mg / g, about 450 mg / g to about 900 mg / g, about 500 mg / g to about 900 mg / g, about 550 mg / g to about 900 mg / g, about 600 mg / g to about 900 mg / g, about 650 mg / g to about 900 mg / g, about 700 mg / g to about 900 mg / g, about 750 mg / g to about 900 mg / g, about 800 mg / g to about 900 mg / g, about 850 mg / g to about 900 mg / g, about 100 mg / g to about 800 mg / g, about 150 mg / g to about 800 mg / g, about 200 mg / g to about 800 mg / g, about 250 mg / g to about 800 mg / g, about 300 mg / g to about 800 mg / g, about 350 mg / g to about 800 mg / g, about 400 mg / g to about 800 mg / g, about 450 mg / g to about 800 mg / g, about 500 mg / g to about 800 mg / g, about 550 mg / g to about 800 mg / g, about 600 mg / g to about 800 mg / g, about 650 mg / g to about 800 mg / g, about 700 mg / g to about 800 mg / g, about 750 mg / g to about 800 mg / g, about 100 mg / g to about 700 mg / g, about 150 mg / g to about 700 mg / g, about 200 mg / g to about 700 mg / g,about 250 mg / g to about 700 mg / g, about 300 mg / g to about 700 mg / g, about 350 mg / g to about 700 mg / g, about 400 mg / g to about 700 mg / g, about 450 mg / g to about 700 mg / g, about 500 mg / g to about 700 mg / g, about 550 mg / g to about 700 mg / g, about 600 mg / g to about 700 mg / g, about 650 mg / g to about 700 mg / g, about 100 mg / g to about 600 mg / g, about 150 mg / g to about 600 mg / g / g, about 200 mg / g to about 600 mg / g, about 250 mg / g to about 600 mg / g, about 300 mg / g to about 600 mg / g, about 350 mg / g to about 600 mg / g, about 400 mg / g to about 600 mg / g, about 450 mg / g to about 600 mg / g, about 500 mg / g to about 600 mg / g, about 550 mg / g to about 600 mg / g, about 100 mg / g to about 500 mg / g, about 150 mg / g to about 500 mg / g, about 200 mg / g to about 500 mg / g, about 250 mg / g to about 500 mg / g, about 300 mg / g to about 500 mg / g, about 350 mg / g to about 500 mg / g, about 400 mg / g to about 500 mg / g, about 450 mg / g to about 500 mg / g, about 100 mg / g to about 400 mg / g, about 150 mg / g to about 400 mg / g, about 200 mg / g to about 4 00 mg / g, about 250 mg / g to about 400 mg / g, about 300 mg / g to about 400 mg / g, about 350 mg / g to about 400 mg / g, about 100 mg / g to about 300 mg / g, about 150 mg / g to about 300 mg / g, about 200 mg / g to about 300 mg / g, about 250 mg / g to about 300 mg / g, about 100 mg / g to about 200 mg / g, or about 150 mg / g to about 200 mg / g.

[0125] Insoluble manganese-containing compounds (e.g., manganese oxide) disclosed herein also show high uric acid clearance capacity in simulated fasting small intestinal fluid (FaSSIF) and / or simulated fed small intestinal fluid (FeSSIF) assays. The simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assays can be measured using methods known to those skilled in the art. In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assays are measured in FaSSIF or FeSSIF at a concentration of about 8.4 ± 0.2 mg / dL, for example, 8.2 mg / dL, 8.3 mg / dL, 8.4 mg / dL, 8.5 mg / dL, or 8.6 mg / dL. In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is performed at a temperature between about 25°C and 37°C, such as about 25°C to 26°C, 25°C to 27°C, 25°C to 28°C, 25°C to 29°C, 25°C to 30°C, 25°C to 31°C, 25°C to 32°C, 25°C to 33°C, 25°C to 34°C, 25°C to 35°C, 25°C to 36°C, 26°C to 37°C, 27°C to 37°C, 28°C to 37°C, 29°C to 37°C, 30°C to 37°C, 31°C to 37°C, 32°C to 37°C, 33°C to 37°C, 34°C to 37°C, 35°C to 37°C, or 36°C to 37°C.In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is performed when the concentration of insoluble manganese-containing compounds is about 0.1 g / L to 2 g / L, such as about 0.1 g / L to 0.2 g / L, 0.1 g / L to 0.3 g / L, 0.1 g / L to 0.4 g / L, 0.1 g / L to 0.5 g / L, 0.1 g / L to 0.6 g / L, 0.1 g / L to 0.7 g / L, 0.1 g / L to 0.8 g / L, 0.1 g / L to 0.9 g / L, 0.1 g / L to 0.10 g / L, 0.1 g / L to 0.11 g / L, 0.1 g / L to 0.12 g / L, 0.1 g / L to 0.6g / L, 0.1g / L to 0.7g / L, 0.1g / L to 0.8g / L, 0.1g / L to 0.9g / L, 0.1g / L to 1.0g / L, 0.1g / L to 1.1g / L, 0.1g / L to 1.2g / L, 0.1g / L to 1.3g / L, 0.1g / L to 1.4g / L, 0.1g / L to 1.5g / L, 0.1g / L to 1.6g / L, 0.1g / L to 1.7g / L, 0.1g / L to 1.8g / L, 0.1g / L to 1.9g / L, 0.2g / L to 2g / L, 0.3g / L to 2g / L, 0.4g / L to 2g / L, 0.5g / L to 2g / L, 0.6g / L to 2g / L, 0.7g / L to 2g / L, 0.8g / L to 2g / L, 0.9 In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is performed under oscillation conditions. The frequency of oscillation can be, for example, ≥50 rpm, ≥100 rpm, ≥150 rpm, ≥200 rpm, ≥250 rpm, ≥300 rpm or higher. In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is performed using simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) having a uric acid concentration of about 8.4±0.2 mg / dL, at a temperature between about 25°C and 37°C, a manganese oxide concentration of about 0.1 g / L to 2 g / L, and under shaking conditions.In some embodiments, the duration of the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is ≥5 min, e.g., ≥10 min, ≥15 min, ≥20 min, ≥25 min, ≥30 min, ≥35 min, ≥40 min, ≥45 min, ≥50 min, ≥55 min, ≥60 min, ≥90 min, ≥120 min, ≥180 min, ≥240 min, ≥300 min, ≥360 min, ≥420 min, ≥480 min, ≥520 min, or ≥600 min.

[0126] In some embodiments, the insoluble manganese-containing compound (eg, manganese oxide) has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fasting small intestinal fluid (FaSSIF) assay.

[0127] In some embodiments, the insoluble manganese-containing compound (eg, manganese oxide) has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fed small intestinal fluid (FeSSIF) assay.

[0128] For example, in some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) has a uric acid clearance capacity as measured in a simulated fasting small intestinal fluid (FaSSIF) assay of about 250 mg / g to about 800 mg / g, about 300 mg / g to about 800 mg / g, about 350 mg / g to about 800 mg / g, about 400 mg / g to about 800 mg / g, about 450 mg / g to about 800 mg / g, about 500 mg / g to about 800 mg / g, about 550 mg / g to about 800 mg / g, about 600 mg / g to about 800 mg / g, or about 800 mg / g. mg / g, about 650 mg / g to about 800 mg / g, about 700 mg / g to about 800 mg / g, about 750 mg / g to about 800 mg / g, about 200 mg / g to about 700 mg / g, about 250 mg / g to about 700 mg / g, about 300 mg / g to about 700 mg / g, about 350 mg / g to about 700 mg / g, about 400 mg / g to about 700 mg / g, about 450 mg / g to about 700 mg / g, about 500 mg / g to about 700 mg / g, about 550 mg / g to about 700 mg / g, about 600 mg / g to about 700 mg / g, about 650 mg / g to about 700 mg / g, about 200 mg / g to about 600 mg / g, about 250 mg / g to about 600 mg / g, about 300 mg / g to about 600 mg / g, about 350 mg / g to about 600 mg / g, about 400 mg / g to about 600 mg / g, about 450 mg / g to about 600 mg / g, about 500 mg / g to about 600 mg / g, about 550 mg / g to about 600 mg / g, about 200 mg / g to about 500 mg / g g, about 250 mg / g to about 500 mg / g, about 300 mg / g to about 500 mg / g, about 350 mg / g to about 500 mg / g, about 400 mg / g to about 500 mg / g, about 450 mg / g to about 500 mg / g, about 200 mg / g to about 400 mg / g, about 250 mg / g to about 400 mg / g, about 300 mg / g to about 400 mg / g, about 350 mg / g to about 400 mg / g, about 200 mg / g to about 300 mg / g, or about 250 mg / g to about 300 mg / g.In some embodiments, the insoluble manganese-containing compound has a uric acid clearance capacity as measured in a simulated fed small intestinal fluid (FeSSIF) assay of about 250 mg / g to about 800 mg / g, about 300 mg / g to about 800 mg / g, about 350 mg / g to about 800 mg / g, about 400 mg / g to about 800 mg / g, about 450 mg / g to about 800 mg / g, about 500 mg / g to about 800 mg / g, about 550 mg / g to about 800 mg / g, about 600 mg / g to about 800 mg / g, about 650 mg / g to about 800 mg / g. / g, about 700 mg / g to about 800 mg / g, about 750 mg / g to about 800 mg / g, about 200 mg / g to about 700 mg / g, about 250 mg / g to about 700 mg / g, about 300 mg / g to about 700 mg / g, about 350 mg / g to about 700 mg / g, about 400 mg / g to about 700 mg / g, about 450 mg / g to about 700 mg / g, about 500 mg / g to about 700 mg / g, about 550 mg / g to about 700 mg / g, about 600 mg / g to about 700 mg / g, about 650 mg / g about 700 mg / g, about 200 mg / g to about 600 mg / g, about 250 mg / g to about 600 mg / g, about 300 mg / g to about 600 mg / g, about 350 mg / g to about 600 mg / g, about 400 mg / g to about 600 mg / g, about 450 mg / g to about 600 mg / g, about 500 mg / g to about 600 mg / g, about 550 mg / g to about 600 mg / g, about 200 mg / g to about 500 mg / g, about 250 mg / g to about 500 In some embodiments, the present invention relates to an oral dosage form of the present invention. In some embodiments, the oral dosage form of the present invention is iodine, iodine, or succinate / antibody. In some embodiments, the oral dosage form is iodine, iodine, or succinate / antibody. In some embodiments, the oral dosage form is iodine, iodine, or succinate / antibody. In some embodiments, the oral dosage form is iodine, iodine, or succinate / antibody.

[0129] In some embodiments, the drug is an oral formulation.

[0130] In some embodiments, the oral formulation is a solid oral formulation. In some embodiments, the solid oral formulation is a powder, granules, tablets, capsules, pills or lozenges. In some embodiments, the oral formulation is a liquid oral formulation.

[0131] In some embodiments, the medicament does not comprise an additional therapeutic agent.

[0132] In some embodiments, the medicament comprises an effective amount of an insoluble manganese-containing compound (e.g., manganese oxide). In some embodiments, the medicament comprises about 3 mg to about 3000 mg, about 3 mg to about 1500 mg, about 5 mg to about 500 mg, or about 10 mg to about 200 mg of an insoluble manganese-containing compound. For example, in some embodiments, the medicament comprises about 3 mg to about 3000 mg, about 3 mg to about 2500 mg, about 3 mg to about 2000 mg, about 3 mg to about 1500 mg, about 3 mg to about 1000 mg, about 3 mg to about 900 mg, about 3 mg to about 800 mg, about 3 mg to about 700 mg, about 3 mg to about 600 mg, about 3 mg to about 500 mg, about 3 mg to about 400 mg, about 3 mg to about 300 mg, about 3 mg to about 200 mg, about 5 mg to about 3000 mg, about 5 mg to about 2500 mg, about 5 mg to about 200 In some embodiments, the present invention provides an insoluble manganese-containing compound in an amount of 10 mg to 200 mg, or about 10 mg to about 300 mg of the insoluble manganese-containing compound. In some embodiments, the medicament comprises about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg of an insoluble manganese-containing compound.

[0133] In some embodiments, the mammal is a human. In some embodiments, the mammal is an adult male aged ≥18 years. In some embodiments, the mammal is an adult male aged ≥18 years and <60 years. In some embodiments, the mammal is an adult male aged ≥60 years. In some embodiments, the mammal is an adult female aged ≥18 years. In some embodiments, the mammal is an adult female aged ≥18 years and <49 years. In some embodiments, the mammal is an adult female aged ≥49 years.

[0134] In some embodiments, the mammal is a mammal with a reduced ability to clear uric acid via the kidneys. For example, in some embodiments, the mammal is a mammal suffering from one or more of gouty urinary stones, gouty nephropathy, and diabetes. In some embodiments, the mammal is a mammal suffering from gouty urinary stones. In some embodiments, the mammal is a mammal suffering from gouty nephropathy, such as at least one of nephritis, pyelonephritis, hydronephrosis, uric acid nephrolithiasis, renal dysfunction, renal failure, and uremia. In some embodiments, the mammal is a mammal suffering from diabetes.

[0135] In some embodiments, the digestive tract is an intestinal tract. For example, in some embodiments, the digestive tract is the small intestine. In some embodiments, the digestive tract is the duodenum. In some embodiments, the digestive tract is the jejunum. In some embodiments, the digestive tract is the ileum. In some embodiments, the digestive tract is the large intestine. In some embodiments, the digestive tract is the cecum. In some embodiments, the digestive tract is the colon (e.g., one or more of the ascending colon, transverse colon, descending colon, and sigmoid colon). In some embodiments, the digestive tract is the rectum. In some embodiments, the digestive tract is the small intestine and / or large intestine. In some embodiments, the digestive tract is one or more of the duodenum, jejunum, and ileum. In some embodiments, the digestive tract is one or more of the cecum, colon, and rectum. In some embodiments, the digestive tract is one or more of the duodenum, jejunum, ileum, cecum, colon, and rectum.

[0136] In some embodiments, the disease or condition associated with elevated uric acid levels in the blood and / or digestive tract is selected from at least one of the following groups: gout, gout complications, hyperuricemia, elevated uric acid levels that do not reach the level typically diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related conditions, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle spasms, localized swelling, joint pain, malignancy, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, nonalcoholic fatty liver disease, stroke, hemolytic anemia, inborn errors of metabolism, poisoning, carbuncle, and transplantation of blood, bone marrow, or solid organs.

[0137] In some embodiments, the gout is acute gout, chronic gout, or refractory gout.

[0138] In some embodiments, the gout complication is at least one of gouty arthritis, gouty urinary stones, and gouty nephropathy.

[0139] In some embodiments, the gouty nephropathy is at least one of nephritis, pyelonephritis, hydronephrosis, uric acid nephrolithiasis, renal dysfunction, renal failure, and uremia.

[0140] In some embodiments, the cardiovascular disease is at least one of hypertension, coronary heart disease, heart failure, congenital heart disease, deep vein thrombosis, pulmonary embolism, aortic aneurysm, aortic dissection, hyperlipidemia, myocardial infarction, and atherosclerosis.

[0141] In some embodiments, the hyperuricemia is primary hyperuricemia or secondary hyperuricemia.

[0142] In some embodiments, the secondary hyperuricemia is at least one of drug-related hyperuricemia and hyperuricemia associated with other medical conditions.

[0143] In some embodiments, the diabetes-related condition is at least one of diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, diabetic macroangiopathy, diabetic microangiopathy, diabetic foot, and diabetic ketoacidosis.

[0144] In some embodiments, the malignancy is a hematological malignancy.

[0145] In some embodiments, the hematological malignancy is at least one of leukemia and multiple myeloma. In some embodiments, the leukemia is acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, or chronic myeloid leukemia.

[0146] In some embodiments, the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

[0147] In some embodiments, the poisoning is at least one of chloroform poisoning, carbon tetrachloride poisoning, and lead poisoning.

[0148] In some embodiments, the inborn error of metabolism is Lesch-Nyhan syndrome.

[0149] In some embodiments, prior to administration of the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 240 μmol / L, 260 μmol / L, 280 μmol / L, 300 μmol / L, 320 μmol / L, 340 μmol / L, 360 μmol / L, 380 μmol / L, 400 μmol / L, or 420 μmol / L. In some embodiments, prior to administration of the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 240 μmol / L. In some embodiments, prior to administering the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 260 μmol / L. In some embodiments, prior to administration of the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 280 μmol / L. In some embodiments, prior to administration of the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 300 μmol / L. In some embodiments, prior to administration of the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 320 μmol / L.In some embodiments, prior to administration of the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 340 μmol / L. In some embodiments, prior to administration of the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 360 ​​μmol / L. In some embodiments, prior to administration of the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 380 μmol / L. In some embodiments, prior to administration of the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 400 μmol / L. In some embodiments, prior to administering the drug to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 420 μmol / L.

[0150] In some embodiments, the blood and / or serum uric acid level of the subject is reduced after administration of the drug compared to before administration of the drug.

[0151] For example, in some embodiments, the individual's blood and / or serum uric acid level is reduced by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% after administration of the drug compared to before administration of the drug.

[0152] For example, in some embodiments, after administration of the drug, the individual's blood and / or serum uric acid level is between 80 μmol / L and 460 μmol / L, between 100 μmol / L and 450 μmol / L, between 150 μmol / L and 440 μmol / L, between 200 μmol / L and 430 μmol / L, between 210 μmol / L and 420 μmol / L, between 80 μmol / L and 380 μmol / L, between 100 μmol / L and 370 μmol / L, or between 150 μmol / L and 360 μmol / L.

[0153] In some embodiments, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days or 7 days after administration of the effective amount of the drug, the individual's blood and / or serum uric acid level is reduced compared to before administration of the drug.

[0154] In a second aspect, the present disclosure provides use of a manganese-containing compound as described herein in the preparation of a medicament for adsorbing uric acid in the digestive tract of a mammal.

[0155] In some embodiments, the manganese-containing compound is an insoluble manganese-containing compound.

[0156] Other embodiments of this aspect may refer to those described in detail in the first aspect above.

[0157] In a third aspect, the present disclosure provides a pharmaceutical composition for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian individual, or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract, wherein the pharmaceutical composition comprises an insoluble manganese-containing compound and a pharmaceutically acceptable excipient.

[0158] In some embodiments, the pharmaceutical composition is an oral formulation.

[0159] In some embodiments, the oral formulation is a solid oral formulation. In some embodiments, the solid oral formulation is a powder, granules, tablets, capsules, pills or lozenges. In some embodiments, the oral formulation is a liquid oral formulation.

[0160] In some embodiments, the pharmaceutical composition does not comprise an additional therapeutic agent.

[0161] In some embodiments, the pharmaceutical composition comprises an effective amount of an insoluble manganese-containing compound (e.g., manganese oxide). In some embodiments, the pharmaceutical composition comprises from about 3 mg to about 3000 mg, from about 3 mg to about 1500 mg, from about 5 mg to about 500 mg, or from about 10 mg to about 200 mg of an insoluble manganese-containing compound. For example, in some embodiments, the pharmaceutical composition comprises about 3 mg to about 3000 mg, about 3 mg to about 2500 mg, about 3 mg to about 2000 mg, about 3 mg to about 1500 mg, about 3 mg to about 1000 mg, about 3 mg to about 900 mg, about 3 mg to about 800 mg, about 3 mg to about 700 mg, about 3 mg to about 600 mg, about 3 mg to about 500 mg, about 3 mg to about 400 mg, about 3 mg to about 300 mg, about 3 mg to about 200 mg, about 5 mg to about 3000 mg, about 5 mg to about 2500 mg, about 5 mg to about 2000 mg, about 5 mg to about 1500 mg, about 5 mg to about 1000 mg, about 5 mg to about 900 mg, about 5 mg to about 800 mg. From about 10 mg to about 800 mg, from about 5 mg to about 700 mg, from about 5 mg to about 600 mg, from about 5 mg to about 500 mg, from about 5 mg to about 400 mg, from about 5 mg to about 300 mg, from about 5 mg to about 200 mg, from about 10 mg to about 3000 mg, from about 10 mg to about 2500 mg, from about 10 mg to about 2000 mg, from about 10 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 900 mg, from about 10 mg to about 800 mg, from about 10 mg to about 700 mg, from about 10 mg to about 600 mg, from about 10 mg to about 500 mg, from about 10 mg to about 400 mg, from about 10 mg to about 300 mg, or from about 10 mg to about 200 mg of an insoluble manganese-containing compound. In some embodiments, the pharmaceutical composition comprises about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg of an insoluble manganese-containing compound.

[0162] In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 240 μmol / L, 260 μmol / L, 280 μmol / L, 300 μmol / L, 320 μmol / L, 340 μmol / L, 360 μmol / L, 380 μmol / L, 400 μmol / L, or 420 μmol / L. In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 240 μmol / L. In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 260 μmol / L. In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 280 μmol / L. In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is above 300 μmol / L by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 320 μmol / L.In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 340 μmol / L. In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 360 ​​μmol / L. In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 380 μmol / L. In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 400 μmol / L. In some embodiments, prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 420 μmol / L.

[0163] In some embodiments, the blood and / or serum uric acid level of the subject is reduced after administration of the pharmaceutical composition compared to before administration of the pharmaceutical composition.

[0164] For example, in some embodiments, the individual's blood and / or serum uric acid level is reduced by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% after administration of the pharmaceutical composition compared to before administration of the pharmaceutical composition.

[0165] For example, in some embodiments, after administration of the pharmaceutical composition, the individual's blood and / or serum uric acid level is between 80 μmol / L and 460 μmol / L, between 100 μmol / L and 450 μmol / L, between 150 μmol / L and 440 μmol / L, between 200 μmol / L and 430 μmol / L, between 210 μmol / L and 420 μmol / L, between 80 μmol / L and 380 μmol / L, between 100 μmol / L and 370 μmol / L, or between 150 μmol / L and 360 μmol / L.

[0166] In some embodiments, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, 24 h, 36 h, 48 h, 3 days, 4 days, 5 days, 6 days or 7 days after administration of the effective amount of the pharmaceutical composition, the individual's blood and / or serum uric acid level is reduced compared to before administration of the pharmaceutical composition.

[0167] Other embodiments of this aspect may refer to those described in detail in the first aspect above.

[0168] In a fourth aspect, the present disclosure provides a pharmaceutical kit comprising: (i) any one of the pharmaceutical compositions according to the present disclosure; and (ii) a pharmaceutical insert and / or a pharmaceutical label.

[0169] As used throughout this article, the term "medicine box" may also be referred to alternatively as a "test kit" and refers to a commercially available package for holding a pharmaceutical composition (optionally in the form of a pharmaceutically acceptable formulation such as a unit dosage form). The package can be made of materials including, but not limited to, one or more of paper, glass, metal, and plastic. In the medicine box described in the present disclosure, the pharmaceutical composition can be placed in at least one container in the package. As a non-limiting example, the container can be, for example, an ampoule, a bottle, a test tube, a bag, a blister pack, a syringe, and / or a dispenser. In addition to the container for placing the pharmaceutical composition, the medicine box may optionally include one or more additional containers containing a pharmaceutically acceptable excipient for diluting or suspending the pharmaceutical composition. In addition, in the medicine box described in the present disclosure, there is also a drug instruction sheet and / or a drug label. In the context of the present disclosure, a "drug instruction sheet" should be understood as a paper instruction sheet placed inside the medicine box, which is intended to provide information about the ingredients, method of administration, side effects, etc. of the pharmaceutical composition. In addition, "drug label" should be understood as a label containing explanatory text related to the pharmaceutical composition, which is attached to the outer surface of the container and / or packaging or constitutes a part of the outer surface of the container and / or packaging.

[0170] In a fifth aspect, the present disclosure provides a method for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian individual, or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract, comprising administering to an individual in need thereof an effective amount of an insoluble manganese-containing compound.

[0171] In a sixth aspect, the present disclosure provides a method for preventing and / or treating elevated blood uric acid levels or a disease or condition associated with elevated blood uric acid levels in a mammalian individual, comprising administering to the individual in need thereof an effective amount of an insoluble manganese-containing compound over an extended period of time.

[0172] In a seventh aspect, the present disclosure provides a method for maintaining blood uric acid levels in a mammalian subject, comprising administering to the subject in need thereof an effective amount of an insoluble manganese-containing compound over an extended period of time.

[0173] In some embodiments, the method is maintained at a blood and / or serum uric acid level of the individual that does not cause or is not prone to cause gout or gout complications. In some embodiments, the method is maintained at a blood and / or serum uric acid level of the individual that is between 80 μmol / L and 460 μmol / L, between 100 μmol / L and 450 μmol / L, between 150 μmol / L and 440 μmol / L, between 200 μmol / L and 430 μmol / L, between 210 μmol / L and 420 μmol / L, between 80 μmol / L and 380 μmol / L, between 100 μmol / L and 370 μmol / L, or between 150 μmol / L and 360 μmol / L.

[0174] In some embodiments, the effective amount is about 3 mg to about 3000 mg of insoluble manganese-containing compound (e.g., manganese oxide) per day. In some embodiments, the effective amount is about 3 mg to about 1500 mg of insoluble manganese-containing compound per day. In some embodiments, the effective amount is about 5 mg to about 500 mg of insoluble manganese-containing compound per day. In some embodiments, the effective amount is about 10 mg to about 200 mg of insoluble manganese-containing compound per day. For example, in some embodiments, the effective amount is from about 3 mg to about 3000 mg of insoluble manganese-containing compound per day, from about 3 mg to about 1500 mg of insoluble manganese-containing compound per day, from about 3 mg to about 1000 mg of insoluble manganese-containing compound per day, from about 3 mg to about 900 mg of insoluble manganese-containing compound per day, from about 3 mg to about 800 mg of insoluble manganese-containing compound per day, from about 3 mg to about 700 mg of insoluble manganese-containing compound per day, from about 3 mg to about 600 mg of insoluble manganese-containing compound per day, from about 3 mg to about 500 mg of insoluble manganese-containing compound per day, compound / day, about 3 mg to about 400 mg of insoluble manganese-containing compound / day, about 3 mg to about 300 mg of insoluble manganese-containing compound / day, about 3 mg to about 200 mg of insoluble manganese-containing compound / day, about 5 mg to about 3000 mg of insoluble manganese-containing compound / day, about 5 mg to about 1500 mg of insoluble manganese-containing compound / day, about 5 mg to about 1000 mg of insoluble manganese-containing compound / day, about 5 mg to about 900 mg of insoluble manganese-containing compound / day, about 5 mg to about 800 mg of insoluble manganese-containing compound / day, about 5 mg to about 7 00 mg of insoluble manganese-containing compound / day, about 5 mg to about 600 mg of insoluble manganese-containing compound / day, about 5 mg to about 500 mg of insoluble manganese-containing compound / day, about 5 mg to about 400 mg of insoluble manganese-containing compound / day, about 5 mg to about 300 mg of insoluble manganese-containing compound / day, about 5 mg to about 200 mg of insoluble manganese-containing compound / day, about 10 mg to about 3000 mg of insoluble manganese-containing compound / day, about 10 mg to about 1500 mg of insoluble manganese-containing compound / day, about 10 mg to about 1000 mg of insoluble manganese-containing compound / day, and about 10 mg to about 1500 mg of insoluble manganese-containing compound / day. The insoluble manganese-containing compound is taken daily, for example, from about 10 mg to about 900 mg of an insoluble manganese-containing compound per day, from about 10 mg to about 800 mg of an insoluble manganese-containing compound per day, from about 10 mg to about 700 mg of an insoluble manganese-containing compound per day, from about 10 mg to about 600 mg of an insoluble manganese-containing compound per day, from about 10 mg to about 500 mg of an insoluble manganese-containing compound per day, from about 10 mg to about 400 mg of an insoluble manganese-containing compound per day, from about 10 mg to about 300 mg of an insoluble manganese-containing compound per day, or from about 10 mg to about 200 mg of an insoluble manganese-containing compound per day.In some embodiments, the effective amount is about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg of an insoluble manganese-containing compound per day.

[0175] In some embodiments, the insoluble manganese-containing compound (eg, manganese oxide) is administered orally.

[0176] In some embodiments, the insoluble manganese-containing compound (eg, manganese oxide) is formulated as an oral preparation.

[0177] In some embodiments, the oral formulation is a solid oral formulation. In some embodiments, the solid oral formulation is a powder, granules, tablets, capsules, pills or lozenges. In some embodiments, the oral formulation is a liquid oral formulation.

[0178] In some embodiments, the oral formulation comprises an effective amount of an insoluble manganese-containing compound (e.g., manganese oxide). In some embodiments, the oral formulation comprises from about 3 mg to about 3000 mg, from about 3 mg to about 1500 mg, from about 5 mg to about 500 mg, or from about 10 mg to about 200 mg of an insoluble manganese-containing compound. For example, in some embodiments, the oral formulation comprises about 3 mg to about 3000 mg, about 3 mg to about 2500 mg, about 3 mg to about 2000 mg, about 3 mg to about 1500 mg, about 3 mg to about 1000 mg, about 3 mg to about 900 mg, about 3 mg to about 800 mg, about 3 mg to about 700 mg, about 3 mg to about 600 mg, about 3 mg to about 500 mg, about 3 mg to about 400 mg, about 3 mg to about 300 mg, about 3 mg to about 200 mg, about 5 mg to about 3000 mg, about 5 mg to about 2500 mg, about 5 mg to about 2000 mg, about 5 mg to about 1500 mg, about 5 mg to about 1000 mg, about 5 mg to about 900 mg, about 5 mg to about 1000 mg. about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 200 mg, about 10 mg to about 3000 mg, about 10 mg to about 2500 mg, about 10 mg to about 2000 mg, about 10 mg to about 1500 mg, about 10 mg to about 1000 mg, about 10 mg to about 900 mg, about 10 mg to about 800 mg, about 10 mg to about 700 mg, about 10 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, or about 10 mg to about 200 mg of an insoluble manganese-containing compound. In some embodiments, the oral formulation comprises about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg of an insoluble manganese-containing compound.

[0179] In some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) is administered to the individual once, twice, or more daily. In some embodiments, the insoluble manganese-containing compound is administered to the individual once daily. In some embodiments, the insoluble manganese-containing compound is administered to the individual twice daily. In some embodiments, the insoluble manganese-containing compound is administered to the individual three times daily. In some embodiments, the insoluble manganese-containing compound is administered to the individual four or more times daily.

[0180] In some embodiments, an effective amount of an insoluble manganese-containing compound (e.g., manganese oxide) is administered to an individual in need thereof over an extended period of time. In view of its favorable biological properties (including but not limited to low solubility and / or physiological inertness), an insoluble manganese-containing compound (e.g., manganese oxide) of the present disclosure can be administered to an individual in need thereof over a long period of time (i.e., over an extended period of time) to prevent and / or treat elevated uric acid levels in the blood and / or digestive tract of a mammalian individual or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract, to adsorb uric acid in the digestive tract of a mammal, and / or to maintain (normal or appropriate) uric acid levels in the blood of a mammalian individual. For example, in some embodiments, the administration continues for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 4 years, 5 years, 10 years or more (e.g., the entire duration of the life of the individual). In some embodiments, the extended period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 4 years, 5 years, 10 years or more (e.g., the entire duration of the life of the individual).

[0181] The insoluble manganese-containing compound (for example, manganese oxide) described in the present disclosure is not affected by, is not substantially affected by, or is less affected by eating to the adsorption effect of uric acid, so the insoluble manganese-containing compound and food can be taken at the same time, or can be taken successively at certain time intervals. Therefore, in some embodiments, the insoluble manganese-containing compound and food are taken at the same time or at intervals less than 1min, 2min, 3min, 4min, 5min, 10min, 15min, 20min, 25min or 30min. In some embodiments, the insoluble manganese-containing compound is taken 30min, 40min, 50min, 1h, 1.5h, 2h or longer after eating. The food can be, but is not limited to, one or more of meat (such as pork, beef, chicken, mutton, fish, shrimp), vegetables, fruits, cereals (such as rice and / or millet).

[0182] In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 240 μmol / L, 260 μmol / L, 280 μmol / L, 300 μmol / L, 320 μmol / L, 340 μmol / L, 360 μmol / L, 380 μmol / L, 400 μmol / L, or 420 μmol / L prior to administration of the insoluble manganese-containing compound (e.g., manganese oxide) to the subject. In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 240 μmol / L prior to administration of the insoluble manganese-containing compound to the subject. In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 260 μmol / L prior to administration of the insoluble manganese-containing compound to the subject. In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 280 μmol / L prior to administration of the insoluble manganese-containing compound to the subject. In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 300 μmol / L prior to administration of the insoluble manganese-containing compound to the subject.In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 320 μmol / L prior to administration of the insoluble manganese-containing compound to the subject. In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 340 μmol / L prior to administration of the insoluble manganese-containing compound to the subject. In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 360 ​​μmol / L prior to administration of the insoluble manganese-containing compound to the subject. In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 380 μmol / L prior to administration of the insoluble manganese-containing compound to the subject. In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 400 μmol / L prior to administration of the insoluble manganese-containing compound to the subject. In some embodiments, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 420 μmol / L prior to administration of the insoluble manganese-containing compound to the subject.

[0183] In some embodiments, the blood and / or serum uric acid level of the subject is reduced after administration of the insoluble manganese-containing compound (eg, manganese oxide) compared to before administration of the insoluble manganese-containing compound.

[0184] For example, in some embodiments, the individual's blood and / or serum uric acid level is reduced by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% after administration of the insoluble manganese-containing compound (e.g., manganese oxide) compared to before administration of the insoluble manganese-containing compound.

[0185] For example, in some embodiments, the individual's blood and / or serum uric acid level after administration of the insoluble manganese-containing compound (e.g., manganese oxide) is between 80 μmol / L and 460 μmol / L, between 100 μmol / L and 450 μmol / L, between 150 μmol / L and 440 μmol / L, between 200 μmol / L and 430 μmol / L, between 210 μmol / L and 420 μmol / L, between 80 μmol / L and 380 μmol / L, between 100 μmol / L and 370 μmol / L, or between 150 μmol / L and 360 μmol / L.

[0186] In some embodiments, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days or 7 days after administration of an effective amount of the insoluble manganese-containing compound (e.g., manganese oxide), the individual's blood and / or serum uric acid level is reduced compared to before administration of the insoluble manganese-containing compound.

[0187] Other embodiments of this aspect may refer to those described in detail in the first aspect above.

[0188] In an eighth aspect, the present disclosure provides a pharmaceutical composition comprising manganese oxide, wherein the amount of manganese oxide is sufficient to reduce the blood and / or serum uric acid levels in at least about 10% of mammalian individuals whose blood and / or serum uric acid levels are above 360 ​​μmol / L or 420 μmol / L by at least about 5% within 24 hours after administration of the pharmaceutical composition.

[0189] In some embodiments, the particle size of the manganese oxide is ≥ 1 μm, for example, 1 μm to 1 mm.

[0190] In some embodiments, the pharmaceutical composition is an oral formulation.

[0191] In some embodiments, the oral formulation is a solid oral formulation. In some embodiments, the solid oral formulation is a powder, granules, tablets, capsules, pills or lozenges. In some embodiments, the oral formulation is a liquid oral formulation.

[0192] In some embodiments, the pharmaceutical composition does not comprise an additional therapeutic agent.

[0193] In some embodiments, the pharmaceutical composition comprises an effective amount of manganese oxide. In some embodiments, the pharmaceutical composition comprises about 3 mg to about 3000 mg, about 3 mg to about 1500 mg, about 5 mg to about 500 mg, or about 10 mg to about 200 mg of manganese oxide. For example, in some embodiments, the pharmaceutical composition comprises about 3 mg to about 3000 mg, about 3 mg to about 2500 mg, about 3 mg to about 2000 mg, about 3 mg to about 1500 mg, about 3 mg to about 1000 mg, about 3 mg to about 900 mg, about 3 mg to about 800 mg, about 3 mg to about 700 mg, about 3 mg to about 600 mg, about 3 mg to about 500 mg, about 3 mg to about 400 mg, about 3 mg to about 300 mg, about 3 mg to about 200 mg, about 5 mg to about 3000 mg, about 5 mg to about 2500 mg, about 5 mg to about 2000 mg, about 5 mg to about 1500 mg, about 5 mg to about 1000 mg, about 5 mg to about 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 5 mg From about 10 mg to about 500 mg, from about 5 mg to about 400 mg, from about 5 mg to about 300 mg, from about 5 mg to about 200 mg, from about 10 mg to about 3000 mg, from about 10 mg to about 2500 mg, from about 10 mg to about 2000 mg, from about 10 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 900 mg, from about 10 mg to about 800 mg, from about 10 mg to about 700 mg, from about 10 mg to about 600 mg, from about 10 mg to about 500 mg, from about 10 mg to about 400 mg, from about 10 mg to about 300 mg, or from about 10 mg to about 200 mg of manganese oxide. In some embodiments, the pharmaceutical composition comprises about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg of manganese oxide.

[0194] In some embodiments, the blood and / or serum uric acid level in the mammalian subject is at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 360 ​​μmol / L or 420 μmol / L. In some embodiments, the blood and / or serum uric acid level in the mammalian subject is at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 360 ​​μmol / L. In some embodiments, the blood and / or serum uric acid level in the mammalian subject is at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 420 μmol / L.

[0195] In some embodiments, the blood and / or serum uric acid levels in the mammalian subject are reduced by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% within 24 hours after administration of the pharmaceutical composition.

[0196] Other embodiments of this aspect may refer to those described in detail in the first aspect above.

[0197] In a ninth aspect, the present disclosure provides a pharmaceutical composition formulated as at least one solid dosage unit for oral administration to a mammalian subject, wherein the solid dosage unit comprises manganese oxide, and wherein the manganese oxide has a uric acid clearance capacity as measured in a simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay that is at least about 100 mg / g higher than the uric acid clearance capacity of activated carbon under equivalent conditions.

[0198] In some embodiments, the manganese oxide has a uric acid clearance capacity as measured in a simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay that is at least about 200 mg / g, 300 mg / g, 400 mg / g, 500 mg / g, or 600 mg / g higher than the uric acid clearance capacity of activated carbon under equivalent conditions.

[0199] The simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay can be measured using methods known to those skilled in the art. In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is measured in FaSSIF or FeSSIF having a uric acid concentration of about 8.4 ± 0.2 mg / dL, e.g., 8.2 mg / dL, 8.3 mg / dL, 8.4 mg / dL, 8.5 mg / dL, or 8.6 mg / dL. In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is performed at a temperature between about 25°C and 37°C, such as about 25°C to 26°C, 25°C to 27°C, 25°C to 28°C, 25°C to 29°C, 25°C to 30°C, 25°C to 31°C, 25°C to 32°C, 25°C to 33°C, 25°C to 34°C, 25°C to 35°C, 25°C to 36°C, 26°C to 37°C, 27°C to 37°C, 28°C to 37°C, 29°C to 37°C, 30°C to 37°C, 31°C to 37°C, 32°C to 37°C, 33°C to 37°C, 34°C to 37°C, 35°C to 37°C, or 36°C to 37°C. In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is performed at a manganese oxide concentration of about 0.1 g / L to 2 g / L, for example about 0.1 g / L to 0.2g / L, 0.1g / L to 0.3g / L, 0.1g / L to 0.4g / L, 0.1g / L to 0.5g / L, 0.1g / L to 0.6g / L, 0.1g / L to 0.7g / L, 0.1g / L to 0.8g / L, 0.1g / L to 0.9g / L, 0.1g / L to 1.0g / L, 0.1g / L to 1.1g / L, 0.1g / L to 1.2g / L, 0.1g / L to 1.3g / L, 0.1g / L to 1.4g / L, 0.1g / L to 1.5g / L, 0.1g / L to 1.6g / L, 0.1g / L to 1.7g / L, 0.1g / L to 1.8g / L, 0. The invention relates to a novel polyvinyl alcohol-containing compound of claim 1, wherein the polyvinyl alcohol-containing compound is a polyvinyl alcohol-containing compound of claim 1, wherein the polyvinyl alcohol-containing compound is a polyvinyl alcohol-containing compound of claim 1, wherein the polyvinyl alcohol-containing compound is a polyvinyl alcohol-containing compound of claim 1, wherein the polyvinyl alcohol-containing compound is a polyvinyl alcohol-containing compound of claim 1, wherein the polyvinyl alcohol-containing compound is a polyvinyl alcohol-containing compound of claim 1, wherein the polyvinyl alcohol-containing compound is a polyvinyl alcohol-containing compound of claim 1, wherein the polyvinyl alcohol-containing compound is a polyvinyl alcohol-containing compound of claim 1,In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) determination is carried out under conditions of vibration. The frequency of vibration can be, for example, ≥50rpm, ≥100rpm, ≥150rpm, ≥200rpm, ≥250rpm, ≥300rpm or higher. In some embodiments, the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) determination is to use a simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) having a concentration of uric acid of about 8.4±0.2mg / dL, at a temperature between about 25°C and 37°C, a concentration of manganese oxide of about 0.1g / L to 2g / L, and is carried out under conditions of vibration. In some embodiments, the duration of the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is ≥5 min, e.g., ≥10 min, ≥15 min, ≥20 min, ≥25 min, ≥30 min, ≥35 min, ≥40 min, ≥45 min, ≥50 min, ≥55 min, ≥60 min, ≥90 min, ≥120 min, ≥180 min, ≥240 min, ≥300 min, ≥360 min, ≥420 min, ≥480 min, ≥520 min, or ≥600 min.

[0200] Other embodiments of this aspect may refer to those described in detail in the first and eighth aspects above.

[0201] Without causing conflict, the features of the various embodiments described in the above aspects of the present disclosure may be combined to obtain one or more additional embodiments within the spirit and / or scope of the present disclosure.

[0202] Example

[0203] The present disclosure is further described in detail below using examples. Obviously, the described examples are only a part of the invention disclosed in this disclosure, and not all of it. These examples are for illustrative purposes only and should not be construed as limiting the scope of protection of the present disclosure in any way. Based on the disclosed examples, all equivalent or similar technical solutions obtained by those skilled in the art without the need for creative work fall within the scope of protection of the present disclosure.

[0204] Example 1 Preparation of each test substance

[0205] This example describes the sources or preparation methods of various test substances used in subsequent assays (when not commercially available).

[0206] 1.1 Preparation of reference substances

[0207] In the examples of the present application, "control substances" refer to substances that do not fall within the category of manganese-containing compounds. Unless otherwise indicated, these substances are commercially available.

[0208] The following is a non-limiting list of commercially available control substances:

[0209] (1) Zeolite molecular sieves, including TS-1, NaY, 10X, ZSM-5, 4A, HY, 13X, zeolite, 5A, 3A and USY;

[0210] (2) Prussian blue;

[0211] (3) Activated carbon, namely medicinal activated carbon AST-120 (also known as "AST120", "Cremejing" ”) and Aixite, and the specific surface area is 600m 2 / g、720m 2 / g、1045m 2 / g、1400m 2 / g、1800m 2 / g and 3500m 2 / g of commercial activated carbon;

[0212] (4) Ion exchange resins, including IRA900 (Amberlite IRA-900 (Cl) ion exchange resin, LOT: 10227274, CAS: 9050-97-9, Alfa Aesar), cholestyramine, sevelamer hydrochloride, CER-1 (Amberlyst 15 (H) ion exchange resin, LOT: 5007R10N, CAS: 39389-20-3, Alfa Aesar), DOWEX (DOWEX (R) 1X8, LOT: 10224593, CAS: 12627-85-9, Alfa Aesar), NAER-1 (ion exchange resin, LOT: 10228055, CAS: 9017-79-2, Alfa Aesar), NAER-2 (macroporous ion exchange resin, LOT: 10229336, CAS: 39339-85-0, Alfa Aesar);

[0213] (5) Metal-organic frameworks (MOFs), including ZIF-8, UIO66, and UIO66NH2; and

[0214] (6) Montmorillonite.

[0215] In addition, some reference materials can be prepared by artificial synthesis. The following lists the preparation methods of different types of hydrotalcite used as reference materials in the examples of this application (Note: "2-1", "3-1" and "4-1" below refer to the magnesium-aluminum ratio):

[0216] 2-1 Preparation of hydrotalcite

[0217] Weigh 570 mg of magnesium chloride, 723 mg of aluminum chloride hexahydrate, and 1.26 g of urea and dissolve them in 10 mL of deionized water. Transfer the resulting solution to a hydrothermal autoclave and react at 160°C for 6 hours. After cooling naturally, centrifuge at 1000 rpm to collect the solid, wash it with water until neutral, and dry it at 70°C for 24 hours to obtain 2-1 hydrotalcite.

[0218] 3-1 Preparation of hydrotalcite

[0219] Weigh 570 mg of magnesium chloride, 482 mg of aluminum chloride hexahydrate, and 1.12 g of urea and dissolve them in 10 mL of deionized water. Transfer the resulting solution to a hydrothermal autoclave and react at 160°C for 6 hours. After cooling, centrifuge at 1000 rpm to collect the solid, wash it with water until neutral, and dry it at 70°C for 24 hours to obtain 3-1 hydrotalcite.

[0220] 4-1 Preparation of hydrotalcite

[0221] Weigh 570 mg of magnesium chloride, 362 mg of aluminum chloride hexahydrate, and 1.048 g of urea and dissolve them in 10 mL of deionized water. Transfer the resulting solution to a hydrothermal autoclave and react at 160°C for 6 hours. After cooling naturally, centrifuge at 1000 rpm to collect the solid, wash it with water until neutral, and dry it at 70°C for 24 hours to obtain 4-1 hydrotalcite.

[0222] Preparation of CTAB (cetyltrimethylammonium bromide) hydrotalcite

[0223] Weigh 82 mg of magnesium chloride, 104 mg of aluminum chloride hexahydrate, and 180 mg of urea and dissolve them in 15 mL of deionized water to create solution 1. Weigh 131 mg of CTAB and dissolve it in 9 mL of deionized water to create solution 2. Mix solutions 1 and 2 thoroughly, transfer to a hydrothermal autoclave, and react at 160°C for 6 hours. After cooling naturally, centrifuge at 1000 rpm to isolate the solid. Wash with deionized water until neutral, and dry at 70°C for 24 hours to obtain CTAB hydrotalcite.

[0224] 1.2 Preparation of insoluble manganese-containing compounds as test samples

[0225] As test samples, the insoluble manganese-containing compounds used in the examples of the present application include insoluble manganese-containing compounds that can be obtained through commercial channels, insoluble manganese-containing compounds in the form of natural minerals, and insoluble manganese-containing compounds that can be prepared by artificial synthesis methods.

[0226] The following is a non-limiting list of commercially available insoluble manganese-containing compounds: βM (β-type crystalline manganese oxide, LOT: A0431349, 99%, 10 mesh, Acros), γM (γ-type crystalline manganese oxide, LOT: G1804053, >90%, Aladdin), and λMLi (lithium-type λ-type crystalline manganese oxide, Spinel LiMn2O4).

[0227] The following is a non-limiting list of insoluble manganese-containing compounds in the form of naturally occurring minerals: romanechite, todorokite, manganite (composed primarily of gamma-type crystalline manganese oxyhydroxide), groutite (composed primarily of alpha-type crystalline manganese oxyhydroxide), feitknechtite (composed primarily of beta-type crystalline manganese oxyhydroxide), hydrohausmannite (composed primarily of beta-type crystalline manganese oxyhydroxide), lithiophorite, chalcophanite, hausmannite, bixbyite, pyrochroite (also known as hydroxyl manganite), manganosite.

[0228] For the purpose of use in the examples of this application, all raw materials of insoluble manganese-containing compounds in the form of natural minerals were ground and sieved to obtain test samples with a particle size ranging from 1 μm to 1 mm.

[0229] In addition, some test samples still need to be prepared by artificial synthesis. The following lists the preparation methods of different forms of insoluble manganese-containing compounds used as test samples in the examples of this application. After preparation, the polymorphic forms of the products obtained by these methods were identified by powder X-ray diffraction using a multifunctional X-ray diffractometer D8ADVANCE Da Vinci. The test conditions of the powder X-ray diffraction method are as follows: the X-ray generator is a Cu target, the X-ray tube is a ceramic tube, the voltage is ≤40kV, the current is ≤40mA, the scanning range is 5° to 90°, the step size is 0.020435°, and the scanning speed is 4° / s.

[0230] Preparation of potassium-type δ-type crystal manganese oxide-1 (δM1K)

[0231] Weigh 0.948g of potassium permanganate, dissolve it in an appropriate amount of deionized water, and stir it on a magnetic stirrer at room temperature to obtain a potassium permanganate solution. Weigh 0.169g of manganese sulfate monohydrate, dissolve it in an appropriate amount of deionized water, and add it dropwise to the potassium permanganate solution (total water volume is 35mL). After the addition is complete, stir at room temperature for 30 minutes to form a uniform solution. Transfer the solution to a hydrothermal autoclave and react at 160°C for 12 hours. After natural cooling, filter and collect the solid, wash it several times with water and ethanol, and air-dry it at 60°C for 12 hours to obtain δM1K.

[0232] The powder X-ray diffraction pattern of δM1K shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.2, 24.9, 37.0, 56.4, and 65.8. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1K are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0233] Preparation of Hydrogen-Form δ-Form Crystalline Manganese Oxide-1 (δM1KH)

[0234] Weigh δM1K and place it in a beaker. Add dilute nitric acid at a ratio of 1 g δM1K / 100 mL of 0.7 M dilute nitric acid. Heat the beaker in a 60°C water bath with stirring for 90 minutes, then cool naturally to room temperature. Filter the solid, wash with water, and air-dry at 60°C for 12 hours to obtain δM1KH.

[0235] The powder X-ray diffraction pattern of δM1KH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.5, 25.1, 36.8, 56.9, and 66.0. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0236] Preparation of ammonium δ-type crystal manganese oxide-1 (δM1KNH4)

[0237] Weigh δM1K and place it in a beaker. Disperse δM1K in 1M ammonium chloride solution at a ratio of 1 g / 100 mL. Stir the beaker at room temperature for 4 hours, then heat and stir in a 60°C water bath for 2 hours, then cool naturally to room temperature. Filter the solid, wash with water, and dry under vacuum at 60°C overnight to obtain δM1KNH4.

[0238] The powder X-ray diffraction pattern of δM1KNH4 shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.6, 24.9, 36.9, 56.9 and 66.1. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KNH4 are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0239] Preparation of calcium-type δ-type crystal manganese oxide-1 (δM1KCa)

[0240] Weigh δM1K and place it in a beaker. Disperse δM1K in a 1M calcium chloride solution at a ratio of 1g / 100mL. Stir the beaker at room temperature for 4 hours, then place it in a hydrothermal reactor at 155°C for 24 hours. Then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C overnight to obtain δM1KCa.

[0241] The powder X-ray diffraction pattern of δM1KCa shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 8.9, 12.6, 18.5, and 37.0. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KCa are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite and buserite in the δ-type crystalline form.

[0242] Preparation of magnesium-type δ-type crystal manganese oxide-1 (δM1KMg)

[0243] Weigh δM1K and place it in a beaker. Disperse δM1K in a 1M magnesium chloride solution at a ratio of 1 g / 100 mL. Stir the beaker at room temperature for 4 hours, then place it in a hydrothermal reactor at 155°C for 24 hours. Then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C overnight to obtain δM1KMg.

[0244] The powder X-ray diffraction pattern of δM1KMg shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 9.0, 18.5, and 28.1. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KMg are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of buserite in the δ-type crystalline form.

[0245] Preparation of Iron-Type δ-Form Crystalline Manganese Oxide-1 (δM1KFe3)

[0246] Weigh δM1K and place it in a beaker. Disperse δM1K in a 1M ferric chloride solution at a ratio of 1g / 100mL. Stir the beaker at room temperature for 4 hours, then place it in a hydrothermal reactor at 155°C for 24 hours. Then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C overnight to obtain δM1KFe3.

[0247] The powder X-ray diffraction pattern of δM1KFe3 shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.3, 25.0, 36.8, 56.7, and 66.2. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KFe3 are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0248] Preparation of Ferrous δ-Type Crystalline Manganese Oxide-1 (δM1KFe2)

[0249] Weigh δM1K and place it in a beaker. Disperse δM1K in a 1M ferrous chloride solution at a ratio of 1 g / 100 mL. Stir the beaker at room temperature for 4 hours, then heat and stir in a 60°C water bath for 2 hours, then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C overnight to obtain δM1KFe2.

[0250] The powder X-ray diffraction pattern of δM1KFe2 shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.6, 24.9, 36.8, 56.5, and 66.7. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KFe2 are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0251] Preparation of Zinc-type δ-type Crystalline Manganese Oxide-1 (δM1KZn)

[0252] Weigh δM1K and place it in a beaker. Disperse δM1K in a 1M zinc chloride solution at a ratio of 1 g / 100 mL. Stir the beaker at room temperature for 4 hours, then heat and stir in a 60°C water bath for 2 hours, then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C overnight to obtain δM1KZn.

[0253] The powder X-ray diffraction pattern of δM1KZn shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.5, 25.2, 36.9, 56.7, and 66.9. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KZn are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0254] Preparation of Lanthanum-type δ-type Crystalline Manganese Oxide-1 (δM1KLa)

[0255] Weigh δM1K and place it in a beaker. Disperse δM1K in a 1 M lanthanum chloride solution at a ratio of 1 g / 100 mL. Stir the beaker at room temperature for 4 hours, then heat and stir in a 60°C water bath for 2 hours, then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C overnight to obtain δM1KLa.

[0256] The powder X-ray diffraction pattern of δM1KLa shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 9.2, 12.5, 18.3, 25.0, and 37.0. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KLa are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite and buserite in the δ-type crystalline form.

[0257] Preparation of Bismuth-Type δ-Form Manganese Oxide-1 (δM1KBi)

[0258] Weigh δM1K and place it in a beaker. Add the dilute bismuth nitrate solution to the beaker at a ratio of 1 g of δM1K per 100 mL of 0.7 M bismuth nitrate solution. Stir the beaker at room temperature for 4 hours, then heat and stir in a 60°C water bath for 2 hours, then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C overnight to yield δM1KBi.

[0259] The powder X-ray diffraction pattern of δM1KBi shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.6, 25.2, 37.1, 56.7, and 67.0. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KBi are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0260] Preparation of Lithium-Form δ-Form Manganese Oxide-1 (δM1KLi)

[0261] Weigh δM1K and place it in a beaker. Disperse δM1K in a 1M lithium chloride solution at a ratio of 1 g / 100 mL. Stir the beaker at room temperature for 4 hours, then heat and stir in a 60°C water bath for 2 hours, then cool naturally to room temperature. Filter the solid, wash with water, and dry under vacuum at 60°C overnight to obtain δM1KLi.

[0262] The powder X-ray diffraction pattern of δM1KLi shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.6, 25.0, 36.9, 56.5, and 66.8. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KLi are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0263] Preparation of silver-type δ-type crystal manganese oxide-1 (δM1KAg)

[0264] Weigh δM1K and place it in a beaker. Disperse δM1K in 1M silver nitrate solution at a ratio of 1 g / 100 mL. Stir the beaker in the dark at room temperature for 4 hours, then filter the solid, wash with water, and dry under vacuum at room temperature overnight to obtain δM1K ag.

[0265] The powder X-ray diffraction pattern of δM1KAg shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.5, 24.9, 36.8, 56.7, and 66.9. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1KAg are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0266] Preparation of potassium-type δ-type crystalline manganese oxide-2 (δM2K) and hydrogen-type δ-type crystalline manganese oxide-2.1 (δM2KH)

[0267] Weigh 9.65g of potassium hydroxide and dissolve it in 180mL of deionized water. Measure 20mL of a 30% aqueous hydrogen peroxide solution, add the solution, mix, and then add dropwise to a vigorously stirred 100mL aqueous manganese nitrate solution (containing 0.03M manganese). Continue stirring at room temperature for 1 hour, then let it stand for 10 minutes. Pour off the supernatant, centrifuge the solid, wash it with water and ethanol, and vacuum dry it at 80°C overnight to obtain δM2K. Place the δM2K obtained above in a beaker. Add dilute nitric acid at a ratio of 1g of δM2K / 100mL of 0.7M dilute nitric acid. Stir the beaker at room temperature for 4 hours, then heat and stir it in a 60°C water bath for 2 hours, then cool it naturally to room temperature. Filter the solid, wash it with water, and vacuum dry it at 60°C overnight to obtain δM2KH.

[0268] The powder X-ray diffraction pattern of δM2K shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.4, 25.0, 36.9, 56.0, and 66.1. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM2K are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0269] The powder X-ray diffraction pattern of δM2KH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.6, 24.8, 36.5, 55.7, and 66.3. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM2KH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0270] Preparation of sodium δ-type crystalline manganese oxide-2 (δM2Na) and hydrogen δ-type crystalline manganese oxide-2.2 (δM2NaH)

[0271] Weigh 3.44g of sodium hydroxide and dissolve it in 90mL of deionized water. Measure 10mL of a 30% aqueous hydrogen peroxide solution, add the above solution and mix, then add dropwise to a vigorously stirred 50mL aqueous manganese nitrate solution (containing 0.03M manganese). Continue stirring at room temperature for 1 hour, then let it stand for 10 minutes. Pour off the supernatant, centrifuge the lower solid, wash with water, and vacuum dry overnight at room temperature to obtain δM2Na. Take the δM2Na obtained above and place it in a beaker. Add dilute nitric acid solution at a ratio of 1g of δM2Na to 100mL of 0.7M dilute nitric acid solution. Place the beaker in a 60°C water bath and heat with stirring for 1.5 hours, then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C overnight to obtain δM2NaH.

[0272] The powder X-ray diffraction pattern of δM2Na shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.7, 37.1, 57.2, and 66.3. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM2Na are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0273] The powder X-ray diffraction pattern of δM2NaH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.6, 37.5, 57.0, and 66.2. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM2NaH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0274] Preparation of potassium-type δ-type crystalline manganese oxide-3 (δM3K) and hydrogen-type δ-type crystalline manganese oxide-3 (δM3KH)

[0275] Weigh 2g of potassium permanganate and dissolve it in 500mL of deionized water. Add 10mL of anhydrous ethanol dropwise with vigorous stirring and allow to react at room temperature for 6h. After standing for 30min, remove the upper turbid liquid. The lower solid layer is centrifuged, washed with water and ethanol, and then vacuum-dried at 80°C overnight to obtain δM3K. Take the δM3K obtained above and place it in a beaker. Add dilute nitric acid solution at a ratio of 1g of δM3K to 100mL of 0.7M dilute nitric acid solution. After stirring the beaker at room temperature for 4h, place it in a 60°C water bath with heating and stirring for 2h, and then cool naturally to room temperature. Filter the solid, wash it with water, and vacuum-dry it at 60°C overnight to obtain δM3KH.

[0276] The powder X-ray diffraction pattern of δM3K shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.7, 37.2, 56.9, and 66.4. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM3K are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0277] The powder X-ray diffraction pattern of δM3KH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.8, 37.3, 56.7, and 66.8. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM3KH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0278] Preparation of potassium-type δ-type crystal manganese oxide-4 (δM4K)

[0279] Weigh 0.75g of potassium permanganate and 0.14g of manganese sulfate monohydrate and dissolve them in 40mL of deionized water. Stir on a magnetic stirrer at room temperature for approximately 30 minutes to obtain a homogeneous solution. Transfer this solution to a 100mL hydrothermal autoclave and react at 140°C for 24 hours. After cooling naturally, filter the solid using a sand core funnel, wash several times with deionized water, and dry it in a freeze dryer for approximately 12 hours to obtain δM4K.

[0280] The powder X-ray diffraction pattern of δM4K shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.5, 24.5, 37.1, and 66.0. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of δM1K are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of birnessite in the δ-type crystalline form.

[0281] Preparation of potassium-type α-type crystal manganese oxide-1 (αM1K) and hydrogen-type α-type crystal manganese oxide-1 (αM1KH)

[0282] Weigh 1.264g of potassium permanganate and dissolve it in 30mL of deionized water. Weigh 0.507g of manganese sulfate monohydrate and dissolve it in 10mL of deionized water. Add the manganese sulfate solution dropwise to the vigorously stirred potassium permanganate solution. After the addition is complete, stir at room temperature for 30 minutes to form a homogeneous solution. Transfer the solution to a hydrothermal autoclave and react at 160°C for 12 hours. After cooling naturally, filter and collect the solid, wash it several times with water and ethanol, and vacuum dry it at 80°C overnight to obtain αM1K. Weigh the αM1K obtained above and place it in a beaker. Add dilute nitric acid at a ratio of 1g of αM1K to 100mL of 0.7M dilute nitric acid. Heat and stir the beaker in a 60°C waterbath for 2 hours, then cool naturally to room temperature. Filter the solid, wash it with water and ethanol, and vacuum dry it at 60°C for 24 hours to obtain αM1KH.

[0283] The powder X-ray diffraction pattern of αM1K shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.8, 18.1, 25.5, 28.7, 39.0, 42.0, 49.9, 56.4, 60.2, 65.1, 70.0, and 72.5. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of αM1K are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the α-type crystal form.

[0284] The powder X-ray diffraction pattern of αM1KH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.8, 18.1, 25.7, 28.8, 36.7, 39.0, 41.9, 49.8, 56.4, 60.1, 65.2, 70.1, and 72.7. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of αM1KH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the α-type crystalline form.

[0285] Preparation of potassium-type α-type crystalline manganese oxide-2 (αM2K) and hydrogen-type α-type crystalline manganese oxide-2 (αM2KH)

[0286] Weigh 24 mmol of potassium permanganate and dissolve it in 60 mL of deionized water. Weigh 8 mmol of manganese sulfate monohydrate and dissolve it in 60 mL of deionized water. Add the manganese sulfate solution dropwise to the vigorously stirred potassium permanganate solution. After the addition is complete, stir at room temperature for 30 minutes to form a homogeneous solution. Transfer the solution to a hydrothermal autoclave and react at 120°C for 12 hours. After cooling naturally, filter and collect the solid, wash it several times with water and ethanol, and vacuum dry it at 80°C overnight to obtain αM2K. Weigh the αM2K obtained above and place it in a beaker. Add dilute nitric acid at a ratio of 1 g of αM2K to 100 mL of 0.7 M dilute nitric acid. Place the beaker in a 60°C waterbath and heat with stirring for 1.5 hours, then cool naturally to room temperature. Filter the solid, wash it with water and ethanol, and vacuum dry it at 60°C overnight to obtain αM2KH.

[0287] The powder X-ray diffraction pattern of αM2K shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.7, 18.0, 25.4, 28.7, 39.1, 42.0, 50.0, 56.5, 60.1, 65.2, 70.1, and 72.5. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of αM2K are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the α-type crystal form.

[0288] The powder X-ray diffraction pattern of αM2KH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.7, 18.0, 25.5, 28.7, 39.1, 42.0, 50.0, 56.5, 60.1, 65.2, 70.1, and 72.5. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of αM2KH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the α-type crystalline form.

[0289] Preparation of potassium-type α-type crystal manganese oxide-3 (αM3K) and hydrogen-type α-type crystal manganese oxide-3 (αM3KH)

[0290] Weigh 10 mmol of potassium permanganate and dissolve it in 30 mL of 1.5 M sulfuric acid solution. Weigh 30 mmol of manganese sulfate monohydrate and dissolve it in 30 mL of 1.5 M sulfuric acid solution. Add the manganese sulfate solution dropwise to the vigorously stirred potassium permanganate solution. After the addition is complete, stir at room temperature for 30 minutes to form a homogeneous solution. Transfer the solution to a hydrothermal autoclave and react at 120°C for 12 hours. After cooling naturally, filter and collect the solid, wash it several times with water and ethanol, and dry it in a vacuum at 80°C overnight to obtain αM3K. Weigh the αM3K obtained above and place it in a beaker. Add dilute nitric acid at a ratio of 1 g of αM3K to 100 mL of 0.7 M dilute nitric acid. Heat and stir the beaker in a 60°C waterbath for 1.5 hours, then cool to room temperature. Filter the solid, wash it with water and ethanol, and dry it in a vacuum at 60°C overnight to obtain αM3KH.

[0291] The powder X-ray diffraction pattern of αM3K shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.7, 18.0, 25.4, 28.7, 39.2, 42.0, 50.0, 56.4, 60.1, 65.2, 70.1, and 72.5. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of αM3K are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the α-type crystal form.

[0292] The powder X-ray diffraction pattern of αM3KH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 12.7, 18.1, 25.4, 28.8, 39.1, 42.0, 50.0, 56.5, 60.0, 65.2, 70.1, and 72.5. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of αM3KH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the α-type crystalline form.

[0293] Preparation of potassium-type β-crystalline manganese oxide (βMK) and hydrogen-type β-crystalline manganese oxide-1 (βMKH)

[0294] Weigh 1 mmol of potassium permanganate and dissolve it in an appropriate amount of deionized water. Weigh 1.5 mmol of manganese sulfate monohydrate and dissolve it in an appropriate amount of deionized water. Add the manganese sulfate solution dropwise to the vigorously stirred potassium permanganate solution. After the addition is complete, stir at room temperature for 30 minutes to form a homogeneous solution (total volume 40 mL). Transfer this solution to a hydrothermal autoclave and react at 160°C for 12 hours. After cooling naturally, filter and collect the solid, wash it several times with water and ethanol, and vacuum dry it at 80°C overnight to obtain βMK. Weigh the βMK obtained above and place it in a beaker. Add dilute nitric acid solution at a ratio of 1 g of βMK to 100 mL of 0.7 M dilute nitric acid solution. Place the beaker in a 60°C water bath and heat with stirring for 2 hours, then cool naturally to room temperature. Filter the solid, wash it with water and ethanol, and vacuum dry it at 60°C for 24 hours to obtain βMKH.

[0295] The powder X-ray diffraction pattern of βMK exhibited characteristic X-ray diffraction peaks at approximately the following 2θ angles: 28.7, 37.4, 41.1, 42.9, 46.2, 56.8, 59.5, 65.0, 67.5, and 72.6. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of βMK are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the β-type crystalline form.

[0296] The powder X-ray diffraction pattern of βMKH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 28.7, 37.4, 41.1, 42.9, 46.2, 56.8, 59.5, 65.0, 67.5, and 72.6. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of βMKH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the β-type crystalline form.

[0297] Preparation of Hydrogenated β-Crystalline Manganese Oxide-2 (βMH)

[0298] Weigh β-M manganese oxide and place it in a beaker. Add dilute nitric acid at a ratio of 1 g β-M manganese oxide to 100 mL of 0.7 M dilute nitric acid. Heat and stir the beaker in a 60°C water bath for 2 hours, then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C for 12 hours to obtain β-MH.

[0299] The powder X-ray diffraction pattern of βMH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 28.7, 37.4, 41.1, 42.9, 46.2, 56.8, 59.5, 65.0, 67.5, and 72.6. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of βMH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the β-type crystalline form.

[0300] Preparation of ammonium γ-type crystal manganese oxide (γMN) and hydrogen γ-type crystal manganese oxide-1 (γMNH)

[0301] Weigh 1.69 g of manganese sulfate monohydrate and 2.28 g of ammonium persulfate and dissolve them in 40 mL of deionized water. Stir at room temperature for 30 minutes to form a colorless, transparent, homogeneous solution. Transfer the solution to a hydrothermal autoclave and react at 80°C for 24 hours. After cooling naturally, filter and collect the solid, wash it several times with water and ethanol, and vacuum dry it at 80°C overnight to obtain γMN. Weigh the γMN obtained above and place it in a beaker. Add dilute nitric acid solution at a ratio of 1 g γMN / 100 mL of 0.7 M dilute nitric acid solution. Place the beaker in a 60°C water bath and heat and stir for 2 hours, then cool naturally to room temperature. Filter the solid, wash it with water and ethanol, and vacuum dry it at 60°C for 24 hours to obtain γMNH.

[0302] The powder X-ray diffraction pattern of the γMN showed characteristic X-ray diffraction peaks at approximately the following 2θ angles: 23.0, 26.7, 34.0, 37.1, 42.5, 50.0, 56.3, 65.5, and 69.4. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of the γMN are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the γ-type crystalline form.

[0303] The powder X-ray diffraction pattern of the γMNH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 23.0, 26.7, 34.0, 37.3, 42.5, 56.3, and 65.5. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of γMNH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the γ-type crystalline form.

[0304] Preparation of Hydrogenated γ-Form Crystalline Manganese Oxide-2 (γMH)

[0305] Weigh γ-M manganese oxide and place it in a beaker. Add dilute nitric acid at a ratio of 1 g γ-M manganese oxide to 100 mL of 0.7 M dilute nitric acid. Heat and stir the beaker in a 60°C water bath for 2 hours, then cool naturally to room temperature. Filter the solid, wash with water, and vacuum dry at 60°C for 12 hours to obtain γ-MH.

[0306] The powder X-ray diffraction pattern of γMH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 23.0, 26.7, 34.0, 37.1, 42.5, 50.0, 56.4, 65.5, and 69.6. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of γMH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the γ-type crystalline form.

[0307] Preparation of Hydrogenated λ-Form Crystalline Manganese Oxide (λMLiH)

[0308] Weigh 2g of λMLi (lithium-type λ-crystalline manganese oxide, Spinel LiMn2O4) and disperse it in 0.5M aqueous sulfuric acid. Stir at room temperature for 1 hour. Filter the resulting mixture, collect the solid, wash it five times with deionized water, and dry it in an 80°C oven overnight to obtain λMLiH.

[0309] The powder X-ray diffraction pattern of λMLiH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 19.0, 37.1, 45.1, 49.5, 59.7, 65.6, and 69.1. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of λMLiH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the λ-type crystal form.

[0310] Preparation of potassium-form ε-type crystal manganese oxide (εMK) and hydrogen-form ε-type crystal manganese oxide (εMKH)

[0311] Weigh 4 mmol of potassium permanganate and dissolve it in 20 mL of deionized water to prepare a 0.2 M potassium permanganate solution. Separately, weigh 6 mmol of manganese sulfate monohydrate and dissolve it in 20 mL of deionized water to prepare a 0.3 M manganese sulfate solution. Mix the manganese sulfate solution and potassium permanganate solution, stir at room temperature for 3 hours, and filter to collect the solid. Wash the resulting solid with water five times and dry it in a 60°C oven for 12 hours to obtain εMK. Weigh the εMK obtained above and place it in a beaker. Add dilute nitric acid solution at a ratio of 1 g of εMK to 100 mL of 0.7 M dilute nitric acid solution. Place the beaker in a 60°C water bath and heat with stirring for 2 hours, then cool naturally to room temperature. Filter the solid, wash it with water five times, and dry it in a 60°C oven for 12 hours to obtain εMKH.

[0312] The powder X-ray diffraction pattern of the εMK exhibits characteristic X-ray diffraction peaks at approximately the following 2θ angles: 21.0, 37.1, 42.5, 56.0, and 66.8. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of the εMK are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the ε-type crystalline form.

[0313] The powder X-ray diffraction pattern of the εMKH exhibits characteristic X-ray diffraction peaks at approximately the following 2θ angles: 21.0, 37.1, 42.5, 56.0, and 66.8. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of εMKH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the ε-type crystalline form.

[0314] Preparation of Amorphous Manganese Oxide Potassium (AMK) and Amorphous Manganese Oxide Hydrogen (AMKH)

[0315] Weigh 1.58g of potassium permanganate and dissolve it in 60mL of deionized water to prepare a potassium permanganate solution. Weigh 2.28g of oxalic acid and dissolve it in 100mL of deionized water to prepare an oxalic acid solution. Add the potassium permanganate solution dropwise to the oxalic acid solution under magnetic stirring. Stir at room temperature for 2 hours and collect the solid by filtration. Wash the resulting solid five times with water, three times with ethanol, and dry it in a 60°C oven overnight to obtain AMK. Weigh the AMK obtained above and place it in a beaker. Add dilute nitric acid solution at a ratio of 1g AMK / 100mL of 0.7M dilute nitric acid solution. Heat and stir the beaker in a 60°C water bath for 2 hours, then cool naturally to room temperature. Filter the solid, wash it five times with water, and dry it in a 60°C oven for 12 hours to obtain AMKH.

[0316] The powder X-ray diffraction patterns of the AMK and AMKH do not show obvious characteristic X-ray diffraction peaks, which indicates that the powder X-ray diffraction patterns of AMK and AMKH are substantially consistent with the powder X-ray diffraction patterns of amorphous manganese oxide.

[0317] Preparation of hydrogen R-type crystal manganese oxide (RMH)

[0318] Weigh 3 g of λMLi (lithium-type λ-crystalline manganese oxide, Spinel LiMn2O4) and disperse it in 15 mL of 2.5 M aqueous sulfuric acid. Stir at 80°C for 2.5 hours. Centrifuge to obtain a precipitate, wash four times with ultrapure water, and dry under vacuum at 80°C overnight to obtain RMH.

[0319] The powder X-ray diffraction pattern of the RMH shows characteristic X-ray diffraction peaks at approximately the following 2θ angles: 22.0, 35.0, 36.9, 38.5, 41.2, 46.8 and 54.0. This indicates that the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of the RMH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the R-type crystal form.

[0320] Example 2 In vitro performance evaluation

[0321] In this example, the uric acid clearance effect of each test substance (ie, uric acid adsorbent) was tested under different in vitro simulated conditions to compare the performance of the insoluble manganese-containing compound according to the present disclosure with that of a control substance.

[0322] The components of human gastrointestinal fluid are very complex, and the components under different conditions (such as different parts (stomach, small intestine and large intestine), before and after eating (fasting, after eating)) vary greatly. Therefore, it is necessary to select different simulated gastrointestinal fluids according to the situation to simulate the gastrointestinal environment under different conditions. In this embodiment, the uric acid clearance capacity of each test substance in simulated intestinal fluid (SIF), simulated fasting small intestinal fluid (FaSSIF), simulated fed small intestinal fluid (FeSSIF), and food enzymatic hydrolyzate was measured respectively. Among them, SIF only simulates the common pH and main inorganic salt components of intestinal fluid, FaSSIF and FeSSIF simulate the small intestinal fluid components before and after eating (including inorganic components and organic components), respectively, and food enzymatic hydrolyzate better simulates the gastrointestinal chyme after eating different types of food. The complexity of the components of the above-mentioned several simulated fluids increases, and their closeness to the real human gastrointestinal environment also increases accordingly. The higher the complexity of the components of the simulated fluid, the greater the interference of other components on the uric acid clearance of the test substance, thereby weakening the clearance effect.

[0323] 2.1 Comparison of uric acid clearance capacity and clearance rate of each control substance and test substance in SIF assay

[0324] The specific experimental method is as follows: A fresh 500 μM uric acid solution in SIF (concentration: 8.4 mg / dL) with a pH of 6.8 and approximately 50 mM phosphate was prepared. 8 mg of each adsorbent was weighed and added to 4 mL of uric acid solution in SIF (adsorbent concentration: 2 g / L). The mixture was shaken at 200 rpm for 4 hours at 25°C. Afterwards, 1 mL of each sample was aspirated and centrifuged at 10,000 rpm for 5 minutes. The supernatant was diluted 10-fold (90 μL SIF + 10 μL supernatant) and plated onto a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. A fresh standard curve was prepared, including points at 0, 12.5, 25, 50, 100, and 500 μM. The uric acid concentration (μM) in the supernatant was calculated based on the standard curve. The uric acid clearance capacity (mg / g) was calculated according to Equation 1, and the uric acid clearance rate (%) was calculated according to Equation 2.

[0325] Formula 1: Q = 0.168*(500-C)*4 / 8

[0326] Formula 2: Uric acid clearance rate = (500-C) / 500*100%

[0327] The results are shown in Figure 1. Figure 1 shows that among various types of uric acid adsorbents, manganese oxide (δM1KH and αM3KH) and activated carbon (AST-120) have the best adsorption effect on uric acid under SIF test conditions.

[0328] 2.2 Comparison of uric acid clearance rates measured by different types of insoluble manganese-containing compounds and activated carbon adsorbents in SIF assays

[0329] The specific experimental method is as follows: a freshly prepared 500 μM uric acid SIF solution (concentration 8.4 mg / dL) with a pH of 6.8 and containing approximately 50 mM phosphate. Weigh different kinds of insoluble manganese-containing compound adsorbents (γM, γMH, βM, βMH, αM1K, αM1KH, αM2K, αM2KH, αM3K, αM3KH, βMK, βMKH, γMN, γMNH, RMH, λMLiH, εMK, εMKH, AMK, AMKH, δM1K, δM1KH, δM2KH, δM2Na, δM2NaH, δM3K, δM3KH, barium psilomelane, barium magnesium manganese ore, hydromanganite, sphene, hexagonal hydromanganite, hydromanganese ore, lithium psilomelane, sphene, sphene, bixbyite, sphene and bixbyite) and different kinds of activated carbon adsorbents (two kinds of medicinal activated carbon: Aisite and AST-120, and two kinds of activated carbon with specific surface areas of 600 m 2 / g、720m 2 / g、1045m 2 / g、1400m 2 / g、1800m2 / g and 3500m 2 / g of commercial activated carbon) were added to 20 mg each, 10 mL of uric acid SIF solution (adsorbent concentration: 2 g / L) was added, placed on a shaker, and shaken at 200 rpm for 1 hour at a temperature of 25°C. After the end, 1 mL of each sample was aspirated and centrifuged at 10,000 rpm for 5 minutes. The supernatant was diluted 10 times (90 μL SIF + 10 μL supernatant) and placed on a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. A fresh standard curve was prepared, including 0, 12.5, 25, 50, 100, and 500 μM point values. The uric acid concentration C (μM) in the supernatant was calculated according to the standard curve, and the uric acid clearance rate (%) was calculated according to Formula 2.

[0330] The results are shown in Figure 2. Figure 2 shows that under the SIF assay conditions, different types of insoluble manganese-containing compounds and different types of activated carbon all have a certain uric acid scavenging effect. Among them, various commercially available insoluble manganese-containing compounds, insoluble manganese-containing compounds prepared according to the method of Example 1, and various activated carbon adsorbents can all achieve high uric acid clearance rates. In addition, it was found that the uric acid clearance rate was changed after potassium, sodium, or ammonium manganese oxide was converted to the corresponding hydrogen manganese oxide.

[0331] 2.3 Comparison of uric acid clearance rates measured by different types of insoluble manganese-containing compounds and activated carbon adsorbents in SIF assays

[0332] The specific experimental method is as follows: A fresh 500 μM uric acid solution in SIF (8.4 mg / dL) with a pH of 6.8 and approximately 50 mM phosphate was prepared. 4 mg each of different adsorbents (δM1KH, αM3KH, δM2KH, βMKH, RMH, γMNH, λMLiH, AMKH, and AST-120) was weighed and added to 2 mL of uric acid solution in SIF (adsorbent concentration: 2 g / L). The mixture was shaken at 200 rpm at 25°C for 10 min, 30 min, 60 min, 120 min, 240 min, and then manually shaken for 5 min. Following this, the mixture was immediately filtered, and the filtrate was diluted 10-fold (90 μL SIF + 10 μL filtrate) and plated in a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. Prepare a fresh standard curve at 0, 12.5, 25, 50, 100, and 500 μM. Calculate the uric acid concentration (μM) in the supernatant based on the standard curve. Calculate the uric acid clearance (%) after different mixing times according to Equation 2. Plot a curve of uric acid clearance versus mixing time.

[0333] The results are shown in Figure 3. Figure 3 shows that the various insoluble manganese-containing compounds and activated carbon prepared according to the method of Example 1 have a relatively fast uric acid clearance rate. Both can effectively clear uric acid within 30-60 minutes and achieve the clearance of most uric acid (≥80%) in the solution system within 120 minutes.

[0334] 2.4 Comparison of uric acid clearance capacity of different types of insoluble manganese-containing compounds and activated carbon adsorbents in SIF assays

[0335] The specific experimental method is as follows: a fresh 500 μM uric acid solution (8.4 mg / dL) in SIF was prepared with a pH of 6.8 and approximately 50 mM phosphate. Different types of adsorbents (γM, γMH, βM, βMH, αM1K, αM1KH, βMK, βMKH, γMN, γMNH, δM1K, δM1KH, δM2KH, δM3K, δM3KH, λMLi, λMLiH, RMH, AMK, AMKH, εMK, εMKH, pyrolusite, pyrolusite, manganite, sphene, hexagonal manganite, hylomanganite, lithium pyrolusite, styromanganite, hylomanganite, bixbyite, sphene, AST-120) and 100 μM uric acid were weighed. 2 / g、720m 2 / g、1045m 2 / g、1400m 2 / g、1800m 2 / g and 3500m 2 / g of commercial activated carbon) were added to 40mL of uric acid SIF solution (adsorbent concentration: 0.1g / L), and placed on a shaker at 200rpm for 4h at a temperature of 37°C. After the end, 1mL of each sample was aspirated, centrifuged at 10000rpm for 5min, 100μL of the supernatant was taken, placed on a 96-well plate, and the absorbance was measured at 291nm using a microplate reader. A fresh standard curve was prepared, including 0, 100, 200, 300, 400 and 500μM point values. The uric acid concentration C (μM) in the supernatant was calculated according to the standard curve, and the uric acid clearance capacity Q (mg / g) was calculated according to Formula 3.

[0336] Formula 3: Q = 0.168 * (500 - C) * 40 / 4

[0337] The results are shown in Figure 4. Figure 4 demonstrates that, under SIF assay conditions, various types of insoluble manganese-containing compounds and activated carbon all exhibited a certain scavenging effect on uric acid. Among all types of insoluble manganese-containing compounds, the lowest scavenging capacity was approximately 10 mg / g, and the highest was approximately 800 mg / g. Among all types of activated carbon, the lowest scavenging capacity was approximately 20 mg / g, and the highest was approximately 600 mg / g. Overall, under SIF assay conditions, the scavenging capacities of insoluble manganese-containing compounds and activated carbon for uric acid were similar.

[0338] 2.5 Comparison of uric acid clearance capacity and rate of insoluble manganese-containing compounds with activated carbon adsorbents, montmorillonite, and ion exchange resins in simple simulated intestinal fluid (SIF) and complex simulated intestinal fluid (FaSSIF) and FeSSIF assays

[0339] Compared to SIF, FaSSIF and FeSSIF have more complex compositions that more closely resemble the actual in vivo environment. Under these complex conditions, the uric acid removal capacity of adsorbents is easily affected by the complex environmental components. Therefore, this example compared the uric acid removal capacity of various insoluble manganese-containing compounds with activated carbon adsorbents, montmorillonite, and ion exchange resins in SIF, FaSSIF, and FeSSIF assays to examine the impact of complex environments on the uric acid adsorption efficiency of adsorbents.

[0340] Specifically, this example is divided into two separate parts. The first part compares the uric acid clearance capacity of various insoluble manganese-containing compounds with activated carbon adsorbent (AST-120) and montmorillonite in SIF, FaSSIF or FeSSIF assays. The second part compares the uric acid clearance capacity and clearance rate of an exemplary insoluble manganese-containing compound δM4K and an ion exchange resin (sevelamer hydrochloride) in SIF, FaSSIF or FeSSIF assays.

[0341] The experimental method for the first part was as follows: A fresh 500 μM uric acid solution in SIF, FaSSIF, or FeSSIF (8.4 mg / dL) was prepared. Each 500 μM uric acid solution prepared above was diluted with SIF, FaSSIF, or FeSSIF to obtain SIF, FaSSIF, or FeSSIF solutions with uric acid concentrations of 400, 300, 200, 100, and 50 μM, respectively. The uric acid concentration was recorded as C0. 4 mg of each adsorbent (δM1KH, δM2KH, αM1KH, βMKH, γMNH, εMKH, RMH, AMKH, AST-120, and montmorillonite) was weighed and added to 40 mL of the solution with varying uric acid concentrations (adsorbent concentration: 0.1 g / L). The mixture was shaken at 200 rpm at 37°C for 4 hours. After completion, aspirate 1 mL of each sample, centrifuge at 10,000 rpm for 5 minutes, and remove 100 μL of the supernatant, place it on a 96-well plate, and measure the absorbance at 291 nm using a microplate reader. Prepare a fresh standard curve using SIF, FaSSIF, or FeSSIF, including points at 0, 100, 200, 300, 400, and 500 μM. Calculate the uric acid concentration (Ct) (μM) in the supernatant based on the standard curve, and calculate the uric acid clearance capacity (Q) (mg / g) according to Equation 4.

[0342] Formula 4: Q = 0.168*(C0-Ct)*40 / 4

[0343] The specific experimental method for the second part was as follows: A fresh 500 μM uric acid solution in SIF, FaSSIF, or FeSSIF (concentration 8.4 mg / dL) was prepared. Each of the 500 μM uric acid solutions prepared above was diluted with SIF, FaSSIF, or FeSSIF solutions to obtain SIF, FaSSIF, or FeSSIF solutions with uric acid concentrations of 500, 400, 300, 200, and 100 μM, respectively. The uric acid concentration was recorded as C0. 4 mg each of the adsorbents (δM4K and sevelamer hydrochloride) was weighed and added to 40 mL of the solutions with different uric acid concentrations (adsorbent concentration: 0.1 g / L). The mixture was shaken at 200 rpm at 37°C for 4 hours. Afterwards, 1 mL of each sample was aspirated and centrifuged at 10,000 rpm for 5 minutes. 100 μL of the supernatant was transferred to a 96-well plate and the absorbance was measured at 291 nm using a microplate reader. Prepare a fresh standard curve using SIF, FaSSIF, or FeSSIF at 0, 100, 200, 300, 400, 500, 750, and 1000 μM. Calculate the uric acid concentration (Ct) (μM) in the supernatant based on the standard curve. Calculate the uric acid clearance capacity (Q) (mg / g) according to Equation 4 and the uric acid clearance rate (%) according to Equation 5, respectively.

[0344] Formula 5: Uric acid clearance = (C0-Ct) / C0*100%

[0345] The results of the first part are shown in Figures 5, 6, and 7. Figures 5, 6, and 7 show that under SIF conditions, the equilibrium removal capacities of various insoluble manganese-containing compounds for uric acid ranged from 400 to 800 mg / g, activated carbon reached approximately 250 mg / g, and montmorillonite reached approximately 100 mg / g. Under FaSSIF conditions, the equilibrium removal capacity of δ-manganese oxide for uric acid remained at approximately 800 mg / g, while that of activated carbon and montmorillonite was approximately 0 mg / g. Under FeSSIF conditions, the equilibrium removal capacity of δ-manganese oxide for uric acid decreased slightly, but still reached approximately 600 mg / g, while that of activated carbon and montmorillonite was essentially 0 mg / g. This demonstrates that under various complex simulated intestinal fluid conditions, δ-manganese oxide retains a high adsorption capacity for uric acid, while the adsorption capacity of activated carbon and montmorillonite is essentially lost.

[0346] The results of the second part are shown in Figures 8 to 13. Figures 8 and 9 show that under the SIF assay conditions, the uric acid clearance capacity of δM4K increases with the increase in uric acid concentration. Under the condition of a uric acid concentration of 500 μM, the uric acid clearance capacity of δM4K reaches about 800 mg / g and the uric acid clearance rate is about 100%, while the uric acid clearance capacity of the ion exchange resin is only about 84 mg / g and the uric acid clearance rate is only about 10%. Figures 10 and 11 show that the uric acid clearance effect of δM4K under FaSSIF assay conditions is similar to that under SIF assay conditions. Specifically, under the condition of a uric acid concentration of 500 μM, the uric acid clearance capacity of δM4K can still reach about 750 mg / g and the uric acid clearance rate is about 90%, while the uric acid clearance capacity of the ion exchange resin is basically 0 mg / g and the uric acid clearance rate is basically 0%. Figures 12 and 13 show that the uric acid clearance activity of δM4K under FeSSIF assay conditions is similar to that under SIF assay conditions. Specifically, at a uric acid concentration of 500 μM, while the uric acid clearance capacity of δM4K decreased slightly, it still reached approximately 700 mg / g, with a uric acid clearance rate of approximately 80%. In contrast, the uric acid clearance capacity of the ion exchange resin was essentially 0 mg / g, and the uric acid clearance rate was also approximately 0%. This demonstrates that δ-manganese oxide can maintain its efficient adsorption of uric acid under various complex simulated intestinal fluid conditions, while the ion exchange resin's adsorption of uric acid is essentially lost under the same conditions.

[0347] 2.6 Comparison of the adsorption effects of different types of insoluble manganese-containing compounds and activated carbon adsorbents on uric acid in pork enzymatic hydrolysate

[0348] Pork hydrolysate is rich in various organic molecules, such as peptides, amino acids, lipids, carbohydrates, and vitamins, which can significantly interfere with the uric acid removal activity of uric acid adsorbents. Therefore, this example compared the uric acid removal capacity of various insoluble manganese-containing compounds with that of activated carbon adsorbents in pork hydrolysate assays to further examine the impact of complex environments on the adsorbent's uric acid adsorption performance.

[0349] The specific experimental method is as follows: the pork is heated and cooked, then blended in a blender, and a mixed enzymatic solution of α-amylase, amyloglucosidase, nuclease, pancreatic lipase, and trypsin is added. The mixture is enzymatically hydrolyzed at 37°C overnight to obtain a pork hydrolyzate. Uric acid (final concentration of 500 μM) and different types of adsorbents (final concentration of 0.1 g / L) are added to the pork hydrolyzate, and the mixture is placed on a shaker at 200 rpm for 4 hours at a temperature of 37°C. The supernatant is filtered to obtain the uric acid concentration C (μM) in the supernatant, and the clearance capacity Q (mg / g) is calculated according to Formula 3.

[0350] The results are shown in Figure 14. Figure 14 shows that under the pork enzymatic hydrolysate assay conditions, amorphous manganese oxide (AMKH) and delta-type manganese oxide (δM1KH and δM2KH) exhibited the best adsorption effects on uric acid, retaining a uric acid clearance capacity exceeding 200 mg / g, while the uric acid clearance effect of activated carbon (AST-120 and Aceite) completely disappeared.

[0351] 2.7 Comparison of the adsorption effects of different types of insoluble manganese-containing compound adsorbents on uric acid in food enzymatic hydrolysates

[0352] Different food enzymatic hydrolysates simulate human gastrointestinal chyme, which significantly interferes with the uric acid removal activity of uric acid adsorbents. Therefore, this example compares the uric acid removal capacity of various insoluble manganese-containing compounds measured in food enzymatic hydrolysates to further examine the impact of complex environments on the uric acid adsorption efficiency of adsorbents.

[0353] The specific experimental method is as follows: pork, rice and vegetables are heated and cooked, then blended in a blender; fruit is directly blended in a blender, and a mixed enzymatic solution of α-amylase, amyloglucosidase, nuclease, pancreatic lipase and trypsin is added. The mixture is enzymatically hydrolyzed at 37°C overnight to obtain food hydrolysates of the four foods. Uric acid (final concentration of 500 μM) and different types of insoluble manganese-containing compounds (manganese oxide) (final concentration of 0.1 g / L) are added to the four food hydrolysates, and the mixture is shaken at 200 rpm for 4 hours at a temperature of 37°C. The supernatant is filtered to obtain the uric acid concentration C (μM) in the supernatant, and the clearance capacity Q (mg / g) is calculated according to Formula 3.

[0354] The results are shown in Figure 15. Figure 15 shows that under the assay conditions of the four food enzymatic hydrolysates, different types of manganese oxide retained a high adsorption effect on uric acid, among which delta-type manganese oxide had the best effect, retaining a uric acid clearance capacity of more than 200 mg / g in the enzymatic hydrolysates of different foods.

[0355] 2.8 Comparison of uric acid clearance capacity of manganese oxide adsorbents with different salt forms in SIF assay

[0356] The purpose of this example is to investigate the effect of the type of cations incorporated into the cavities between atoms in the manganese oxide structure on the uric acid adsorption effect of the corresponding salt-type manganese oxide adsorbent.

[0357] The specific experimental method was as follows: A fresh 500 μM uric acid solution in SIF (8.4 mg / dL) was prepared at a pH of 6.8, containing approximately 50 mM phosphate. Four mg each of various manganese oxide adsorbents (δM1K, δM1KLi, δM1KH, δM1KNH4, δM1KCa, δM1KMg, δM1KFe2, δM1KFe3, δM1KZn, δM1KLa, δM1KBi, and δM1KAg) was added to 40 mL of uric acid solution in SIF (adsorbent concentration: 0.1 g / L). The mixture was shaken at 200 rpm for 4 hours at 37°C. Afterwards, 1 mL of each sample was aspirated and centrifuged at 10,000 rpm for 5 minutes. 100 μL of the supernatant was transferred to a 96-well plate, and the absorbance was measured at 291 nm using a microplate reader. Prepare a fresh standard curve at 0, 100, 200, 300, 400, and 500 μM. Calculate the uric acid concentration (C) (μM) in the supernatant based on the standard curve, and calculate the uric acid clearance capacity (Q) (mg / g) according to Equation 3.

[0358] The results are shown in Figure 16. Figure 16 demonstrates that under SIF assay conditions, manganese oxide adsorbents of varying salt types all exhibited a certain degree of uric acid scavenging activity. Among all types of manganese oxide adsorbents, the lowest scavenging capacity was approximately 500 mg / g, while the highest was approximately 800 mg / g. Overall, under SIF assay conditions, manganese oxide adsorbents of varying salt types exhibited similar uric acid scavenging capacities.

[0359] 2.9 Comparison of uric acid clearance capacity and uric acid clearance rate measured in SIF assays with different concentrations of insoluble manganese-containing compounds

[0360] The specific experimental method was as follows: A fresh 500 μM uric acid solution in SIF (8.4 mg / dL) was prepared at a pH of 6.8, containing approximately 50 mM phosphate. 2, 2.4, 2.8, 3, 3.2, 3.6, 4, 6, or 8 mg of an insoluble manganese-containing compound (δM4K) was added to 40 mL of the uric acid solution in SIF to achieve an adsorbent concentration (Cx) of 0.06, 0.07, 0.075, 0.08, 0.09, 0.1, 0.15, or 0.2 g / L, respectively. The adsorbent was shaken at 200 rpm for 4 hours at 37°C. Afterwards, 1 mL of each sample was aspirated and centrifuged at 10,000 rpm for 5 minutes. 100 μL of the supernatant was transferred to a 96-well plate and the absorbance was measured at 291 nm using a microplate reader. Prepare a fresh standard curve at 0, 100, 200, 300, 400, and 500 μM. Calculate the uric acid concentration (μM) in the supernatant based on the standard curve. Calculate the uric acid clearance capacity (mg / g) according to Equation 6 and the uric acid clearance rate (%) according to Equation 2.

[0361] Formula 6: Q = 0.168*(500-C) / Cx

[0362] The results are shown in Figures 17 and 18, respectively. Figure 17 shows that under SIF assay conditions, different concentrations of δM4K adsorbent all had a certain uric acid clearance effect, with the lowest clearance capacity being approximately 400 mg / g and the highest clearance capacity being approximately 1100 mg / g. Furthermore, the clearance capacity gradually decreased with increasing adsorbent concentration. Figure 18 shows that under SIF assay conditions, the uric acid clearance rate of different concentrations of δM4K adsorbent increased with increasing adsorbent concentration. When the adsorbent concentration reached 0.1 g / L, the uric acid clearance rate reached approximately 100%, and the uric acid clearance rate remained at approximately 100% as the adsorbent concentration continued to increase.

[0363] 2.10 Cumulative uric acid clearance capacity of insoluble manganese-containing compounds measured in multiple SIF assays

[0364] It is known that uric acid levels in the intestine are not constant. Specifically, uric acid levels vary at different intestinal locations and at different times, but generally range from 100 μM to 1300 μM. Repeated adsorption measurements of an adsorbent in low-concentration uric acid solutions (e.g., 100 μM uric acid solutions) can reveal the adsorbent's ability to continuously adsorb uric acid in low-concentration environments as it passes through the intestine.

[0365] The specific experimental method is as follows: A fresh 100 μM uric acid solution in SIF (concentration 1.68 mg / dL) with a pH of approximately 6.8 and approximately 50 mM phosphate is prepared. 4 mg of the insoluble manganese-containing compound (δM4K) is weighed and added to 40 mL of uric acid solution in SIF (adsorbent concentration: 0.1 g / L). The mixture is shaken on a shaker at 200 rpm at 37°C for 0.5 h, which counts as the first adsorption. The solid is then filtered and placed in a fresh 40 mL of 100 μM uric acid solution in SIF for a second adsorption, using the same shaking conditions. This procedure is repeated until a total of 12 adsorption cycles have been completed. After each adsorption, 1 mL of the filtrate is aspirated and centrifuged at 10,000 rpm for 5 min. 100 μL of the supernatant is then transferred to a 96-well plate and the absorbance is measured at 291 nm using a microplate reader. Prepare a fresh standard curve at 0, 25, 50, 100, 200, and 500 μM. Calculate the uric acid concentration (μM) in the supernatant based on the standard curve. Calculate the uric acid clearance capacity (mg / g) according to Equation 7 and the uric acid clearance rate (%) according to Equation 8.

[0366] Formula 7: Q = 0.168*(100-C)*40 / 4

[0367] Formula 8: Uric acid clearance rate = (100-C) / 100*100%

[0368] The results are shown in Figure 19. Figure 19 shows that in multiple adsorption measurements in SIF solutions with low uric acid concentrations, δM4K exhibited excellent uric acid scavenging effects. Specifically, at the first adsorption, the uric acid clearance capacity of δM4K was about 170 mg / g, and the uric acid clearance rate was about 100%. As the number of adsorptions continued to increase, the uric acid clearance capacity of δM4K gradually decreased. Nevertheless, even at the 12th adsorption, the uric acid clearance capacity of δM4K was still about 60 mg / g, and the cumulative uric acid clearance capacity for a total of 12 adsorptions was about 1250 mg / g. The above results indicate that δM4K has the ability to continuously adsorb uric acid at lower uric acid concentrations, and can still maintain effective uric acid adsorption after multiple adsorptions.

[0369] Example 3 Size and solubility considerations of manganese-containing compounds and calculation of safe oral doses

[0370] Manganese is an essential trace element for normal function. As a component of various enzymes, manganese plays many important physiological roles. However, excessive intake of manganese can also cause damage to the body. For example, some manganese mine workers have been reported to suffer severe neurological damage due to long-term inhalation of air containing excessive manganese levels. Inhaled manganese can be directly transported to brain tissue and can cause a permanent neurological disorder known as "manganism." Compared to inhalation, oral intake of insoluble inorganic manganese compounds such as manganese oxide is generally considered relatively safe, but excessive intake still poses a risk of severe toxicity. For example, manganese oxide with nanometer-sized particles and trace amounts of dissolved manganese ions can enter the body's circulation through the gastrointestinal tract, becoming a major source of toxicity. The magnitude of the toxic effect depends primarily on the dose of manganese absorbed.

[0371] In this example, the applicant conducted an in vitro manganese dissolution experiment in simulated gastrointestinal fluid. The solubility of various manganese oxides with particle sizes of 1 micron or larger (this size is designed to reduce the probability of nano-sized manganese-containing compounds being absorbed into the body's circulation) in simulated intestinal fluid (SIF) was measured (expressed as the manganese dissolution amount of manganese oxide in SIF measured in the "Manganese Dissolution Test Method" below) to compare the dissolution of different types of manganese oxide. Because the amount of manganese-containing compounds dissolved in gastrointestinal fluid generally determines the amount absorbed by the body, the applicant also hypothesized, based on these results, the safe dosage of each of these different types of manganese oxide for oral administration to humans.

[0372] Method of manganese dissolution test

[0373] Different types of manganese oxide from different synthesis batches were dispersed in SIF at a concentration of 2 g / L, incubated on a 37°C shaker for 4 hours, and then filtered to obtain a filtrate. The manganese content in the filtrate was measured using inductively coupled plasma mass spectrometry (ICP-MS) to obtain the manganese dissolution amount of the manganese oxide in SIF, which was set as C mg / L.

[0374] Method for calculating safe oral dose

[0375] The oral safe dose was calculated based on a tolerable upper intake level (TUIL) of 0.16 mg / kg / day or 11 mg / day (recommended by the American Society of Toxic Substances and Drug Administration (ATSDR)). It is known that approximately 9 liters of fluid (V) pass through the gastrointestinal tract daily (Kvietys, PR, and Granger, DN (2010). Role of intestinal lymphatics in interstitial volume regulation and transmucosal water transport. Annals of the New York Academy of Sciences, 1207: E29-E43. https: / / doi.org / 10.1111 / j.1749-6632.2010.05709.x). Assuming that it takes one day for manganese oxide to pass through the gastrointestinal tract and be excreted from the body, based on the amount of manganese dissolved in SIF (C mg / L) and an additional uncertainty factor (UF) of 10, the formula for calculating the safe oral dose of different types of manganese oxide can be expressed as follows:

[0376] Oral safe dose (grams) = (TUIL*2 grams) / (C*V) / UF.

[0377] The dissolution amounts of manganese of different types of manganese oxide in SIF and their respective estimated safe oral doses determined in this example are shown in the following table:

[0378] The above results show that the manganese oxides prepared by different methods have extremely low solubility in simulated intestinal fluid, which allows them to be administered at very high oral safe doses without causing unacceptable side effects.

[0379] Example 4 In vivo functional evaluation

[0380] This example compares the uric acid-lowering properties of manganese oxide and a control substance in animals.

[0381] Specifically, the test substances and control substances were administered to healthy rats, healthy mice, hyperuricemia model rats and hyperuricemia model mice, and the effect of the test substances in reducing the uric acid content in body fluids of the animals was examined.

[0382] 4.1 Healthy rat experiments

[0383] Experimental methods

[0384] Male Sprague-Dawley rats aged 7 to 8 weeks were randomly divided into five groups, each consisting of six rats: a blank group (administered with sterile water), a low-dose manganese oxide group, a medium-dose manganese oxide group, a high-dose manganese oxide group, and an ultra-high-dose manganese oxide group. From day 1 to day 7, the blank group was gavaged with sterile water daily, while the remaining treatment groups were administered a fixed dose of the test substance suspension. Uric acid levels in the rats' body fluids were measured on day 0 and day 7.

[0385] result

[0386] The rats in each treatment group tolerated the manganese oxide well and had no adverse reactions. Manganese oxide can effectively reduce the uric acid content in the rats' body fluids.

[0387] 4.2 Healthy mouse experiments

[0388] Experimental methods

[0389] Male mice aged 7 to 8 weeks were randomly divided into five groups, each consisting of six mice: a blank group (administered with sterile water), a low-dose manganese oxide group, a medium-dose manganese oxide group, a high-dose manganese oxide group, and an ultra-high-dose manganese oxide group. From day 1 to day 7, the blank group was gavaged with sterile water daily, while the remaining treatment groups were administered a fixed dose of the test substance suspension. Uric acid levels in the mice's body fluids were measured on day 0 and day 7.

[0390] result

[0391] Mice in all treatment groups tolerated the manganese oxide well, with no adverse reactions. Manganese oxide effectively reduced uric acid levels in the mice's body fluids.

[0392] 4.3 Experiments on hyperuricemia model rats

[0393] The method for establishing a hyperuricemia rat model (refer to J.Agric.Food Chem.2019,67,220-228) is: gavage with 450 mg / kg / day of potassium oxonate (physiological saline solution) + 100 mg / kg / d of adenine (physiological saline solution) for 7 days.

[0394] Experimental methods

[0395] Seven- to eight-week-old male Sprague-Dawley rats were randomly divided into nine groups, each consisting of six rats: a blank group (administered sterile water), a model group (administered only the induction drug), an activated carbon control group (administered the induction drug plus activated carbon), a montmorillonite control group (administered the induction drug plus montmorillonite), an allopurinol control group (administered the induction drug plus allopurinol), a lecithinide control group (administered the induction drug plus lecithinide), a low-dose group (administered the induction drug plus a low-dose manganese oxide), a medium-dose group (administered the induction drug plus a medium-dose manganese oxide), and a high-dose group (administered the induction drug plus a high-dose manganese oxide). The rats were gavaged daily with the corresponding drug for seven days. On the seventh day, the uric acid content in the body fluids of the hyperuricemia model rats was measured.

[0396] result

[0397] Under drug-induced conditions, uric acid levels in rat body fluids increase. However, manganese oxide can effectively reduce uric acid levels in the body fluids of rats with hyperuricemia; at some doses, the uric acid-lowering effect of manganese oxide is superior to or equivalent to that of allopurinol.

[0398] 4.4 Experiments on hyperuricemia model mice

[0399] 4.4.1 Urate oxidase knockout (UOX KO) mouse experiments

[0400] Experimental methods

[0401] Six to eight-week-old urate oxidase knockout (UOX KO) mice were taken and, after one week of adaptive feeding, urine and blood were collected to test urine uric acid and blood uric acid levels. Based on the absence of significant differences in blood uric acid levels between groups, the mice were randomly divided into five groups of nine each: a model group (administered with sterile water), a positive control group (administered with allopurinol), a low-dose group (administered with a low dose of manganese oxide), a medium-dose group (administered with a medium dose of manganese oxide), and a high-dose group (administered with a high dose of manganese oxide). Mice were gavaged daily with the corresponding drugs. Blood was collected every other week after the start of drug administration to prepare serum, and urine was collected for 24 hours. The uric acid content in the urine was measured using a uric acid detection kit.

[0402] result

[0403] UOX KO mice have elevated serum and urine uric acid levels. Allopurinol effectively reduces uric acid levels in the body fluids of UOX KO mice; at some doses, manganese oxide has a uric acid-lowering effect that is superior to or equivalent to that of allopurinol.

[0404] 4.4.2 Experiments on hyperuricemia model mice induced by potassium oxonate and adenine

[0405] It is known that potassium oxonate and adenine are model drugs that can induce hyperuricemia in mice. Specifically, potassium oxonate is a urate oxidase inhibitor, which can suppress the further metabolism of uric acid in mice, thereby increasing the concentration of uric acid in the blood of mice; Adenine can damage the kidneys, thereby reducing the excretion of uric acid from the kidneys of mice. In the present embodiment, healthy mice are randomly divided into 7 groups, by applying potassium oxonate and adenine (both of which are co-mixed in basic mouse food) to 6 groups of mice, a mouse hyperuricemia model is set up, with 1 group of healthy mice fed only with basic mouse food as a blank control group, and the corresponding experimental substance is given to each experimental group mouse according to the dosage regimen described in the following experimental method. 6 days after the start of the experiment, the 24-hour urine of each group of mice is collected and the uric acid content in urine is detected with a uric acid detection kit, to investigate the effects of various experimental substances on the amount of uric acid excreted by mice through urine.

[0406] Experimental methods

[0407] Forty-two six-week-old male KM mice were randomly divided into seven groups, with six mice in each group. The groups were: blank control group, hyperuricemia model group, allopurinol group, febuxostat group, δM1KH group, δM2KH group, and δM4K group. From the first day after the start of the experiment (i.e., the day of the experiment) to the seventh day, the blank control group was fed with a basic mouse diet, and the other groups were fed with a model mouse diet (4.4w / w% potassium oxonate and 0.44w / w% adenine were added to the basic mouse diet) to induce hyperuricemia. From the first day after the start of the experiment to the seventh day, the allopurinol group was free to drink water containing 50mg / L allopurinol every day. The febuxostat group was given febuxostat (5mg / kg / day) by gavage every day. For the δM1KH group, δM2KH group, and δM4K group, mice were fed with a medicated mouse diet (1.16 w / w% δM1KH, δM2KH, or δM4K was added to the model mouse diet, respectively). On the sixth day after the start of the experiment, the mice were placed in metabolic cages, and urine was collected for 24 hours to analyze uric acid levels. 1-2 drops of 8 mol / L NaOH aqueous solution were added to the urine collection container to prevent urate precipitation. The uric acid level in urine was measured using a uric acid content assay kit (Solarbio, Beijing, China), and the amount of uric acid excreted through urine over 24 hours was calculated based on the urine volume.

[0408] result

[0409] The results are shown in Figure 20. Figure 20 shows that after applying potassium oxonate and adenine to mice for 7 consecutive days, the amount of uric acid excreted by mice through urine increased significantly. The amount of uric acid excreted by mice that were administered allopurinol or febuxostat, respectively, was also at a higher level. In comparison, the amount of uric acid excreted by mice administered manganese oxide through urine was significantly reduced. Without being bound by any theory, it is believed that the reason why manganese oxide (e.g., delta-type manganese oxide) significantly reduces the excretion of uric acid through urine is related to its effect of significantly increasing the excretion of uric acid through the digestive tract (through feces).

[0410] 4.4.3 Uric acid-induced hyperuricemia model mouse experiment

[0411] Uric acid itself can also be used to set up a mouse hyperuricemia model. Specifically, after intraperitoneal injection, uric acid can be rapidly absorbed into the blood through the mesentery, thereby increasing the uric acid level in the blood. Therefore, intraperitoneal injection of uric acid can be used to set up a hyperuricemia model caused by non-intestinal causes. In the present embodiment, a mouse hyperuricemia model was set up by injecting uric acid into the peritoneal cavity of healthy mice (the experimental group was gavaged with manganese oxide while injecting uric acid), and the blood of mice was extracted at different times after injection to prepare serum, and the uric acid content in the serum was tested to investigate the impact of manganese oxide on the uric acid level in the blood of hyperuricemia model mice caused by non-intestinal causes.

[0412] Experimental methods

[0413] Eighteen six-week-old male KM mice were randomly divided into three groups of six: a blank control group, a hyperuricemia model group, and a δM4K group. After one week of adaptive feeding, at 9:00 AM on the day of the experiment, the blank control group received pure water orally, the hyperuricemia model group received pure water orally, and the δM4K group received 500 mg / kg of δM4K orally. The mice were fasted for 16 hours overnight. At 8:00 AM on the second day of the experiment, 100 μL of blood was collected from the retinal venous plexus of each group. Serum was separated, and serum uric acid levels were measured using a uric acid detection kit. This was recorded as the serum uric acid level at 0 minutes. At 9:00 AM, the blank control group received pure water orally and a normal saline solution was injected intraperitoneally. The hyperuricemia model group received pure water orally and a uric acid solution (1000 mg / kg) was injected intraperitoneally. The δM4K group received 500 mg / kg of δM4K orally and a uric acid solution (1000 mg / kg) was injected intraperitoneally. For each group of mice, 100 μL of blood was collected from the retinal venous plexus 15 minutes, 30 minutes, 60 minutes and 120 minutes after the injection of uric acid, and the serum was separated and the serum uric acid level was measured using a uric acid detection kit.

[0414] result

[0415] The results are shown in Figure 21. Figure 21 shows that after uric acid was injected into the peritoneal cavity of healthy mice, the serum uric acid level of the mice increased significantly. However, oral administration of manganese oxide can effectively offset the effect of intraperitoneal injection of uric acid on the serum uric acid level of mice: compared with mice not simultaneously administered manganese oxide by oral administration, oral administration of manganese oxide reduced the area under the curve (AUC) of the serum uric acid level-time curve of mice by about 40%. The above results indicate that oral administration of manganese oxide (e.g., delta-type manganese oxide) can significantly reduce the uric acid level in the blood of mice after intraperitoneal injection of uric acid, and thus can be used to treat hyperuricemia caused by non-intestinal causes.

[0416] 4.4.4 Experiments on hyperuricemia model mice induced by potassium oxonate and hypoxanthine

[0417] Hypoxanthine can be metabolized to uric acid in vivo, therefore can also be used in conjunction with potassium oxonate as a model drug for inducing hyperuricemia in mice. In the present embodiment, healthy mice are randomly divided into 7 groups, by applying potassium oxonate and hypoxanthine (by the common intraperitoneal injection of the two) to 6 groups of mice, set up mouse hyperuricemia model, with 1 group of healthy mice of only intraperitoneal injection of normal saline as blank control group, and give corresponding experimental substance to each experimental group mouse according to the dosage regimen described in the following experimental method. On the 8th day after the experiment started, the blood of each group of mice was extracted and serum was made, and the uric acid content in the serum was tested to investigate the impact of the uric acid level in the blood of the hyperuricemia model mice induced by potassium oxonate and hypoxanthine.

[0418] Experimental methods

[0419] Twenty-one six-week-old male C57BL / 6J mice were randomly divided into seven groups (three mice each): a blank control group, a hyperuricemia model group, a benzbromarone group, an allopurinol group, a δM1KH group, a δM2KH group, and a δM4K group. From day 1 to day 8 of the experiment, the blank control group received intraperitoneal injections of normal saline at 9:00 AM and 5:00 PM daily, respectively. The remaining groups received intraperitoneal injections of a modeling solution (100 mg / kg hypoxanthine and 100 mg / kg potassium oxalate) at 9:00 AM and 5:00 PM daily, respectively. The benzbromarone group received an oral gavage of a 10 mg / kg benzbromarone solution at 10:00 AM daily. The allopurinol group had free access to allopurinol-containing water (50 mg / L) daily, while the other groups had free access to normal drinking water. The δM1KH, δM2KH, and δM4K groups were given free access to a diet supplemented with δM1KH, δM2KH, or δM4K (basal diet supplemented with 1.14 w / w% δM1KH, δM2KH, or δM4K, respectively). The other groups were given a basic diet. Four hours after intraperitoneal injection at 9:00 AM on the eighth day of the experiment (i.e., at 1:00 PM), 100-200 μL of blood was collected from the retinal vein of each mouse. Serum was centrifuged and measured for serum uric acid levels using a uric acid assay kit.

[0420] result

[0421] The results are shown in Figure 22. Figure 22 shows that after potassium oxonate and hypoxanthine were administered to mice for 7 consecutive days, the serum uric acid levels of the mice increased significantly. In comparison, the administration of benzbromarone, allopurinol or manganese oxide significantly reduced the serum uric acid levels of the mice, wherein the ability of manganese oxide to reduce the serum uric acid levels of mice was better than benzbromarone and comparable to allopurinol. The above results indicate that the administration of manganese oxide (e.g., delta-type manganese oxide) can significantly reduce the increase in uric acid levels in the blood of mice induced by potassium oxonate and hypoxanthine.

[0422] 4.4.5 Experiments on hyperuricemia model mice induced by potassium oxonate and uric acid

[0423] Potassium oxonate is a urate oxidase inhibitor, can suppress the further metabolism of uric acid in mice, thus raise the concentration of uric acid in mouse blood.Using uric acid through gavage can increase the uric acid intake of intestinal tract, can also raise the uric acid level in blood.In the present embodiment, healthy mice are randomly divided into 5 groups, by using potassium oxonate (through intraperitoneal injection) and uric acid (through gavage) to healthy mice, set up mouse hyperuricemia model, with 1 group of healthy mice of only intraperitoneal injection normal saline and gavage SIF as blank control group, and give corresponding experimental substance to each experimental group mouse according to the dosage regimen described in the following experimental method.Complete gavage operation after 60 minutes, extract the blood of mouse and prepare serum, and test the uric acid content in serum, to investigate the impact of the uric acid level in the blood of the hyperuricemia model mouse of potassium oxonate and uric acid induction by various experimental substances.

[0424] Experimental methods

[0425] Thirty six-week-old male KM mice were randomly divided into five groups (n=6) each: a blank control group, a potassium oxonate group, a hyperuricemia model group, a sevelamer hydrochloride group, and a δM4K group. The blank control group received an intraperitoneal injection of normal saline followed by an immediate oral gavage of SIF. The potassium oxonate group received an intraperitoneal injection of a potassium oxonate solution (300 mg / kg) followed by an immediate oral gavage of SIF. The hyperuricemia model group received an intraperitoneal injection of a potassium oxonate solution (300 mg / kg) followed by an immediate oral gavage of a SIF solution containing uric acid (30 mg / kg). The sevelamer hydrochloride group received an intraperitoneal injection of a potassium oxonate solution (300 mg / kg) followed by an immediate oral gavage of a SIF suspension containing uric acid and sevelamer hydrochloride (30 mg / kg for uric acid and 50 mg / kg for sevelamer hydrochloride). The δM4K group received an intraperitoneal injection of potassium oxonate solution (300 mg / kg) and was immediately gavaged with a SIF suspension containing uric acid and δM4K (30 mg / kg uric acid and 50 mg / kg δM4K). The intraperitoneal injection and gavage procedures for each mouse were completed sequentially, with the first mouse undergoing the same procedure followed by the second. Venous blood was collected from each mouse 60 minutes after gavage into a microtube and centrifuged at 3000 g for 15 minutes at 4°C. Serum uric acid levels were measured using a uric acid detection kit.

[0426] result

[0427] The results are shown in Figure 23. Figure 23 shows that after administering potassium oxonate or a combination of potassium oxonate and uric acid to mice, the serum uric acid levels of the mice increased significantly. The administration of sevelamer hydrochloride had almost no effect on the serum uric acid levels of the mice. In contrast, the administration of manganese oxide significantly reduced the serum uric acid levels of the mice. The above results indicate that the administration of manganese oxide (e.g., delta-type manganese oxide) can significantly reduce the increase in uric acid levels in the blood of mice induced by potassium oxonate and uric acid.

[0428] Example 5 In vivo safety evaluation of manganese-containing compounds

[0429] Experimental methods

[0430] In this example, 8-week-old healthy C57BL / 6J mice (half male and half female) were used as model animals to evaluate the safety of in vivo administration of manganese-containing compounds. Specifically, the mice were randomly divided into a control group (administered with normal saline), a low-dose group (administered with 250 mg / kg / day of δM4K), a medium-dose group (administered with 500 mg / kg / day of δM4K), a high-dose group (administered with 1000 mg / kg / day of δM4K), and an ultra-high-dose group (administered with 2000 mg / kg / day of δM4K). The various experimental substances were then administered orally to each group of mice for 14 consecutive days according to the above-mentioned dosing regimen. During the experiment, changes in body weight (g), food intake (g), and water intake (g) of mice in each group were monitored over time. After the experiment, blood was drawn from each group of mice for blood biochemical analysis. The mice were then sacrificed, and the heart, kidney, blood cells, spleen, liver, brain, lung, and hair were isolated and the Mn content (mg / kg) was determined.

[0431] result

[0432] The results showed that during the 14-day oral administration of manganese oxide, the mice showed no abnormalities in body weight, food intake, or water intake. After the experiment, the mice's blood biochemical parameters (including WBC, RBC, HGB, W-MCR, W-LCR, W-SCC, HCT, MCV, MCH, W-MCC, W-LCC, RDW-SD, MCHC, PLT, W-SCR, and RDW-CV) and Mn content in various tissues (except the liver) were found to be no significant difference compared with the control group. Although a slight increase in liver Mn content was observed compared with the control group, further studies revealed that liver Mn content returned to the same level as the control group 7 days after drug withdrawal. This indicates that manganese oxide is poorly absorbed in mice and is rapidly cleared, with no accumulation in the body. In summary, the above results suggest that oral administration of manganese oxide (e.g., delta-type manganese oxide) has a high in vivo safety profile.

Claims

1. Use of an insoluble manganese-containing compound in the preparation of a medicament for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian individual, or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract.

2. The method of claim 1 , wherein the insoluble manganese-containing compound is a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved in 1 mL of water at saturation, as measured at about 37° C. and about 1 atmosphere.

3. The use according to claim 1 or 2, wherein the insoluble manganese-containing compound refers to a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved in 1 mL of simulated intestinal fluid (SIF) at saturation as measured at about 37°C and about 1 atmosphere.

4. The use according to any one of claims 1 to 3, wherein the insoluble manganese-containing compound refers to a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved at saturation in 1 mL of simulated fasting small intestinal fluid (FaSSIF) measured at about 37°C and about 1 atmosphere.

5. The use according to any one of claims 1 to 4, wherein the insoluble manganese-containing compound is a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved in 1 mL of simulated fed small intestinal fluid (FeSSIF) at saturation as measured at about 37°C and about 1 atmosphere.

6. The use according to any one of claims 1 to 5, wherein the insoluble manganese-containing compound is a manganese-containing compound that is absorbed into the blood circulation through the gastrointestinal tract in an amount less than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose.

7. The use according to any one of claims 1 to 6, wherein the insoluble manganese-containing compound is a manganese-containing compound that does not chemically react with surrounding substances or tissues in the body after administration or only less than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose chemically reacts with surrounding substances or tissues in the body.

8. The use according to any one of claims 1 to 7, wherein the particle size of the insoluble manganese-containing compound is ≥ 1 μm, such as from 1 μm to 1 mm.

9. The method according to claim 1, wherein the insoluble manganese-containing compound is selected from one or more of manganese oxide, manganese sulfide, manganese carbonate, manganese silicate, manganese borate, manganese ferrocyanide, manganese oxalate, manganese selenite, manganese iodate, manganese tungstate and manganese phosphate, and solvates thereof (e.g., hydrates).

10. The use according to any one of claims 1 to 9, wherein the insoluble manganese-containing compound is a manganese oxide or a solvate (e.g., a hydrate) thereof, wherein the manganese oxide is, for example, one or more selected from the following: (1) a manganese oxide consisting solely of manganese atoms and oxygen atoms, for example, a manganese oxide selected from one or more of manganese monoxide, manganese dioxide, manganese trioxide, manganese trioxide, manganese pentaoxide, manganese tetraoxide, manganese heptoxide, manganese dodecaoxide, and manganese heptadecaoxide; (2) a manganese oxide consisting solely of manganese atoms, hydrogen atoms, and oxygen atoms, for example, a manganese oxide selected from one or both of manganese oxyhydroxide and manganese hydroxide; and (3) a manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, for example, a salt-type manganese oxide.

11. The use according to any one of claims 1 to 10, wherein the salt-type manganese oxide is selected from one or more of potassium-type manganese oxide, hydrogen-type manganese oxide, ammonium-type manganese oxide, sodium-type manganese oxide, calcium-type manganese oxide, magnesium-type manganese oxide, iron-type manganese oxide, ferrous-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide.

12. The method according to claim 1 , wherein the manganese oxide is a manganese oxide in the form of a natural mineral, wherein the manganese oxide in the form of a natural mineral is, for example, selected from one or more of formosite, cryptomelane, pyrolusite, hexagonite, birnessite, buseltite, ramsdellite, psilomelane, ferromanganite, sphene, spheneite, hexagonite, harzburgite, philomena, philomena, tauromanite, sphene, harzburgite, sphene, sphene, sphene, sphene, philomena, sphene ...

13. The use according to any one of claims 1 to 12, wherein the manganese oxide is a manganese oxide in the form of a polymorph, wherein the manganese oxide in the form of a polymorph is, for example, one or more selected from α-type crystalline manganese oxide, β-type crystalline manganese oxide, γ-type crystalline manganese oxide, δ-type crystalline manganese oxide, λ-type crystalline manganese oxide, ε-type crystalline manganese oxide, R-type crystalline manganese oxide, amorphous manganese oxide, α-type crystalline manganese oxyhydroxide, β-type crystalline manganese oxyhydroxide, and γ-type crystalline manganese oxyhydroxide.

14. The use according to any one of claims 1 to 13, wherein the manganese oxide is a manganese oxide in the form of a salt polymorph, wherein the manganese oxide in the form of a salt polymorph is, for example, selected from one or more of salt-type α-type crystalline manganese oxide, salt-type β-type crystalline manganese oxide, salt-type γ-type crystalline manganese oxide, salt-type δ-type crystalline manganese oxide, salt-type λ-type crystalline manganese oxide, salt-type ε-type crystalline manganese oxide, salt-type R-type crystalline manganese oxide, and salt-type amorphous manganese oxide, and wherein the salt-type α-type crystalline manganese oxide is, for example, selected from one or both of potassium-type α-type crystalline manganese oxide and hydrogen-type α-type crystalline manganese oxide, the salt-type β-type crystalline manganese oxide is, for example, selected from one or both of potassium-type β-type crystalline manganese oxide and hydrogen-type β-type crystalline manganese oxide, the salt-type γ-type crystalline manganese oxide is, for example, selected from one or both of ammonium-type γ-type crystalline manganese oxide and hydrogen-type γ-type crystalline manganese oxide, and the salt-type δ-type crystalline manganese oxide is The manganese oxide is, for example, selected from one or more of potassium-type δ-type crystalline manganese oxide, hydrogen-type δ-type crystalline manganese oxide, sodium-type δ-type crystalline manganese oxide, ammonium-type δ-type crystalline manganese oxide, calcium-type δ-type crystalline manganese oxide, magnesium-type δ-type crystalline manganese oxide, iron-type δ-type crystalline manganese oxide, ferrous-type δ-type crystalline manganese oxide, zinc-type δ-type crystalline manganese oxide, lanthanum-type δ-type crystalline manganese oxide, bismuth-type δ-type crystalline manganese oxide, lithium-type δ-type crystalline manganese oxide, and silver-type δ-type crystalline manganese oxide. The salt-type λ-type crystalline manganese oxide is, for example, selected from one or both of lithium-type λ-type crystalline manganese oxide and hydrogen-type λ-type crystalline manganese oxide. The salt-type ε-type crystalline manganese oxide is, for example, selected from one or both of potassium-type ε-type crystalline manganese oxide and hydrogen-type ε-type crystalline manganese oxide. The salt-type R-type crystalline manganese oxide is, for example, hydrogen-type R-type crystalline manganese oxide. The salt-type amorphous manganese oxide is, for example, selected from one or both of potassium-type amorphous manganese oxide and hydrogen-type amorphous manganese oxide.

15. The use according to any one of claims 1 to 14, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 50 mg / g to about 1000 mg / g as measured in a simulated intestinal fluid (SIF) assay.

16. The use according to any one of claims 1 to 15, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 100 mg / g to about 900 mg / g as measured in a simulated intestinal fluid (SIF) assay.

17. The use according to any one of claims 1 to 16, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated intestinal fluid (SIF) assay.

18. The use according to any one of claims 1 to 17, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fasting small intestinal fluid (FaSSIF) assay.

19. The use according to any one of claims 1 to 18, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fed small intestinal fluid (FeSSIF) assay.

20. The use according to any one of claims 1 to 19, wherein the medicament is an oral preparation.

21. The use according to any one of claims 1 to 20, wherein the oral formulation is a solid oral formulation or a liquid oral formulation.

22. The use according to any one of claims 1 to 21, wherein the solid oral preparation is a powder, granules, tablet, capsule, pill or lozenge.

23. The use according to any one of claims 1 to 22, wherein the medicament does not comprise an additional therapeutic agent.

24. The use according to any one of claims 1 to 23, wherein the medicament comprises an effective amount of an insoluble manganese-containing compound.

25. The use of any one of claims 1-24, wherein the medicament comprises about 3 mg to about 3000 mg, about 3 mg to about 1500 mg, about 5 mg to about 500 mg, or about 10 mg to about 200 mg of an insoluble manganese-containing compound.

26. The use according to any one of claims 1 to 25, wherein the mammal is a human.

27. The use according to any one of claims 1 to 26, wherein the digestive tract is the intestine.

28. The method of claim 1 , wherein the disease or condition associated with elevated uric acid levels in the blood and / or digestive tract is selected from at least one of the group consisting of gout, gout complications, hyperuricemia, elevated uric acid levels that do not reach the level typically diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related conditions, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle spasms, localized swelling, joint pain, malignant tumors, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, nonalcoholic fatty liver disease, stroke, hemolytic anemia, inborn errors of metabolism, poisoning, carbuncle, and transplantation of blood, bone marrow, or solid organs.

29. The use according to any one of claims 1 to 28, wherein the gout is acute gout, chronic gout or refractory gout.

30. The use according to any one of claims 1 to 29, wherein the gout complication is at least one of gouty arthritis, gouty urinary stones and gouty nephropathy.

31. The use according to any one of claims 1 to 30, wherein the gouty nephropathy is at least one of nephritis, pyelonephritis, hydronephrosis, uric acid nephrolithiasis, renal dysfunction, renal failure and uremia.

32. The method of claim 1, wherein the cardiovascular disease is at least one of hypertension, coronary heart disease, heart failure, congenital heart disease, deep vein thrombosis, pulmonary embolism, aortic aneurysm, aortic dissection, hyperlipidemia, myocardial infarction, and atherosclerosis.

33. The use according to any one of claims 1-32, wherein the hyperuricemia is primary hyperuricemia or secondary hyperuricemia.

34. The use according to any one of claims 1 to 33, wherein the secondary hyperuricemia is at least one of drug-related hyperuricemia and hyperuricemia associated with other medical conditions.

35. The use according to any one of claims 1-34, wherein the diabetes-related condition is at least one of diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, diabetic macroangiopathy, diabetic microangiopathy, diabetic foot and diabetic ketoacidosis.

36. Use according to any one of claims 1 to 35, wherein the malignancy is a hematological malignancy.

37. The use according to any one of claims 1 to 36, wherein the hematological malignancy is at least one of leukemia and multiple myeloma.

38. The use according to any one of claims 1-37, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

39. The use according to any one of claims 1 to 38, wherein the poisoning is at least one of chloroform poisoning, carbon tetrachloride poisoning, and lead poisoning.

40. The use according to any one of claims 1 to 39, wherein the inborn error of metabolism is Lesch-Nyhan syndrome.

41. The method of any one of claims 1 to 40, wherein prior to administration of the drug to the subject, the subject's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% above 240 μmol / L, 260 μmol / L, 280 μmol / L, 300 μmol / L, 320 μmol / L, 340 μmol / L, 360 μmol / L, 380 μmol / L, 400 μmol / L or 420 μmol / L.

42. The method of any one of claims 1 to 41, wherein the individual's blood and / or serum uric acid levels are reduced by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% after administration of the drug compared to before administration of the drug.

43. The method of claim 1 , wherein the individual's blood and / or serum uric acid level after administration of the drug is between 80 μmol / L and 460 μmol / L, between 100 μmol / L and 450 μmol / L, between 150 μmol / L and 440 μmol / L, between 200 μmol / L and 430 μmol / L, between 210 μmol / L and 420 μmol / L, between 80 μmol / L and 380 μmol / L, between 100 μmol / L and 370 μmol / L, or between 150 μmol / L and 360 μmol / L.

44. Use of a manganese-containing compound in the preparation of a medicament for adsorbing uric acid in the digestive tract of a mammal.

45. The use according to claim 44, wherein the manganese-containing compound is an insoluble manganese-containing compound.

46. ​​The use of claim 44 or 45, wherein the insoluble manganese-containing compound is a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved in 1 mL of water at saturation, measured at about 37°C and about 1 atmosphere.

47. The use of any one of claims 44-46, wherein the insoluble manganese-containing compound is a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved at saturation in 1 mL of simulated intestinal fluid (SIF) measured at about 37°C and about 1 atmosphere.

48. The use of any one of claims 44-47, wherein the insoluble manganese-containing compound is less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng of the manganese-containing compound dissolved at saturation in 1 mL of simulated fasting small intestinal fluid (FaSSIF) measured at about 37°C and about 1 atmosphere.

49. The use of any one of claims 44-48, wherein the insoluble manganese-containing compound is less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng of the manganese-containing compound dissolved at saturation in 1 mL of simulated fed small intestinal fluid (FeSSIF) measured at about 37°C and about 1 atmosphere.

50. The use according to any one of claims 44 to 49, wherein the insoluble manganese-containing compound is a manganese-containing compound that is absorbed from the gastrointestinal tract into the blood circulation in an amount less than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose.

51. The use according to any one of claims 44 to 50, wherein the insoluble manganese-containing compound is a manganese-containing compound that does not chemically interact with surrounding substances or tissues in the body after administration or only has less than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose chemically interacting with surrounding substances or tissues in the body.

52. Use according to any one of claims 44 to 51, wherein the particle size of the insoluble manganese-containing compound is ≥ 1 μm, such as from 1 μm to 1 mm.

53. The use according to any one of claims 44 to 52, wherein the insoluble manganese-containing compound is selected from one or more of manganese oxide, manganese sulfide, manganese carbonate, manganese silicate, manganese borate, manganese ferrocyanide, manganese oxalate, manganese selenite, manganese iodate, manganese tungstate and manganese phosphate, and solvates thereof (e.g., hydrates).

54. The use according to any one of claims 44 to 53, wherein the insoluble manganese-containing compound is a manganese oxide or a solvate (e.g., a hydrate) thereof, wherein the manganese oxide is, for example, one or more selected from the following: (1) a manganese oxide consisting solely of manganese atoms and oxygen atoms, for example, a manganese oxide selected from one or more of manganese monoxide, manganese dioxide, manganese trioxide, manganese trioxide, manganese pentaoxide, manganese tetraoxide, manganese heptoxide, manganese dodecaoxide, and manganese trioxide; (2) a manganese oxide consisting solely of manganese atoms, hydrogen atoms, and oxygen atoms, for example, a manganese oxide selected from one or both of manganese oxyhydroxide and manganese hydroxide; and (3) a manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, for example, a salt-type manganese oxide.

55. The use according to any one of claims 44 to 54, wherein the salt-type manganese oxide is selected from one or more of potassium-type manganese oxide, hydrogen-type manganese oxide, ammonium-type manganese oxide, sodium-type manganese oxide, calcium-type manganese oxide, magnesium-type manganese oxide, iron-type manganese oxide, ferrous-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide.

56. The use according to any one of claims 44 to 55, wherein the manganese oxide is a manganese oxide in the form of a natural mineral, wherein the manganese oxide in the form of a natural mineral is, for example, selected from one or more of formosite, cryptomelane, pyrolusite, hexagonite, birnessite, buseltite, ramsdellite, psilomelane, ferromanganite, spheneite, spheneite, hexagonite, harzburgite, philomena, philomena, tauromanite, hausmannite, hausmannite, bixbyite, spheneite and harzburgite.

57. The use according to any one of claims 44 to 56, wherein the manganese oxide is a manganese oxide in the form of a polymorph, wherein the manganese oxide in the form of a polymorph is, for example, one or more selected from α-type crystalline manganese oxide, β-type crystalline manganese oxide, γ-type crystalline manganese oxide, δ-type crystalline manganese oxide, λ-type crystalline manganese oxide, ε-type crystalline manganese oxide, R-type crystalline manganese oxide, amorphous manganese oxide, α-type crystalline manganese oxyhydroxide, β-type crystalline manganese oxyhydroxide, and γ-type crystalline manganese oxyhydroxide.

58. The use according to any one of claims 44 to 57, wherein the manganese oxide is a manganese oxide in the form of a salt polymorph, wherein the manganese oxide in the form of a salt polymorph is, for example, selected from one or more of salt-type α-type crystalline manganese oxide, salt-type β-type crystalline manganese oxide, salt-type γ-type crystalline manganese oxide, salt-type δ-type crystalline manganese oxide, salt-type λ-type crystalline manganese oxide, salt-type ε-type crystalline manganese oxide, salt-type R-type crystalline manganese oxide, and salt-type amorphous manganese oxide, and wherein the salt-type α-type crystalline manganese oxide is, for example, selected from one or both of potassium-type α-type crystalline manganese oxide and hydrogen-type α-type crystalline manganese oxide, the salt-type β-type crystalline manganese oxide is, for example, selected from one or both of potassium-type β-type crystalline manganese oxide and hydrogen-type β-type crystalline manganese oxide, the salt-type γ-type crystalline manganese oxide is, for example, selected from one or both of ammonium-type γ-type crystalline manganese oxide and hydrogen-type γ-type crystalline manganese oxide, and the salt-type δ-type crystalline manganese oxide is The manganese oxide is, for example, selected from one or more of potassium-type δ-type crystalline manganese oxide, hydrogen-type δ-type crystalline manganese oxide, sodium-type δ-type crystalline manganese oxide, ammonium-type δ-type crystalline manganese oxide, calcium-type δ-type crystalline manganese oxide, magnesium-type δ-type crystalline manganese oxide, iron-type δ-type crystalline manganese oxide, ferrous-type δ-type crystalline manganese oxide, zinc-type δ-type crystalline manganese oxide, lanthanum-type δ-type crystalline manganese oxide, bismuth-type δ-type crystalline manganese oxide, lithium-type δ-type crystalline manganese oxide, and silver-type δ-type crystalline manganese oxide. The salt-type λ-type crystalline manganese oxide is, for example, selected from one or both of lithium-type λ-type crystalline manganese oxide and hydrogen-type λ-type crystalline manganese oxide. The salt-type ε-type crystalline manganese oxide is, for example, selected from one or both of potassium-type ε-type crystalline manganese oxide and hydrogen-type ε-type crystalline manganese oxide. The salt-type R-type crystalline manganese oxide is, for example, hydrogen-type R-type crystalline manganese oxide. The salt-type amorphous manganese oxide is, for example, selected from one or both of potassium-type amorphous manganese oxide and hydrogen-type amorphous manganese oxide.

59. The use according to any one of claims 44-58, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 50 mg / g to about 1000 mg / g as measured in a simulated intestinal fluid (SIF) assay.

60. The use according to any one of claims 44-59, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 100 mg / g to about 900 mg / g as measured in a simulated intestinal fluid (SIF) assay.

61. The use according to any one of claims 44-60, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated intestinal fluid (SIF) assay.

62. The use according to any one of claims 44-61, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fasting small intestinal fluid (FaSSIF) assay.

63. The use according to any one of claims 44-62, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fed small intestinal fluid (FeSSIF) assay.

64. The use according to any one of claims 44 to 63, wherein the medicament is an oral formulation.

65. The use according to any one of claims 44-64, wherein the oral formulation is a solid oral formulation or a liquid oral formulation.

66. The use according to any one of claims 44-65, wherein the solid oral dosage form is a powder, granules, tablet, capsule, pill or lozenge.

67. The use according to any one of claims 44 to 66, wherein the medicament does not comprise an additional therapeutic agent.

68. The use according to any one of claims 44 to 67, wherein the medicament comprises an effective amount of an insoluble manganese-containing compound.

69. The use of any one of claims 44-68, wherein the medicament comprises about 3 mg to about 3000 mg, about 3 mg to about 1500 mg, about 5 mg to about 500 mg, or about 10 mg to about 200 mg of the insoluble manganese-containing compound.

70. The use according to any one of claims 44-69, wherein the mammal is a human.

71. The use according to any one of claims 44-70, wherein the digestive tract is the intestine.

72. A pharmaceutical composition for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian subject, or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract, wherein the pharmaceutical composition comprises an insoluble manganese-containing compound and a pharmaceutically acceptable excipient.

73. The pharmaceutical composition of claim 71 , wherein the insoluble manganese-containing compound is a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved in 1 mL of water at saturation as measured at about 37° C. and about 1 atmosphere.

74. The pharmaceutical composition of claim 72 or 73, wherein the insoluble manganese-containing compound is less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng of the manganese-containing compound dissolved at saturation in 1 mL of simulated intestinal fluid (SIF) measured at about 37°C and about 1 atmosphere.

75. The pharmaceutical composition of any one of claims 72-74, wherein the insoluble manganese-containing compound refers to a mass of the manganese-containing compound that is dissolved at saturation in 1 mL of simulated fasting small intestinal fluid (FaSSIF) measured at about 37°C and about 1 atmosphere of pressure less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng.

76. The pharmaceutical composition of any one of claims 72-75, wherein the insoluble manganese-containing compound is less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng of the manganese-containing compound dissolved at saturation in 1 mL of simulated fed small intestinal fluid (FeSSIF) measured at about 37°C and about 1 atmosphere of pressure.

77. The pharmaceutical composition of any one of claims 72-76, wherein the insoluble manganese-containing compound is a manganese-containing compound that is absorbed into the blood circulation through the gastrointestinal tract in an amount less than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose.

78. The pharmaceutical composition of any one of claims 72-77, wherein the insoluble manganese-containing compound is a manganese-containing compound that does not chemically interact with surrounding substances or tissues in the body after administration or only has less than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose chemically interacting with surrounding substances or tissues in the body.

79. The pharmaceutical composition according to any one of claims 72 to 78, wherein the particle size of the insoluble manganese-containing compound is ≥ 1 μm, such as from 1 μm to 1 mm.

80. The pharmaceutical composition of any one of claims 72-79, wherein the insoluble manganese-containing compound is selected from one or more of manganese oxide, manganese sulfide, manganese carbonate, manganese silicate, manganese borate, manganese ferrocyanide, manganese oxalate, manganese selenite, manganese iodate, manganese tungstate and manganese phosphate, and solvates thereof (e.g., hydrates).

81. The pharmaceutical composition according to any one of claims 72 to 80, wherein the insoluble manganese-containing compound is a manganese oxide or a solvate (e.g., a hydrate) thereof, wherein the manganese oxide is, for example, selected from one or more of the following: (1) a manganese oxide consisting solely of manganese atoms and oxygen atoms, for example, a manganese oxide selected from one or more of manganese monoxide, manganese dioxide, manganese trioxide, manganese trioxide, manganese pentaoxide, manganese tetraoxide, manganese heptoxide, manganese dodecaoxide, and manganese heptadecaoxide; (2) a manganese oxide consisting solely of manganese atoms, hydrogen atoms, and oxygen atoms, for example, a manganese oxide selected from one or both of manganese oxyhydroxide and manganese hydroxide; and (3) a manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, for example, a salt-type manganese oxide.

82. The pharmaceutical composition according to any one of claims 72 to 81, wherein the salt-type manganese oxide is selected from one or more of potassium-type manganese oxide, hydrogen-type manganese oxide, ammonium-type manganese oxide, sodium-type manganese oxide, calcium-type manganese oxide, magnesium-type manganese oxide, iron-type manganese oxide, ferrous-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide.

83. The pharmaceutical composition of any one of claims 72 to 82, wherein the manganese oxide is a manganese oxide in the form of a natural mineral, wherein the manganese oxide in the form of a natural mineral is, for example, selected from one or more of formosite, cryptomelane, pyrolusite, hexagonite, birnessite, buseltite, ramsdellite, psilomelane, ferromanganite, sphene, spheneite, hexagonite, harzburgite, philomena, tauromanite, hausmannite, hausmannite, harzburgite, sphene ...

84. The pharmaceutical composition according to any one of claims 72-83, wherein the manganese oxide is a manganese oxide in the form of a polymorph, wherein the manganese oxide in the form of a polymorph is, for example, one or more selected from α-type crystalline manganese oxide, β-type crystalline manganese oxide, γ-type crystalline manganese oxide, δ-type crystalline manganese oxide, λ-type crystalline manganese oxide, ε-type crystalline manganese oxide, R-type crystalline manganese oxide, amorphous manganese oxide, α-type crystalline manganese oxyhydroxide, β-type crystalline manganese oxyhydroxide, and γ-type crystalline manganese oxyhydroxide.

85. The pharmaceutical composition according to any one of claims 72 to 84, wherein the manganese oxide is a manganese oxide in the form of a salt polymorph, wherein the manganese oxide in the form of a salt polymorph is, for example, selected from one or more of salt-type α-type crystalline manganese oxide, salt-type β-type crystalline manganese oxide, salt-type γ-type crystalline manganese oxide, salt-type δ-type crystalline manganese oxide, salt-type λ-type crystalline manganese oxide, salt-type ε-type crystalline manganese oxide, salt-type R-type crystalline manganese oxide, and salt-type amorphous manganese oxide, and wherein the salt-type α-type crystalline manganese oxide is, for example, selected from one or both of potassium-type α-type crystalline manganese oxide and hydrogen-type α-type crystalline manganese oxide, the salt-type β-type crystalline manganese oxide is, for example, selected from one or both of potassium-type β-type crystalline manganese oxide and hydrogen-type β-type crystalline manganese oxide, the salt-type γ-type crystalline manganese oxide is, for example, selected from one or both of ammonium-type γ-type crystalline manganese oxide and hydrogen-type γ-type crystalline manganese oxide, and the salt-type δ-type The crystalline manganese oxide is, for example, one or more selected from potassium-type δ-type crystalline manganese oxide, hydrogen-type δ-type crystalline manganese oxide, sodium-type δ-type crystalline manganese oxide, ammonium-type δ-type crystalline manganese oxide, calcium-type δ-type crystalline manganese oxide, magnesium-type δ-type crystalline manganese oxide, iron-type δ-type crystalline manganese oxide, ferrous-type δ-type crystalline manganese oxide, zinc-type δ-type crystalline manganese oxide, lanthanum-type δ-type crystalline manganese oxide, bismuth-type δ-type crystalline manganese oxide, lithium-type δ-type crystalline manganese oxide, and silver-type δ-type crystalline manganese oxide. The salt-type λ-type crystalline manganese oxide is, for example, one or both selected from lithium-type λ-type crystalline manganese oxide and hydrogen-type λ-type crystalline manganese oxide. The salt-type ε-type crystalline manganese oxide is, for example, one or both selected from potassium-type ε-type crystalline manganese oxide and hydrogen-type ε-type crystalline manganese oxide. The salt-type R-type crystalline manganese oxide is, for example, hydrogen-type R-type crystalline manganese oxide. The salt-type amorphous manganese oxide is, for example, one or both selected from potassium-type amorphous manganese oxide and hydrogen-type amorphous manganese oxide.

86. The pharmaceutical composition of any one of claims 72-85, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 50 mg / g to about 1000 mg / g as measured in a simulated intestinal fluid (SIF) assay.

87. The pharmaceutical composition of any one of claims 72-86, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 100 mg / g to about 900 mg / g as measured in a simulated intestinal fluid (SIF) assay.

88. The pharmaceutical composition of any one of claims 72-87, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated intestinal fluid (SIF) assay.

89. The pharmaceutical composition of any one of claims 72-88, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fasting small intestinal fluid (FaSSIF) assay.

90. The pharmaceutical composition of any one of claims 72-89, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fed small intestinal fluid (FeSSIF) assay.

91. The pharmaceutical composition of any one of claims 72-90, wherein the pharmaceutical composition is an oral formulation.

92. The pharmaceutical composition of any one of claims 72-91, wherein the oral formulation is a solid oral formulation or a liquid oral formulation.

93. The pharmaceutical composition of any one of claims 72-92, wherein the solid oral dosage form is a powder, granules, tablet, capsule, pill or lozenge.

94. The pharmaceutical composition of any one of claims 72-93, wherein the pharmaceutical composition does not comprise an additional therapeutic agent.

95. The pharmaceutical composition of any one of claims 72-94, wherein the pharmaceutical composition comprises an effective amount of an insoluble manganese-containing compound.

96. The pharmaceutical composition of any one of claims 72-95, wherein the pharmaceutical composition comprises about 3 mg to about 3000 mg, about 3 mg to about 1500 mg, about 5 mg to about 500 mg, or about 10 mg to about 200 mg of an insoluble manganese-containing compound.

97. The pharmaceutical composition of any one of claims 72-96, wherein the mammal is a human.

98. The pharmaceutical composition of any one of claims 72-97, wherein the digestive tract is the intestine.

99. The pharmaceutical composition of any one of claims 72-98, wherein the disease or condition associated with elevated uric acid levels in the blood and / or digestive tract is selected from at least one of the group consisting of gout, gout complications, hyperuricemia, elevated uric acid levels that do not reach the level typically diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related conditions, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle spasms, localized swelling, joint pain, malignant tumors, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, nonalcoholic fatty liver disease, stroke, hemolytic anemia, inborn errors of metabolism, poisoning, carbuncle, and transplantation of blood, bone marrow, or a solid organ.

100. The pharmaceutical composition of any one of claims 72-99, wherein the gout is acute gout, chronic gout, or refractory gout.

101. The pharmaceutical composition of any one of claims 72-100, wherein the gout complication is at least one of gouty arthritis, gouty urinary stones, and gouty nephropathy.

102. The pharmaceutical composition according to any one of claims 72-101, wherein the gouty nephropathy is at least one of nephritis, pyelonephritis, hydronephrosis, uric acid nephrolithiasis, renal dysfunction, renal failure and uremia.

103. The pharmaceutical composition of any one of claims 72-102, wherein the cardiovascular disease is at least one of hypertension, coronary heart disease, heart failure, congenital heart disease, deep vein thrombosis, pulmonary embolism, aortic aneurysm, aortic dissection, hyperlipidemia, myocardial infarction, and atherosclerosis.

104. The pharmaceutical composition according to any one of claims 72-103, wherein the hyperuricemia is primary hyperuricemia or secondary hyperuricemia.

105. The pharmaceutical composition according to any one of claims 72-104, wherein the secondary hyperuricemia is at least one of drug-related hyperuricemia and hyperuricemia associated with other medical conditions.

106. The pharmaceutical composition of any one of claims 72-105, wherein the diabetes-related condition is at least one of diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, diabetic macroangiopathy, diabetic microangiopathy, diabetic foot, and diabetic ketoacidosis.

107. The pharmaceutical composition of any one of claims 72-106, wherein the malignancy is a hematological malignancy.

108. The pharmaceutical composition of any one of claims 72-107, wherein the hematological malignancy is at least one of leukemia and multiple myeloma.

109. The pharmaceutical composition of any one of claims 72-108, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

110. The pharmaceutical composition of any one of claims 72-109, wherein the poisoning is at least one of chloroform poisoning, carbon tetrachloride poisoning, and lead poisoning.

111. The pharmaceutical composition of any one of claims 72-110, wherein the inborn error of metabolism is Lesch-Nyhan syndrome.

112. The pharmaceutical composition of any one of claims 72-111, wherein prior to administering the pharmaceutical composition to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 240 μmol / L, 260 μmol / L, 280 μmol / L, 300 μmol / L, 320 μmol / L, 340 μmol / L, 360 μmol / L, 380 μmol / L, 400 μmol / L, or 420 μmol / L.

113. The pharmaceutical composition of any one of claims 72-112, wherein the individual's blood and / or serum uric acid levels are reduced by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% after administration of the pharmaceutical composition compared to before administration of the pharmaceutical composition.

114. The pharmaceutical composition of any one of claims 72-113, wherein the individual's blood and / or serum uric acid level after administration of the pharmaceutical composition is between 80 μmol / L and 460 μmol / L, between 100 μmol / L and 450 μmol / L, between 150 μmol / L and 440 μmol / L, between 200 μmol / L and 430 μmol / L, between 210 μmol / L and 420 μmol / L, between 80 μmol / L and 380 μmol / L, between 100 μmol / L and 370 μmol / L, or between 150 μmol / L and 360 μmol / L.

115. A kit comprising: (i) a pharmaceutical composition according to any one of claims 72 to 114; and (ii) Drug inserts and / or drug labels.

116. A method for preventing and / or treating elevated uric acid levels in the blood and / or digestive tract of a mammalian subject, or a disease or condition associated with elevated uric acid levels in the blood and / or digestive tract, comprising administering to the subject in need thereof an effective amount of an insoluble manganese-containing compound.

117. A method for preventing and / or treating elevated blood uric acid levels or a disease or condition associated with elevated blood uric acid levels in a mammalian subject, comprising administering to the subject in need thereof an effective amount of an insoluble manganese-containing compound over an extended period of time.

118. A method for maintaining blood uric acid levels in a mammalian subject comprising administering to the subject in need thereof an effective amount of an insoluble manganese-containing compound over an extended period of time.

119. The method of any one of claims 116-118, wherein the method maintains the individual's blood and / or serum uric acid level between 80 μmol / L and 460 μmol / L, between 100 μmol / L and 450 μmol / L, between 150 μmol / L and 440 μmol / L, between 200 μmol / L and 430 μmol / L, between 210 μmol / L and 420 μmol / L, between 80 μmol / L and 380 μmol / L, between 100 μmol / L and 370 μmol / L, or between 150 μmol / L and 360 μmol / L.

120. The method of any one of claims 116-119, wherein the insoluble manganese-containing compound is a manganese-containing compound having a mass of less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng dissolved in 1 mL of water at saturation as measured at about 37°C and about 1 atmosphere.

121. The method of any one of claims 116-120, wherein the insoluble manganese-containing compound is less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng of the manganese-containing compound dissolved at saturation in 1 mL of simulated intestinal fluid (SIF) measured at about 37°C and about 1 atmosphere.

122. The method of any one of claims 116-121, wherein the insoluble manganese-containing compound is less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng of the manganese-containing compound dissolved at saturation in 1 mL of simulated fasting small intestinal fluid (FaSSIF) measured at about 37°C and about 1 atmosphere of pressure.

123. The method of any one of claims 116-122, wherein the insoluble manganese-containing compound is less than about 100 μg, 75 μg, 50 μg, 40 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, 1 μg, 750 ng, 500 ng, 400 ng, 300 ng, 250 ng, 200 ng, 150 ng, 100 ng, 75 ng, 50 ng, 40 ng, 30 ng, 25 ng, 20 ng, 15 ng, 10 ng, 5 ng or 1 ng of the manganese-containing compound dissolved at saturation in 1 mL of simulated fed small intestinal fluid (FeSSIF) measured at about 37°C and about 1 atmosphere of pressure.

124. The method of any one of claims 116-123, wherein the insoluble manganese-containing compound is a manganese-containing compound that is absorbed from the gastrointestinal tract into the blood circulation in an amount less than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose.

125. The method of any one of claims 116-124, wherein the insoluble manganese-containing compound is a manganese-containing compound that, after administration, does not chemically interact with surrounding materials or tissues in the body or only about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% of the administered dose chemically interacts with surrounding materials or tissues in the body.

126. The method according to any one of claims 116 to 125, wherein the particle size of the insoluble manganese-containing compound is ≥ 1 μm, such as from 1 μm to 1 mm.

127. The method of any one of claims 116 to 126, wherein the insoluble manganese-containing compound is selected from one or more of manganese oxide, manganese sulfide, manganese carbonate, manganese silicate, manganese borate, manganese ferrocyanide, manganese oxalate, manganese selenite, manganese iodate, manganese tungstate and manganese phosphate, and solvates thereof (e.g., hydrates).

128. The method according to any one of claims 116 to 127, wherein the insoluble manganese-containing compound is a manganese oxide or a solvate (e.g., a hydrate) thereof, wherein the manganese oxide is, for example, one or more selected from the following: (1) a manganese oxide consisting solely of manganese atoms and oxygen atoms, for example, a manganese oxide selected from one or more of manganese monoxide, manganese dioxide, manganese trioxide, manganese trioxide, manganese pentaoxide, manganese tetraoxide, manganese heptoxide, manganese dodecaoxide, and manganese heptadecaoxide; (2) a manganese oxide consisting solely of manganese atoms, hydrogen atoms, and oxygen atoms, for example, a manganese oxide selected from one or both of manganese oxyhydroxide and manganese hydroxide; and (3) a manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, for example, a salt-type manganese oxide.

129. The method according to any one of claims 116 to 128, wherein the salt-type manganese oxide is selected from one or more of potassium-type manganese oxide, hydrogen-type manganese oxide, ammonium-type manganese oxide, sodium-type manganese oxide, calcium-type manganese oxide, magnesium-type manganese oxide, iron-type manganese oxide, ferrous-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide.

130. The method according to any one of claims 116 to 129, wherein the manganese oxide is a manganese oxide in the form of a natural mineral, wherein the manganese oxide in the form of a natural mineral is, for example, selected from one or more of formosite, cryptomelane, pyrolusite, hexagonite, birnessite, buseltite, ramsdellite, psilomelane, ferromanganite, spheneite, spheneite, hexagonite, harzburgite, philomena, philomena, taurine, hausmannite, hausmannite, harzburgite, spheneite and spheneite.

131. The method of any one of claims 116 to 130, wherein the manganese oxide is a manganese oxide in the form of a polymorph, wherein the manganese oxide in the form of a polymorph is, for example, selected from one or more of α-type crystalline manganese oxide, β-type crystalline manganese oxide, γ-type crystalline manganese oxide, δ-type crystalline manganese oxide, λ-type crystalline manganese oxide, ε-type crystalline manganese oxide, R-type crystalline manganese oxide, amorphous manganese oxide, α-type crystalline manganese oxyhydroxide, β-type crystalline manganese oxyhydroxide, and γ-type crystalline manganese oxyhydroxide.

132. The method according to any one of claims 116 to 131, wherein the manganese oxide is a manganese oxide in the form of a salt polymorph, wherein the manganese oxide in the form of a salt polymorph is, for example, selected from one or more of salt-type α-type crystalline manganese oxide, salt-type β-type crystalline manganese oxide, salt-type γ-type crystalline manganese oxide, salt-type δ-type crystalline manganese oxide, salt-type λ-type crystalline manganese oxide, salt-type ε-type crystalline manganese oxide, salt-type R-type crystalline manganese oxide, and salt-type amorphous manganese oxide, and wherein the salt-type α-type crystalline manganese oxide is, for example, selected from one or both of potassium-type α-type crystalline manganese oxide and hydrogen-type α-type crystalline manganese oxide, the salt-type β-type crystalline manganese oxide is, for example, selected from one or both of potassium-type β-type crystalline manganese oxide and hydrogen-type β-type crystalline manganese oxide, the salt-type γ-type crystalline manganese oxide is, for example, selected from one or both of ammonium-type γ-type crystalline manganese oxide and hydrogen-type γ-type crystalline manganese oxide, and the salt-type δ-type The crystalline manganese oxide is, for example, one or more selected from potassium-type δ-type crystalline manganese oxide, hydrogen-type δ-type crystalline manganese oxide, sodium-type δ-type crystalline manganese oxide, ammonium-type δ-type crystalline manganese oxide, calcium-type δ-type crystalline manganese oxide, magnesium-type δ-type crystalline manganese oxide, iron-type δ-type crystalline manganese oxide, ferrous-type δ-type crystalline manganese oxide, zinc-type δ-type crystalline manganese oxide, lanthanum-type δ-type crystalline manganese oxide, bismuth-type δ-type crystalline manganese oxide, lithium-type δ-type crystalline manganese oxide, and silver-type δ-type crystalline manganese oxide. The salt-type λ-type crystalline manganese oxide is, for example, one or both selected from lithium-type λ-type crystalline manganese oxide and hydrogen-type λ-type crystalline manganese oxide. The salt-type ε-type crystalline manganese oxide is, for example, one or both selected from potassium-type ε-type crystalline manganese oxide and hydrogen-type ε-type crystalline manganese oxide. The salt-type R-type crystalline manganese oxide is, for example, hydrogen-type R-type crystalline manganese oxide. The salt-type amorphous manganese oxide is, for example, one or both selected from potassium-type amorphous manganese oxide and hydrogen-type amorphous manganese oxide.

133. The method of any one of claims 116-132, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 50 mg / g to about 1000 mg / g as measured in a simulated intestinal fluid (SIF) assay.

134. The method of any one of claims 116-133, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 100 mg / g to about 900 mg / g as measured in a simulated intestinal fluid (SIF) assay.

135. The method of any one of claims 116-134, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated intestinal fluid (SIF) assay.

136. The method of any one of claims 116-135, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fasting small intestinal fluid (FaSSIF) assay.

137. The method of any one of claims 116-136, wherein the insoluble manganese-containing compound has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fed small intestinal fluid (FeSSIF) assay.

138. The method of any one of claims 116-137, wherein the effective amount is about 3 mg to about 3000 mg of manganese oxide per day.

139. The method of any one of claims 116-138, wherein the effective amount is about 3 mg to about 1500 mg of manganese oxide per day.

140. The method of any one of claims 116-139, wherein the effective amount is about 5 mg to about 500 mg of manganese oxide per day.

141. The method of any one of claims 116-140, wherein the effective amount is about 10 mg to about 200 mg of manganese oxide per day.

142. The method of any one of claims 116-141, wherein the insoluble manganese-containing compound is administered orally.

143. The method of any one of claims 116-142, wherein the insoluble manganese-containing compound is formulated as an oral formulation.

144. The method of any one of claims 116-143, wherein the oral dosage form is a solid oral dosage form or a liquid oral dosage form.

145. The method of any one of claims 116-144, wherein the solid oral dosage form is a powder, granules, tablet, capsule, pill, or lozenge.

146. The method of any one of claims 116-145, wherein the oral formulation comprises an effective amount of an insoluble manganese-containing compound.

147. The method of any one of claims 116-146, wherein the oral formulation comprises about 3 mg to about 3000 mg, about 3 mg to about 1500 mg, about 5 mg to about 500 mg, or about 10 mg to about 200 mg of an insoluble manganese-containing compound.

148. The method of any one of claims 116-147, wherein the insoluble manganese-containing compound is administered to the subject once, twice, or more daily.

149. The method of any one of claims 116-148, wherein the administration continues for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 4 years, 5 years, 10 years or longer.

150. The method of any one of claims 116-149, wherein the extended period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 4 years, 5 years, 10 years or longer.

151. The method of any one of claims 116-150, wherein the insoluble manganese-containing compound and food are taken simultaneously or with an interval of less than 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes.

152. The method of any one of claims 116-151, wherein the insoluble manganese-containing compound is taken 30 min, 40 min, 50 min, 1 h, 1.5 h, 2 h or more after eating.

153. The method of any one of claims 116-152, wherein the mammal is a human.

154. The method of any one of claims 116-153, wherein the digestive tract is the intestine.

155. The method of any one of claims 116-154, wherein the disease or condition associated with elevated uric acid levels in the blood and / or digestive tract is selected from at least one of the group consisting of gout, gout complications, hyperuricemia, elevated uric acid levels that do not reach the level typically diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related conditions, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle spasms, localized swelling, joint pain, malignancy, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, nonalcoholic fatty liver disease, stroke, hemolytic anemia, inborn errors of metabolism, poisoning, carbuncle, and transplantation of blood, bone marrow, or solid organs.

156. The method of any one of claims 116-155, wherein the gout is acute gout, chronic gout, or refractory gout.

157. The method of any one of claims 116-156, wherein the gout complication is at least one of gouty arthritis, gouty urinary stones, and gouty nephropathy.

158. The method of any one of claims 116-157, wherein the gouty nephropathy is at least one of nephritis, pyelonephritis, hydronephrosis, uric acid nephrolithiasis, renal dysfunction, renal failure, and uremia.

159. The method of any one of claims 116-158, wherein the cardiovascular disease is at least one of hypertension, coronary heart disease, heart failure, congenital heart disease, deep vein thrombosis, pulmonary embolism, aortic aneurysm, aortic dissection, hyperlipidemia, myocardial infarction, and atherosclerosis.

160. The method of any one of claims 116-159, wherein the hyperuricemia is primary hyperuricemia or secondary hyperuricemia.

161. The method of any one of claims 116-160, wherein the secondary hyperuricemia is at least one of drug-related hyperuricemia and hyperuricemia associated with other medical conditions.

162. The method of any one of claims 116-161, wherein the diabetes-related condition is at least one of diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, diabetic macroangiopathy, diabetic microangiopathy, diabetic foot, and diabetic ketoacidosis.

163. The method of any one of claims 116-162, wherein the malignancy is a hematological malignancy.

164. The method of any one of claims 116-163, wherein the hematological malignancy is at least one of leukemia and multiple myeloma.

165. The method of any one of claims 116-164, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

166. The method of any one of claims 116-165, wherein the poisoning is at least one of chloroform poisoning, carbon tetrachloride poisoning, and lead poisoning.

167. The method of any one of claims 116-166, wherein the inborn error of metabolism is Lesch-Nyhan syndrome.

168. The method of any one of claims 116-167, wherein prior to administering the insoluble manganese-containing compound to the individual, the individual's blood and / or serum uric acid level is at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% above 240 μmol / L, 260 μmol / L, 280 μmol / L, 300 μmol / L, 320 μmol / L, 340 μmol / L, 360 μmol / L, 380 μmol / L, 400 μmol / L, or 420 μmol / L.

169. The method of any one of claims 116-168, wherein the individual's blood and / or serum uric acid levels are reduced by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% after administration of the insoluble manganese-containing compound compared to before administration of the insoluble manganese-containing compound.

170. The method of any one of claims 116-169, wherein the individual's blood and / or serum uric acid level after administration of the insoluble manganese-containing compound is between 80 μmol / L and 460 μmol / L, between 100 μmol / L and 450 μmol / L, between 150 μmol / L and 440 μmol / L, between 200 μmol / L and 430 μmol / L, between 210 μmol / L and 420 μmol / L, between 80 μmol / L and 380 μmol / L, between 100 μmol / L and 370 μmol / L, or between 150 μmol / L and 360 μmol / L.

171. A pharmaceutical composition comprising manganese oxide, wherein the amount of manganese oxide is sufficient to reduce the blood and / or serum uric acid levels in at least about 10% of mammalian subjects whose blood and / or serum uric acid levels are above 360 ​​μmol / L or 420 μmol / L by at least about 5% within 24 hours after administration of the pharmaceutical composition.

172. The pharmaceutical composition according to claim 171, wherein the particle size of the manganese oxide is ≥ 1 μm, such as 1 μm to 1 mm.

173. The pharmaceutical composition according to claim 171 or 172, wherein the manganese oxide is selected from one or more of the following: (1) a manganese oxide consisting only of manganese atoms and oxygen atoms, such as one or more manganese oxides selected from manganese monoxide, manganese dioxide, manganese trioxide, manganese trioxide, manganese pentaoxide, manganese tetraoxide, manganese heptoxide, manganese dodecaoxide and manganese trioxide; (2) a manganese oxide consisting only of manganese atoms, hydrogen atoms and oxygen atoms, such as one or two manganese oxides selected from manganese oxyhydroxide and manganese hydroxide; and (3) a manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms and optionally hydrogen atoms, such as salt-type manganese oxide.

174. The pharmaceutical composition of any one of claims 171-173, wherein the salt-type manganese oxide is selected from one or more of potassium-type manganese oxide, hydrogen-type manganese oxide, ammonium-type manganese oxide, sodium-type manganese oxide, calcium-type manganese oxide, magnesium-type manganese oxide, iron-type manganese oxide, ferrous-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide.

175. The pharmaceutical composition of any one of claims 171-174, wherein the manganese oxide is a manganese oxide in the form of a natural mineral, wherein the manganese oxide in the form of a natural mineral is, for example, selected from one or more of forsmerite, cryptomelane, pyrolusite, hexagonite, birnessite, buselite, ramsdellite, psilomelane, ferromanganite, spheneite, sphenesite, hexagonite, harzburgite, philomena, tauromanite, hausmannite, hausmannite, harzburgite, sphenesite and sphenesite.

176. The pharmaceutical composition according to any one of claims 171 to 175, wherein the manganese oxide is a manganese oxide in the form of a polymorph, wherein the manganese oxide in the form of a polymorph is, for example, one or more selected from α-type crystalline manganese oxide, β-type crystalline manganese oxide, γ-type crystalline manganese oxide, δ-type crystalline manganese oxide, λ-type crystalline manganese oxide, ε-type crystalline manganese oxide, R-type crystalline manganese oxide, amorphous manganese oxide, α-type crystalline manganese oxyhydroxide, β-type crystalline manganese oxyhydroxide, and γ-type crystalline manganese oxyhydroxide.

177. The pharmaceutical composition according to any one of claims 171-176, wherein the manganese oxide is a manganese oxide in the form of a salt polymorph, wherein the manganese oxide in the form of a salt polymorph is, for example, selected from one or more of salt-type α-type crystalline manganese oxide, salt-type β-type crystalline manganese oxide, salt-type γ-type crystalline manganese oxide, salt-type δ-type crystalline manganese oxide, salt-type λ-type crystalline manganese oxide, salt-type ε-type crystalline manganese oxide, salt-type R-type crystalline manganese oxide, and salt-type amorphous manganese oxide, and wherein the salt-type α-type crystalline manganese oxide is, for example, selected from one or both of potassium-type α-type crystalline manganese oxide and hydrogen-type α-type crystalline manganese oxide, the salt-type β-type crystalline manganese oxide is, for example, selected from one or both of potassium-type β-type crystalline manganese oxide and hydrogen-type β-type crystalline manganese oxide, the salt-type γ-type crystalline manganese oxide is, for example, selected from one or both of ammonium-type γ-type crystalline manganese oxide and hydrogen-type γ-type crystalline manganese oxide, and the salt-type δ-type crystalline manganese oxide is, for example, selected from one or both of ammonium-type γ-type crystalline manganese oxide and hydrogen-type γ-type crystalline manganese oxide. The crystalline manganese oxide is, for example, selected from one or more of potassium-type δ-type crystalline manganese oxide, hydrogen-type δ-type crystalline manganese oxide, sodium-type δ-type crystalline manganese oxide, ammonium-type δ-type crystalline manganese oxide, calcium-type δ-type crystalline manganese oxide, magnesium-type δ-type crystalline manganese oxide, iron-type δ-type crystalline manganese oxide, ferrous-type δ-type crystalline manganese oxide, zinc-type δ-type crystalline manganese oxide, lanthanum-type δ-type crystalline manganese oxide, bismuth-type δ-type crystalline manganese oxide, lithium-type δ-type crystalline manganese oxide, and silver-type δ-type crystalline manganese oxide. The salt-type λ-type crystalline manganese oxide is, for example, selected from one or both of lithium-type λ-type crystalline manganese oxide and hydrogen-type λ-type crystalline manganese oxide. The salt-type ε-type crystalline manganese oxide is, for example, selected from one or both of potassium-type ε-type crystalline manganese oxide and hydrogen-type ε-type crystalline manganese oxide. The salt-type R-type crystalline manganese oxide is, for example, hydrogen-type R-type crystalline manganese oxide. The salt-type amorphous manganese oxide is, for example, selected from one or both of potassium-type amorphous manganese oxide and hydrogen-type amorphous manganese oxide.

178. The pharmaceutical composition of any one of claims 171-177, wherein the manganese oxide has a uric acid clearance capacity of about 50 mg / g to about 1000 mg / g as measured in a simulated intestinal fluid (SIF) assay.

179. The pharmaceutical composition of any one of claims 171-178, wherein the manganese oxide has a uric acid clearance capacity of about 100 mg / g to about 900 mg / g as measured in a simulated intestinal fluid (SIF) assay.

180. The pharmaceutical composition of any one of claims 171-179, wherein the manganese oxide has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated intestinal fluid (SIF) assay.

181. The pharmaceutical composition of any one of claims 171-180, wherein the manganese oxide has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fasting small intestinal fluid (FaSSIF) assay.

182. The pharmaceutical composition of any one of claims 171-181, wherein the manganese oxide has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fed small intestinal fluid (FeSSIF) assay.

183. The pharmaceutical composition of any one of claims 171-182, wherein the pharmaceutical composition is an oral formulation.

184. The pharmaceutical composition of any one of claims 171-183, wherein the oral formulation is a solid oral formulation or a liquid oral formulation.

185. The pharmaceutical composition of any one of claims 171-184, wherein the solid oral dosage form is a powder, granules, tablet, capsule, pill or lozenge.

186. The pharmaceutical composition of any one of claims 171-185, wherein the pharmaceutical composition does not comprise an additional therapeutic agent.

187. The pharmaceutical composition of any one of claims 171-186, wherein the pharmaceutical composition comprises an effective amount of manganese oxide.

188. The pharmaceutical composition of any one of claims 171-187, wherein the pharmaceutical composition comprises about 3 mg to about 3000 mg, about 3 mg to about 1500 mg, about 5 mg to about 500 mg, or about 10 mg to about 200 mg of manganese oxide.

189. The pharmaceutical composition of any one of claims 171-188, wherein the mammal is a human.

190. The pharmaceutical composition of any one of claims 171-189, wherein the blood and / or serum uric acid level in the mammalian subject is at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% above 360 ​​μmol / L or 420 μmol / L.

191. The pharmaceutical composition of any one of claims 171-190, wherein blood and / or serum uric acid levels in the mammalian subject are reduced by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% within 24 hours after administration of the pharmaceutical composition.

192. A pharmaceutical composition formulated as at least one solid dosage unit for oral administration to a mammalian subject, wherein the solid dosage unit comprises manganese oxide, and wherein the manganese oxide has a uric acid clearance capacity as measured in a simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay that is at least about 100 mg / g higher than the uric acid clearance capacity of activated carbon under equivalent conditions.

193. The pharmaceutical composition of claim 192, wherein the manganese oxide has a uric acid clearance capacity as measured in a simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay that is at least about 200 mg / g, 300 mg / g, 400 mg / g, 500 mg / g, or 600 mg / g higher than the uric acid clearance capacity of activated carbon under equivalent conditions.

194. A pharmaceutical composition according to claim 192 or 193, wherein the simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) assay is performed using simulated fasting small intestinal fluid (FaSSIF) or simulated fed small intestinal fluid (FeSSIF) having a uric acid concentration of approximately 8.4±0.2 mg / dL, at a temperature between approximately 25°C and 37°C, a manganese oxide concentration of approximately 0.1 g / L to 2 g / L, and under shaking conditions.

195. The pharmaceutical composition according to any one of claims 192-194, wherein the particle size of the manganese oxide is ≥ 1 μm, such as 1 μm to 1 mm.

196. The pharmaceutical composition according to any one of claims 192-195, wherein the manganese oxide is selected from one or more of the following: (1) a manganese oxide consisting only of manganese atoms and oxygen atoms, such as one or more manganese oxides selected from manganese monoxide, manganese dioxide, manganese trioxide, manganese trioxide, manganese pentaoxide, manganese tetraoxide, manganese heptoxide, manganese dodecaoxide and manganese trioxide; (2) a manganese oxide consisting only of manganese atoms, hydrogen atoms and oxygen atoms, such as one or two manganese oxides selected from manganese oxyhydroxide and manganese hydroxide; and (3) a manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms and optionally hydrogen atoms, such as salt-type manganese oxide.

197. The pharmaceutical composition of any one of claims 192-196, wherein the salt-type manganese oxide is selected from one or more of potassium-type manganese oxide, hydrogen-type manganese oxide, ammonium-type manganese oxide, sodium-type manganese oxide, calcium-type manganese oxide, magnesium-type manganese oxide, iron-type manganese oxide, ferrous-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide.

198. The pharmaceutical composition of any one of claims 192-197, wherein the manganese oxide is a manganese oxide in the form of a natural mineral, wherein the manganese oxide in the form of a natural mineral is, for example, selected from one or more of forsmerite, cryptomelane, pyrolusite, hexagonite, birnessite, buselite, ramsdellite, psilomelane, ferromanganite, spheneite, spheneite, hexagonite, harzburgite, philomena, tauromanite, hausmannite, hausmannite, harzburgite, spheneite, and spheneite.

199. The pharmaceutical composition according to any one of claims 192-198, wherein the manganese oxide is a manganese oxide in the form of a polymorph, wherein the manganese oxide in the form of a polymorph is, for example, selected from one or more of α-type crystalline manganese oxide, β-type crystalline manganese oxide, γ-type crystalline manganese oxide, δ-type crystalline manganese oxide, λ-type crystalline manganese oxide, ε-type crystalline manganese oxide, R-type crystalline manganese oxide, amorphous manganese oxide, α-type crystalline manganese oxyhydroxide, β-type crystalline manganese oxyhydroxide, and γ-type crystalline manganese oxyhydroxide.

200. The pharmaceutical composition according to any one of claims 192-199, wherein the manganese oxide is a manganese oxide in the form of a salt polymorph, wherein the manganese oxide in the form of a salt polymorph is, for example, selected from one or more of salt-type α-type crystalline manganese oxide, salt-type β-type crystalline manganese oxide, salt-type γ-type crystalline manganese oxide, salt-type δ-type crystalline manganese oxide, salt-type λ-type crystalline manganese oxide, salt-type ε-type crystalline manganese oxide, salt-type R-type crystalline manganese oxide, and salt-type amorphous manganese oxide, and wherein the salt-type α-type crystalline manganese oxide is, for example, selected from one or both of potassium-type α-type crystalline manganese oxide and hydrogen-type α-type crystalline manganese oxide, the salt-type β-type crystalline manganese oxide is, for example, selected from one or both of potassium-type β-type crystalline manganese oxide and hydrogen-type β-type crystalline manganese oxide, the salt-type γ-type crystalline manganese oxide is, for example, selected from one or both of ammonium-type γ-type crystalline manganese oxide and hydrogen-type γ-type crystalline manganese oxide, and the salt-type δ-type crystalline manganese oxide is, for example, selected from one or both of ammonium-type γ-type crystalline manganese oxide and hydrogen-type γ-type crystalline manganese oxide. The crystalline manganese oxide is, for example, selected from one or more of potassium-type δ-type crystalline manganese oxide, hydrogen-type δ-type crystalline manganese oxide, sodium-type δ-type crystalline manganese oxide, ammonium-type δ-type crystalline manganese oxide, calcium-type δ-type crystalline manganese oxide, magnesium-type δ-type crystalline manganese oxide, iron-type δ-type crystalline manganese oxide, ferrous-type δ-type crystalline manganese oxide, zinc-type δ-type crystalline manganese oxide, lanthanum-type δ-type crystalline manganese oxide, bismuth-type δ-type crystalline manganese oxide, lithium-type δ-type crystalline manganese oxide, and silver-type δ-type crystalline manganese oxide. The salt-type λ-type crystalline manganese oxide is, for example, selected from one or both of lithium-type λ-type crystalline manganese oxide and hydrogen-type λ-type crystalline manganese oxide. The salt-type ε-type crystalline manganese oxide is, for example, selected from one or both of potassium-type ε-type crystalline manganese oxide and hydrogen-type ε-type crystalline manganese oxide. The salt-type R-type crystalline manganese oxide is, for example, hydrogen-type R-type crystalline manganese oxide. The salt-type amorphous manganese oxide is, for example, selected from one or both of potassium-type amorphous manganese oxide and hydrogen-type amorphous manganese oxide.

201. The pharmaceutical composition of any one of claims 192-200, wherein the manganese oxide has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fasting small intestinal fluid (FaSSIF) assay.

202. The pharmaceutical composition of any one of claims 192-201, wherein the manganese oxide has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a simulated fed small intestinal fluid (FeSSIF) assay.

203. The pharmaceutical composition of any one of claims 192-202, wherein the solid dosage unit is a powder, granules, tablet, capsule, pill, or lozenge.

204. The pharmaceutical composition of any one of claims 192-203, wherein the pharmaceutical composition does not comprise an additional therapeutic agent.

205. The pharmaceutical composition of any one of claims 192-204, wherein the pharmaceutical composition comprises an effective amount of manganese oxide.

206. The pharmaceutical composition of any one of claims 192-205, wherein the pharmaceutical composition comprises about 3 mg to about 3000 mg, about 3 mg to about 1500 mg, about 5 mg to about 500 mg, or about 10 mg to about 200 mg of manganese oxide.

207. The pharmaceutical composition of any one of claims 192-206, wherein the mammal is a human.

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