Use of a manganese-containing compound for reducing uric acid levels in a mammalian subject

Abstract

Use of a manganese-containing compound for reducing uric acid levels in a mammalian subject. In particular, the present invention relates to the use of an insoluble manganese-containing compound in the preparation of a medicament for preventing and / or treating an increase in the level of uric acid in the blood and / or gastrointestinal tract of a mammalian subject, or a disease or condition associated with an increase in the level of uric acid in the blood and / or gastrointestinal tract, a pharmaceutical composition, a kit for such use, and a method for preventing and / or treating related diseases or conditions.

Description

Technical Field

[0001] Technical Field The present invention generally relates to the use of manganese-containing compounds for reducing uric acid levels in mammalian subjects, particularly to the elevation of uric acid levels in the blood and / or gastrointestinal tract of mammalian subjects, or to the use of insoluble manganese-containing compounds in the preparation of drugs for preventing and / or treating diseases or disorders associated with the elevation of uric acid levels in the blood and / or gastrointestinal tract, pharmaceutical compositions and kits for such use, and methods for preventing and / or treating related diseases or disorders.

Background Art

[0002] Background Art Uric acid, a heterocyclic compound containing nitrogen and oxygen and having the molecular formula C5H4N4O3, is the end product of purine metabolism in the body. Disorders associated with abnormally elevated uric acid levels in the blood and / or serum include hyperuricemia, gout and its complications, such as gouty arthritis (with or without tophi), gouty urinary calculi (i.e., urolithiasis), gouty nephropathy (i.e., urate nephropathy) and sequelae of these disorders. Hyperuricemia is associated with an increased risk of developing gout. The more severe and prolonged the hyperuricemia in a subject, the higher the risk of developing gout. In addition to gouty arthritis, chronic hyperuricemia can cause deposition of urate crystals in the urinary tract, renal parenchyma and soft tissues, potentially resulting in gouty urolithiasis, gouty nephropathy and soft tissue tophi, respectively.

[0003] Currently, the clinical treatment of hyperuricemia or gout mainly involves the administration of drugs to reduce the concentration of uric acid in the blood. Furthermore, the symptoms of acute gout can be controlled by the administration of anti-inflammatory drugs. These drugs are mainly used to address inflammation but do not have the effect of lowering uric acid levels. By reducing the uric acid level in the blood and / or serum of the subject to the normal range, the recurrence rate of acute gout is reduced, and other diseases or disorders associated with elevated uric acid levels are prevented. To date, there are still many patients who cannot efficiently control their uric acid levels after standard treatment with existing drugs. Furthermore, many drugs currently available for hyperuricemia or gout are accompanied by various harmful side effects. The level of uric acid in the blood and / or serum of interest is determined by the balance among the amount of purines obtained through food or beverage 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, approximately 80% of uric acid is synthesized by the body itself, while approximately 20% of uric acid enters the body through uptake in the intestine (Current hypertension reports, 2016, 18(10): 1-6). In some patients with hyperuricemia, intestinal uric acid uptake is increased due to factors such as eating habits and intestinal lesions. On the other hand, regarding the excretion of uric acid in the body, in normal people, approximately 70% of uric acid is excreted through the kidneys, while approximately 30% of uric acid is also excreted through the intestine. In patients with chronic kidney disease, the ability of the kidneys to clear uric acid is reduced, so intestinal excretion of uric acid becomes the main route of uric acid excretion (Mini Reviews in Medicinal Chemistry, 2020, 20(18): 1857-1866). It can be seen that by removing uric acid in the digestive tract, it is possible to help reduce the uric acid level in the body of interest. On the other hand, drugs that act only locally in the digestive tract (for example, drugs Veltassa and Lokelma for treating hyperkalemia) are not absorbed into the blood and do not cause systemic side effects, so these have good safety. Therefore, developing uric acid-lowering drugs based on the mechanism of clearing uric acid in the digestive tract is of great significance, which will be a good complement to existing uric acid-lowering drugs.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Means for Solving the Problems

[0005] Summary of the Invention This application is based, at least in part, on the unexpected discovery that manganese-containing compounds have excellent properties for adsorbing and / or removing uric acid (including its salts, such as sodium urate), and that the adsorption and / or clearance of uric acid (including its salts, such as sodium urate) by manganese-containing compounds is not substantially affected, or is hardly affected, by various substances present in the mammalian gastrointestinal tract (including, but not limited to, digestive fluids such as gastric juice, intestinal juice, and chyle), as compared to materials having known adsorptive properties in the prior art. Furthermore, the inventors unexpectedly discovered that manganese-containing compounds can be administered at extremely high safe oral doses without causing unacceptable side effects, thereby having a desirable safety profile. Based on the above findings, technical solutions that meet the above and other requirements are provided below.

[0006] In one aspect, the present disclosure provides the use of an insoluble manganese-containing compound in the preparation of a drug for preventing and / or treating an increase in uric acid levels in the blood and / or gastrointestinal tract of a mammalian subject, or a disease or disorder associated with an increase in uric acid levels in the blood and / or gastrointestinal tract.

[0007] In another aspect, the present disclosure provides the use of a manganese-containing compound in the preparation of a drug for adsorbing uric acid in the gastrointestinal tract of a mammal.

[0008] In another aspect, the present disclosure provides a pharmaceutical composition for preventing and / or treating an increase in uric acid levels in the blood and / or gastrointestinal tract of a mammalian subject, or a disease or disorder associated with an increase in uric acid levels in the blood and / or gastrointestinal tract, the pharmaceutical composition comprising an insoluble manganese-containing compound and a pharmaceutically acceptable additive.

[0009] In another aspect, the present disclosure provides a kit comprising: (i) any of the pharmaceutical compositions according to the present disclosure, and (ii) a drug instruction manual and / or drug label.

[0010] In another aspect, the present disclosure provides a method for preventing and / or treating an increase in uric acid level in the blood and / or gastrointestinal tract of a mammalian subject, or a disease or disorder associated with an increase in uric acid level in the blood and / or gastrointestinal tract, the method comprising administering an effective amount of an insoluble manganese-containing compound to a subject in need thereof.

[0011] In another aspect, the present disclosure provides a method for preventing and / or treating an increase in uric acid level in the blood and / or gastrointestinal tract of a mammalian subject, or a disease or disorder associated with an increase in uric acid level in the blood and / or gastrointestinal tract, the method comprising administering an effective amount of an insoluble manganese-containing compound to a subject in need thereof over an extended period of time.

[0012] In another aspect, the present disclosure provides a method for maintaining the uric acid level in the blood of a mammalian subject, the method comprising administering an effective amount of an insoluble manganese-containing compound to a subject in need thereof over an extended period of time.

[0013] In another aspect, the present disclosure provides a pharmaceutical composition in which the amount of manganese oxide is sufficient to reduce the blood and / or serum uric acid level by at least about 5% within 24 hours after administration of the pharmaceutical composition in a mammalian subject whose blood and / or serum uric acid level is at least 10% higher than 360 μmol / L or 420 μmol / L.

[0014] 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 the manganese oxide has a uric acid clearance capacity that is at least about 100 mg / g higher than the uric acid clearance capacity of activated carbon measured in a fasted state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay.

[0015] Exemplary embodiments of the present disclosure are illustrated and described in detail below, from which other aspects and advantages of the present disclosure will become apparent to those skilled in the art. As will be recognized by those skilled in the art, the accompanying drawings and description are illustrative and not restrictive.

[0016] By referring to the exemplary embodiments and drawings detailed below, a better understanding of the features and advantages of the invention to which this application pertains is possible. The following is a brief description of the information in each of the accompanying drawings. It should be understood that the drawings are illustrative in nature and do not constitute a limitation to any aspect of the invention to which this application pertains.

Brief Description of the Drawings

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[0018] DETAILED DESCRIPTION OF THE INVENTION Various exemplary embodiments or examples of the present 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 present invention included in this application. Many changes, modifications and substitutions of these exemplary embodiments or examples will occur to those skilled in the art without departing from the spirit of this disclosure. These embodiments or examples obtained through changes, modifications or substitutions should also be understood to be within the scope of protection of this application.

[0019] When publications, patents and patent applications are cited in this specification, all of the cited publications, patents and patent applications are incorporated herein by reference 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. If the publications, patents and patent applications incorporated by reference do not match the present disclosure included in this specification, the interpretation and / or explanation in this specification shall prevail.

[0020] When this specification refers to a numerical range, it should be understood that all numerical ranges referred to in this disclosure are intended to include the two endpoints of this range (i.e., the upper and lower limits), all numerical values (especially integers) within this range, and sub-ranges formed by these numerical values (especially integers).

[0021] DEFINITIONS As used throughout this document, the singular forms "a", "an", "the" and "this" also include plural referents unless the context clearly indicates otherwise. Further, unless specifically stated whether an indicator is singular or plural, this application includes both singular and plural indicators.

[0022] As used throughout this document, the term "plural" refers to more than one and includes, but is not limited to, two, three, four, five, six, etc.

[0023] As used throughout this document, the terms "comprise", "comprising", "include", "including" and their variations are intended to represent open-ended transitional phrases, terms or words that do not exclude the possibility of additional steps, materials or structures. When such terms are used to describe a drug, pharmaceutical composition, kit, use or method, etc. of the present disclosure, it also covers the situation where the drug, pharmaceutical composition, kit, use or method, etc. is composed of the recited factors or elements. With respect to the present disclosure, the term "consisting of" means that there are no factors or elements (such as steps, materials, structures, etc.) other than the recited factors or elements in the subject matter or method.

[0024] As used throughout this document, the term "optionally" means that the subsequently described element or event may or may not be present / occur and includes both the presence / occurrence and non-presence / non-occurrence of the element or event.

[0025] As used throughout this document, the term "about" means approximately, near, roughly or around, and is used to indicate that the described characteristics are within the error range acceptable to those skilled in the art with respect to a given value. When the term "about" is used with respect to a numerical value, it is used to indicate a value within the range of ±20% of the recited numerical value. In some embodiments, the term "about" may be used to encompass a value within the range of ±10%, ±5%, ±1%, ±0.5% or ±0.1% of a particular value.

[0026] As used throughout this document, the term "manganese-containing compound" refers to a chemical substance composed of manganese and any one or more other elements (usually in a fixed mass ratio) bonded to each other by chemical bonds (i.e., the forces that bind the atoms or ions constituting the compound, including but not limited to covalent and ionic bonds).

[0027] As used throughout this document, the term "insoluble manganese-containing compound" refers to a manganese-containing compound that is insoluble or has extremely low solubility in water and / or gastrointestinal fluids (including but not limited to gastric juice, intestinal juice, colonic juice, pancreatic juice, and / or bile) under physiological conditions. The insoluble manganese-containing compounds according to the present disclosure can be identified by measuring the mass of the manganese-containing compound dissolved in 1 mL of water or artificial gastrointestinal fluid (including but not limited to simulated intestinal fluid (SIF), fasted-state simulated intestinal fluid (FaSSIF), or fed-state simulated intestinal fluid (FeSSIF)) when saturated at about 37°C and about 1 atmosphere. When the mass of the manganese-containing compound dissolved under the above conditions is less than about 100 μg, for example, 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 less than 1 ng, it can be regarded as an "insoluble manganese-containing compound" according to the present disclosure. On the other hand, "insoluble manganese-containing compounds" can also be characterized by their physiological inactivity, that is, they are essentially unable to enter the bloodstream through the gastrointestinal tract (i.e., the digestive tract), and / or do not substantially chemically react with the surrounding substances or tissues in the body after administration. For example, an "insoluble manganese-containing compound" is a manganese-containing compound in which less than about 20% of the dose, for example, 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, enters the bloodstream through absorption in the gastrointestinal tract, and / or does not chemically react with the surrounding substances or tissues in the body after administration, or is a manganese-containing compound that chemically reacts with the surrounding substances or tissues in the body only in an amount less than about 20% of the dose, for example, 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.Although not limited by theory, due to its physiological inactivity and insolubility, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the amount of the insoluble manganese-containing compound of the present application administered 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 their solvates (such as hydrates).

[0028] As used throughout this document, the terms "particle size" and "particle diameter" are used interchangeably and refer to the measured value of the particle diameter (or dimension) that characterizes a particle population (e.g., the particle population of the insoluble manganese-containing compound according to the present disclosure). Methods for measuring the particle diameter are known in the art. For example, dynamic image analysis (DIA) can be used to measure the particle diameter of a particle population. For example, dynamic light scattering can be used to measure the particle diameter of a particle population. For example, a laser particle size analyzer (also called a laser diffraction particle size analyzer) can be used to measure the particle diameter of a particle population. When referring to the particle diameter range of a certain particle population according to the present disclosure, a small amount of particles that do not meet the particle diameter range may still be present in the particle population (e.g., particles that do not meet the particle diameter 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 population), but it should be understood that the presence of these particles does not substantially affect the overall properties of the particle population.

[0029] 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 metals (atomic groups having metallic properties, such as including ammonia) or hydrogen (represented by M; M = H, K, Na, Li, Ba, Pb, Ca, Zn, etc.) atoms that are bonded to each other by chemical bonds (Note: The "atoms" referred to in this specification also include 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. Its basic structural unit is typically an octahedral unit [MnO6] formed by one manganese atom coordinated to six oxygen atoms, which form various crystal structures by sharing sides or corners and stacking. In the stacked structure, atomic layers form tetrahedral and octahedral holes. In manganese oxide, manganese can be assumed to be in oxidation states of +2, +3, +4, +6, +7 so that manganese oxide can exist in various forms, or mixtures of these forms. Further, various cations can be incorporated into the holes between atoms in the structure of manganese oxide; herein, such manganese oxide doped with impurity cations is referred to as "salt-type manganese oxide". In some embodiments of the present disclosure, manganese oxide is: (1) manganese oxide consisting only of manganese atoms and oxygen atoms, such as manganese monoxide (MnO), manganese dioxide (MnO2), manganese trioxide (MnO3), dimanganese trioxide (Mn2O3), manganese pentoxide octoxide (Mn5O8), trimanganese tetroxide (Mn3O4), dimanganese heptoxide (Mn2O7), heptamanganese dodecoxide (Mn7O 12 ) and heptamanganese tridecoxide (Mn7O 13) (2) manganese oxides consisting only of manganese atoms, hydrogen atoms and oxygen atoms, such as manganese oxyhydroxide (MnOOH) and manganese hydroxide (Mn(OH)₂), and (3) manganese oxides consisting 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, divalent iron-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 the above embodiments, the various atoms mentioned including manganese, oxygen, hydrogen, and metal atoms may exist in their ionic forms if desired. Manganese oxides are generally obtained from one or more of natural minerals such as hollandite, cryptomelane, pyrolusite, nsutit, bernardite, buserite, bernardite, ramsdellite, romanechite, fulgurite, hydromanganite, groutite, phytochroite, hydrohausmannite, lithiophorite, calcoffite, hausmannite, vicksite, pyrochlore and green manganese ore. Thus, in some embodiments, the manganese oxide is in the form of a natural mineral. Manganese oxides and their solvates (e.g., hydrates) can also exist in polymorphic forms. In some embodiments, the manganese oxide is in a crystalline form, such as α, β, γ, δ, λ, ε or R form, or an amorphous form. In some embodiments, during the preparation of the polymorphs of manganese oxide, the formation of a particular phase is promoted by structurally oriented impurity ions. Depending on the type of ions in the solution used to prepare the polymorphs of manganese oxide, various cations can be incorporated into the holes between atoms in the structure of the polymorphs of manganese oxide being formed, thereby forming manganese oxide in the form of "salt-type polymorphs".In some embodiments, the cation is a potassium ion, a sodium ion, an ammonium ion, a calcium ion, a magnesium ion, a ferric ion, a ferrous ion, a zinc ion, a lanthanum ion, a bismuth ion, a lithium ion or a hydrogen ion; thus, the polymorphs of manganese oxide doped with potassium ions, sodium ions, ammonium ions, calcium ions, magnesium ions, ferric ions, ferrous ions, zinc ions, lanthanum ions, bismuth ions, lithium ions and hydrogen ions in these holes are respectively referred to as the "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" polymorphs of manganese oxide.

[0030] As used throughout this document, the terms "disease", "disorder", "condition", "(medical) condition", etc. are used interchangeably and refer to any deviation from the normal condition of the subject. For example, these terms can refer to physical discomfort or distress in the subject, or any change in the state of an organ or tissue that prevents or interferes with the normal performance of its functions.

[0031] As used throughout this document, the term "adsorption" refers to the attachment of uric acid (including urate, e.g., sodium urate) to the surface of the manganese-containing compound.

[0032] As used throughout this document, 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, and having a molecular formula of C5H4N4O3. In humans and most other primates, uric acid is the end product of the oxidative metabolism of purines. Under physiological pH, uric acid is mainly in the form of its ionic urate (radical). Thus, the term "uric acid" includes urate (e.g., sodium urate).

[0033] As used throughout this document, the terms "elevated uric acid level" or "higher uric acid level" refer to blood and / or serum uric acid levels that exceed normal. In humans, the upper limit of normal levels is typically about 420 μmol / L in men and about 360 μmol / L in women. In some embodiments, a subject in whom an "elevated uric acid level" or "higher uric acid level" is recognized has a blood and / or serum uric acid level that 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% higher than 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. An excessive elevation of blood and / or serum uric acid levels may be associated with various diseases or disorders. In some embodiments, the disease or disorder may be at least one disease or disorder selected from the group consisting of gout, gout complications, hyperuricemia, elevated uric acid levels that typically do not reach levels diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related conditions, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle cramps, local swelling, joint pain, malignant disease, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, non-alcoholic fatty liver disease, stroke, hemolytic anemia, inborn errors of metabolism, poisoning, epididymitis and orchitis, and blood, bone marrow or solid organ transplantation.

[0034] As used throughout this document, the term hyperuricemia (HUA) refers to abnormally high levels of uric acid in the blood and / or serum. Under a low body fluid pH, uric acid is mainly in its ionic urate form. The urate content in the human body is determined by the balance among the amount of purines ingested in the diet, the amount of urate synthesized by the human body, and the amount of urate excreted through urine and the digestive system. Hyperuricemia can be caused by overproduction of uric acid, reduced uric acid excretion, or both. Clinically, hyperuricemia can be divided into two main categories: primary hyperuricemia and secondary hyperuricemia. Primary hyperuricemia is typically caused by congenital abnormalities in purine metabolism. Secondary hyperuricemia can result from taking certain drugs that inhibit uric acid excretion (such as thiazide diuretics, aspirin, pyrazinamide, levodopa, ethambutol), or from certain other medical conditions (such as hematological malignancies, chronic kidney disease).

[0035] As used throughout this document, the term "high uric acid levels that typically do not reach levels diagnostic of hyperuricemia" refers to blood and / or serum uric acid levels that exceed the appropriate blood and / or serum uric acid levels in a given population (such as a population defined by a particular gender, age, and / or the presence of a disease or disorder), but do not reach the blood and / or serum uric acid levels required for a typical diagnosis of hyperuricemia. For the purposes of this disclosure, in a given population, the 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.

[0036] As used throughout this document, the term "gout" refers to a recurrent inflammatory disease caused by an increase in uric acid in the blood and the deposition of urate crystals in joint synovium, bursae, cartilage, and other tissues resulting from enhanced purine biosynthesis metabolism, excessive uric acid production, or lack of uric acid excretion. For the purposes of this disclosure, gout includes, but is not limited to, acute gout, chronic gout, and refractory gout. The term "acute gout" refers to gout present in a subject in whom at least one symptom of a sudden onset of gout (e.g., podagra) is recognized. The term "chronic gout" refers to gout present in a subject in whom recurrent or persistent acute gout attacks, tophus development, chronic inflammatory arthritis, or joint degeneration associated with gout are recognized, including the stage following recovery from acute gout and the stage during acute gout attacks (i.e., intermittent gout). The term "refractory gout" refers to gout that does not respond, or responds poorly, to one or more oral hypouricemic (uric acid-lowering) agents (e.g., xanthine oxidase inhibitors), and for which it is thus difficult to return the subject's blood uric acid level to normal.

[0037] As used throughout this document, the term "gout complication" refers to a disease or disorder resulting from a secondary reaction during the development of gout. For example, gout can cause complications such as gouty arthritis resulting from the deposition of urate (e.g., sodium urate) crystals in joints. For the purposes of this disclosure, the gout complication can be at least one of gouty arthritis, gouty urolithiasis, and gouty nephropathy.

[0038] As used throughout this document, the term "effective amount" refers to an amount sufficient to achieve, or at least partially achieve, a desired effect. With respect to the present disclosure, a "therapeutically effective amount" of a drug, pharmaceutical composition or therapeutic agent (e.g., an insoluble manganese-containing compound, such as the manganese-containing compounds of the present disclosure including manganese oxide) means an amount that promotes regression of a disease or disorder, which is evidenced by a decrease in the severity of symptoms of the disease or disorder, an increase in the frequency and duration of asymptomatic periods of the disease or disorder, or prevention of damage or disability due to the disease or disorder. A "prophylactically effective amount" of a drug, pharmaceutical composition or therapeutic agent is an amount that inhibits the onset or recurrence of a disease or disorder when administered to a subject at risk of developing or recurring the disease or disorder. The "effective amount" of a drug, pharmaceutical composition or therapeutic agent can be determined using various methods known to those of skill in the art, e.g., by evaluating human subjects during clinical trials, by using animal model systems to predict efficacy in humans, or by measuring the activity of the drug, pharmaceutical composition or therapeutic agent in in vitro assays. Generally, the exact amount of a drug, pharmaceutical composition or therapeutic agent required to achieve an effective amount will vary depending on factors such as the species, age and general condition of the subject, the severity of the disease or disorder, 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 according to the present disclosure once a day, twice a day, three times a day, every other day, once every three days, once a week, once every two weeks, once every three weeks or once every four weeks. In some embodiments, an effective amount is obtained by administering an insoluble manganese-containing compound, such as the manganese-containing compounds of the present disclosure including manganese oxide, at a dosage level sufficient to deliver from about 0.001 mg to about 10 g, e.g., from about 0.005 mg to about 5000 mg, from about 0.01 mg to about 2500 mg, from about 0.05 mg to about 1000 mg, from about 0.1 mg to about 750 mg, from about 0.2 mg to about 500 mg, from about 0.5 mg to about 250 mg, from about 0.5 mg to about 100 mg, from about 0.5 mg to about 75 mg or from about 1 mg to about 50 mg per kilogram of the subject's body weight per day, once, twice or more times a day.In some embodiments, the effective amount is obtained by administering a manganese-containing compound of the present disclosure that includes an insoluble manganese-containing compound, such as manganese oxide, at a dosing level sufficient to deliver from about 3 mg to about 3000 mg of manganese oxide per day (such as from about 100 mg to about 3000 mg of manganese oxide per day, from about 200 mg to about 3000 mg of manganese oxide per day, or from about 500 mg to about 3000 mg of manganese oxide per day), once, twice, or more times per day. In some embodiments, it is also possible to obtain an effective amount by administering a manganese-containing compound of the present disclosure that includes an insoluble manganese-containing compound, such as manganese oxide, at a higher dosing level, i.e., from about 3 g to about 50 g of manganese oxide per day (such as 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), once, twice, or more times per day, provided that such high dosing levels of administration do not cause unacceptable side effects in the subject. Determination of the effective amount of a drug, pharmaceutical composition, or therapeutic agent appropriate for a particular disease or disorder is within the skill of the art.

[0039] As used throughout this document, the term "administration" refers to the process of introducing the drugs, pharmaceutical compositions or therapeutic agents of the present disclosure into the body of a subject by any route of introduction or delivery. Administration can be carried out by any method known to those skilled in the art to bring a cell, tissue or organ into contact with a drug, pharmaceutical composition or therapeutic agent. Routes of administration can include, but are not limited to, parenteral, topical or oral administration. For the purposes of the present disclosure, the term "parenteral administration" refers to a mode of administration typically by injection other than gastrointestinal and topical administration. Means of parenteral administration include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subdural, intrathecal, epidural and intrasternal injections and infusions, as well as in vivo electroporation. For the purposes of the present disclosure, topical routes of administration can include, but are not limited to, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal or sublingual administration. The daily dose of a drug, pharmaceutical composition or therapeutic agent can be divided into one, two or more doses in a suitable form for administration at one, two or more times during a period of time.

[0040] As used throughout this document, the term "prevention" refers to preventing the occurrence of a disease or disorder in a subject at risk of developing the disease or of having a disease or disorder that has disappeared recur, and "treatment" refers to controlling, reducing or alleviating the pathological progression of a disease or disorder and prolonging the survival period of the affected subject. Thus, with respect to the present disclosure, the term "prevention and / or treatment" covers preventing the onset or further increase in severity of a disease or disorder, or one or more symptoms associated therewith; reducing and / or alleviating the severity and / or duration of a disease or disorder, or one or more symptoms associated therewith; slowing or reversing the progression of a disease or disorder, or one or more symptoms associated therewith; preventing, reducing or reversing a certain physiological damage caused by a disease or disorder, or one or more symptoms associated therewith; and covering certain pharmacological effects generally beneficial to the subject being treated, etc.

[0041] 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 disorder, such as a human (including neonatal, infant, adolescent and adult subjects), non-human primates (such as apes (such as macaques), orangutans (such as gorillas, chimpanzees), macaques, cynomolgus monkeys, rhesus monkeys), companion animals (such as dogs and cats), agricultural animals (such as poultry, such as chickens and ducks, horses, cows, goats, sheep, pigs) and laboratory animals (such as mice, rats, rabbits, guinea pigs).

[0042] As used throughout this document, the term "pharmaceutically acceptable" refers to a substance that does not cause excessive toxicity, irritation, allergic reaction or other problems, but has a reasonable benefit / risk ratio and is suitable for use in contact with the tissues of the subject mammal within the limits of reasonable medical judgment.

[0043] As used throughout this document, the term "pharmaceutically acceptable additive" refers to an additive (or carrier) that does not cause excessive irritation to mammalian target tissues or organs and does not remove the pharmacological activity and properties of the administered drug, pharmaceutical composition, or therapeutic agent. For the purposes of this disclosure, the term "pharmaceutically acceptable additive" 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, adhesives, disintegrants, lubricants, flow promoters, sweeteners, flavoring agents, coloring agents, and the like, and combinations of one or more of them. By way of non-limiting example, pharmaceutically acceptable additives include: ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffering 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; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; polyethylene glycol; and lanolin, among others. Examples of suitable pharmaceutically acceptable additives can be found, for example, in Remington's Pharmaceutical Sciences, version 18, Mack Printing Company, 1990, pp. 1289-1329, which is hereby incorporated by reference into this specification. The use of such conventional additives is contemplated in this disclosure, except where a particular conventional additive is immiscible with the active ingredient.

[0044] As used throughout this document, the term "drug" refers to a substance that can produce a beneficial biological effect in humans or other mammals. For the purposes of this disclosure, "drug" can refer to only the active pharmaceutical ingredient (bulk pharmaceutical chemical), but also encompasses pharmaceutical compositions (including their formulations).

[0045] As used throughout this document, the term "pharmaceutical composition" refers to a substance or material having a specific pharmaceutical use (e.g., for increasing uric acid levels in the blood and / or gastrointestinal tract in mammalian subjects, and / or for preventing and / or treating diseases or disorders associated with increased uric acid levels in the blood and / or gastrointestinal tract), which is formed by mixing an active pharmaceutical ingredient (e.g., a manganese-containing compound, optionally in combination with additional therapeutic agents) and a pharmaceutically acceptable additive in a certain ratio.

[0046] As used throughout this document, the terms "formulation" and "pharmaceutical formulation" or "dosage form" are used interchangeably and refer to a pharmaceutical composition in a dosage form that meets the requirements of a certain dosage form for treatment or prevention and can be directly used by a subject. As non-limiting examples, the formulation can be for parenteral administration, topical administration or oral administration. As oral formulations, solid oral formulations or liquid oral formulations can be mentioned, and the solid oral formulation can be any one of powders, granules, tablets, capsules, pills and lozenges.

[0047] As used throughout this document, the terms "crystalline form" and "crystal" can be used interchangeably to represent that atoms, ions or molecules forming a substance according to a certain periodicity form a solid with a regular geometric shape in spatial arrangement during the crystallization process. Depending on the different periodic spatial arrangements of atoms, ions or molecules, a substance can exist in two or more different crystalline forms, which is also known as polymorphism.

[0048] As used throughout this document, the term "amorphous form" or "amorphous" refers to a solid in which the atoms, ions or molecules constituting the substance are not periodically arranged in a certain spatial order (i.e., they are in a disordered distribution state) in contrast to a crystal.

[0049] As used throughout this specification, the term "polymorph" refers to the various different forms of a solid material that exist in more than one form. For the purposes of this disclosure, the term "polymorph" encompasses both "crystalline forms" and "amorphous forms".

[0050] As used throughout this document, the term "solvate" refers to a complex compound formed by the combination of solute molecules and one or more pharmaceutically acceptable solvent molecules. When the solvent is water, the "solvate" is specifically a "hydrate".

[0051] As used throughout this document, the term "simulated intestinal fluid (SIF)" refers to a solution that mimics the main inorganic salt components and pH value of intestinal fluid in the human small intestine. Simulated intestinal fluid can be obtained commercially or prepared by methods well known to those skilled in the art. For example, in some embodiments, simulated intestinal fluid is prepared as follows: Prepare 6.8 g of potassium dihydrogen phosphate and dissolve it in 500 mL of water; adjust the pH value to 6.8 with 0.1 mol / L sodium hydroxide solution; prepare 10 g of pancreatic enzymes and dissolve them in an appropriate amount of water; and then mix these two solutions, add water to make 1000 mL, thereby obtaining simulated intestinal fluid.

[0052] As used throughout this document, the term "fasting state simulated intestinal fluid (FaSSIF)" refers to a solution that mimics the intestinal fluid in the human small intestine in the fasting state before a meal. The components of FaSSIF and their respective concentrations are as follows: 3 mM taurocholate, 0.75 mM phospholipid, 148 mM sodium, 106 mM chloride, and 29 mM phosphate. FaSSIF can be obtained commercially or prepared by methods well known to those skilled in the art. For example, in some embodiments, FaSSIF is prepared as follows: (1) Preparation of buffer: Mix 37.48 g of FaSSIF buffer concentrate with 865.0 g of purified water, (2) Add FaSSIF powder to the buffer: Add 2.016 g of FaSSIF powder to the buffer, (3) Stir the resulting mixture until all solids are dissolved, and (4) Let the resulting solution stand (equilibrate) for at least 2 hours to obtain FaSSIF. FaSSIF buffer concentrate and FaSSIF powder are commercially available, for example, from Biorelevant.com Ltd.

[0053] As used throughout this document, the term "fed state simulated intestinal fluid (FeSSIF)" refers to a solution that mimics the intestinal fluid in the human small intestine in the fed state after a meal. The components of FeSSIF and their respective concentrations are as follows: 15 mM taurocholate, 3.75 mM phospholipid, 319 mM sodium, 203 mM chloride, and 144 mM acetate. FeSSIF can be obtained commercially or prepared by methods well known to those skilled in the art. For example, in some embodiments, FeSSIF is prepared as follows: (1) Preparation of buffer: Mix 73.27 g of FeSSIF buffer concentrate with 827.5 g of purified water, (2) Add FeSSIF powder to the buffer: Add 10.08 g of FeSSIF powder to the buffer, (3) Stir the resulting mixture until all solids are dissolved to obtain FeSSIF. FeSSIF buffer concentrate and FeSSIF powder are commercially available, for example, from Biorelevant.com Ltd.

[0054] Detailed Description of Embodiments As far as the inventors know, drugs based on the uric acid clearance mechanism in the digestive tract have not been approved to lower uric acid levels in patients with hyperuricemia. Known adsorbents, such as activated carbon, have a large specific surface area and have been shown to adsorb various substances, but such adsorption often does not have good selectivity. Therefore, in the complex physiological environment of the gastrointestinal tract, the adsorption effect of activated carbon on uric acid is hindered by many other components in the intestinal tract, thereby preventing efficient adsorption of uric acid. Therefore, a method for achieving efficient adsorption of uric acid in the complex gastrointestinal environment is an important issue in developing drugs based on the uric acid clearance mechanism in the digestive tract.

[0055] The present disclosure describes the use of manganese-containing compounds for lowering uric acid levels in mammalian subjects, particularly for preventing and / or treating an increase in uric acid levels in the blood and / or digestive tract of mammalian subjects, or diseases or disorders associated with an increase in uric acid levels in the blood and / or digestive tract, the use of insoluble manganese-containing compounds in the preparation of drugs for the same, pharmaceutical compositions and kits for such use, and methods for preventing and / or treating related diseases or disorders.

[0056] The manganese-containing compounds of the present disclosure are particularly useful and / or beneficial for increasing uric acid levels in the blood and / or gastrointestinal tract in mammalian subjects, or for preventing and / or treating diseases or disorders associated with increased uric acid levels in the blood and / or gastrointestinal tract, adsorbing uric acid in the gastrointestinal tract of mammals, and / or maintaining (normal or appropriate) uric acid levels in the blood of mammalian subjects. In some embodiments of the present disclosure, the manganese-containing compounds of the present disclosure exhibit excellent adsorption and / or clearance of uric acid (including its salts, such as sodium urate) from the gastrointestinal tract of mammalian subjects. In some embodiments, the manganese-containing compounds of the present disclosure outperform zeolite molecular sieves, Prussian blue, activated carbon, montmorillonite, ion exchange resins (such as sevelamer hydrochloride), metal-organic framework materials, etc., which are known to have adsorption / or clearance properties for uric acid (including its salts, such as sodium urate) in the gastrointestinal tract of mammalian subjects. In some embodiments, the adsorption / clearance of uric acid (including its salts, such as sodium urate) from the gastrointestinal tract of mammalian subjects by the manganese-containing compounds of the present disclosure is not affected, essentially not affected, or not significantly affected by various substances present in the gastrointestinal tract of mammals, including but not limited to digestive fluids such as gastric juice, 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 sodium urate) at low concentrations of uric acid (including its salts, such as sodium urate), and can maintain the ability to effectively adsorb uric acid (including its salts, such as sodium urate) even after multiple adsorptions. In some embodiments, the manganese-containing compounds of the present disclosure can be administered at extremely high safe oral doses (e.g., about 50 g / day, or even more) without causing unacceptable side effects, and thus have 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 mammals, and have no significant effect on the blood biochemical indices of mammalian subjects.

[0057] In some embodiments, the manganese-containing compound is an insoluble manganese-containing compound. The insoluble manganese-containing compound of the present disclosure is characterized by its insolubility or extremely low solubility in water and / or gastrointestinal fluids (including, but not limited to, gastric juice, intestinal juice, colonic juice, pancreatic juice, and / or bile) under physiological conditions, and / or its physiological inertness (i.e., the insoluble manganese-containing compound is substantially unable to enter the bloodstream through absorption in the gastrointestinal tract (i.e., the digestive tract), and / or after administration, it does not substantially chemically react with surrounding substances or tissues in the body).

[0058] Accordingly, in a first aspect, the present disclosure provides the use of an insoluble manganese-containing compound in the preparation of a drug for preventing and / or treating an increase in uric acid levels in the blood and / or digestive tract of a mammalian subject, or a disease or disorder associated with an increase in uric acid levels in the blood and / or digestive tract.

[0059] 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 when dissolved and saturated in 1 mL of water, measured at about 37°C and about 1 atmosphere.

[0060] In some embodiments, an 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 when dissolved to saturation in 1 mL of simulated intestinal fluid (SIF) measured at about 37 °C and about 1 atmosphere.

[0061] In some embodiments, an 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 when dissolved to saturation in 1 mL of fasted-state simulated intestinal fluid (FaSSIF) measured at about 37 °C and about 1 atmosphere.

[0062] In some embodiments, an 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 when dissolved to saturation in 1 mL of fed-state simulated intestinal fluid (FeSSIF) measured at about 37 °C and about 1 atmosphere.

[0063] In some embodiments, an insoluble manganese-containing compound is a manganese-containing compound in which 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 enters the blood circulation by absorption in the gastrointestinal tract.

[0064] In some embodiments, an 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 in which 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 of the manganese-containing compound chemically interacts with surrounding substances or tissues in the body.

[0065] In some embodiments, the particle size of the insoluble manganese-containing compound is ≧1 μm, for example, from 1 μm to 1 mm.

[0066] 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 ferricyanide, manganese oxalate, manganese selenite, manganese iodate, manganese tungstate and manganese phosphate, and solvates (such as hydrates) thereof.

[0067] In some embodiments, the insoluble manganese-containing compound is manganese oxide or a solvate thereof (e.g., hydrate). In some embodiments, the manganese oxide is selected from one or more of: (1) manganese oxide consisting only of manganese atoms and oxygen atoms, (2) manganese oxide consisting only of manganese atoms, hydrogen atoms and oxygen atoms, and (3) manganese oxide consisting only of manganese atoms, oxygen atoms, metal atoms only, and optionally hydrogen atoms. In some embodiments, the manganese oxide is manganese oxide consisting only of manganese atoms and oxygen atoms. In some embodiments, the manganese oxide is manganese oxide consisting only of manganese atoms, hydrogen atoms and oxygen atoms. In some embodiments, the manganese oxide is manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms and optionally hydrogen atoms.

[0068] In some embodiments, the manganese oxide is 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, nsutite, bernardite, buserite, bernardite, ramsdellite, romanechite, khatyrkite, manganite, groutite, fightite, hydrohausmannite, lithiophorite, calcoffite,hausmannite, bikitaite, pyrochlore, and green manganese ore. 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 nsutite. In some embodiments, the manganese oxide in the form of a natural mineral is bernardite. 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 bernardite. 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 khatyrkite. 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 fightite. 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 calcoffite. 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 bikitaite. In some embodiments, the manganese oxide in the form of a natural mineral is pyrochlore. In some embodiments, the manganese oxide in the form of a natural mineral is green manganese ore.

[0069] In some embodiments, manganese oxide is manganese oxide consisting of only manganese atoms and oxygen atoms. In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese monoxide (MnO), manganese dioxide (MnO2), manganese trioxide (MnO3), manganese sesquioxide (Mn2O3), manganese pentoxide octoxide (Mn5O8), manganese tetroxide (Mn3O4), manganese heptoxide (Mn2O7), manganese heptoxide dodecoxide (Mn7O 12 ) and manganese heptoxide tridecoxide (Mn7O 13 ) selected from one or more of them. In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese monoxide (MnO). In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese dioxide (MnO2). In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese trioxide (MnO3). In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese sesquioxide (Mn2O3). In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese pentoxide octoxide (Mn5O8). In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese tetroxide (Mn3O4). In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese heptoxide (Mn2O7). In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese heptoxide dodecoxide (Mn7O 12 ). In some embodiments, manganese oxide consisting of only manganese atoms and oxygen atoms is manganese heptoxide tridecoxide (Mn7O 13 ).

[0070] 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 composed only of manganese atoms, hydrogen atoms, and oxygen atoms is selected from one or both of manganese oxyhydroxide (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 oxyhydroxide. In some embodiments, the manganese oxyhydroxide is manganese oxyhydroxide in the form of a polymorph. In some embodiments, the manganese oxyhydroxide in the form of a polymorph is selected from one or more of α-form crystalline manganese oxyhydroxide, β-form crystalline manganese oxyhydroxide, and γ-form crystalline manganese oxyhydroxide. In some embodiments, the manganese oxyhydroxide in the form of a polymorph is α-form crystalline manganese oxyhydroxide. In some embodiments, the α-form crystalline manganese oxyhydroxide is α-form crystalline manganese oxyhydroxide in the form of groutite. In some embodiments, the manganese oxyhydroxide in the form of a polymorph is β-form crystalline manganese oxyhydroxide. In some embodiments, the β-form crystalline manganese oxyhydroxide is β-form crystalline manganese oxyhydroxide in one or both forms of phytochroite and hydrohausmannite. In some embodiments, the manganese oxyhydroxide in the form of a polymorph is γ-form crystalline manganese oxyhydroxide. In some embodiments, the γ-form crystalline manganese oxyhydroxide is γ-form 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 manganese hydroxide in the form of a polymorph.

[0071] In some embodiments, the manganese oxide is a manganese oxide composed of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms. In some embodiments, the manganese oxide composed of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms is a salt-form manganese oxide. In some embodiments, the salt-form 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, divalent iron-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-form manganese oxide is potassium-type manganese oxide. In some embodiments, the salt-form manganese oxide is hydrogen-type manganese oxide. In some embodiments, the salt-form manganese oxide is ammonium-type manganese oxide. In some embodiments, the salt-form manganese oxide is sodium-type manganese oxide. In some embodiments, the salt-form manganese oxide is calcium-type manganese oxide. In some embodiments, the salt-form manganese oxide is magnesium-type manganese oxide. In some embodiments, the salt-form manganese oxide is iron-type manganese oxide. In some embodiments, the salt-form manganese oxide is divalent iron-type manganese oxide. In some embodiments, the salt-form manganese oxide is zinc-type manganese oxide. In some embodiments, the salt-form manganese oxide is lanthanum-type manganese oxide. In some embodiments, the salt-form manganese oxide is bismuth-type manganese oxide. In some embodiments, the salt-form manganese oxide is lithium-type manganese oxide. In some embodiments, the salt-form manganese oxide is silver-type manganese oxide.

[0072] In some embodiments, the manganese oxide is a manganese oxide in the form of a polymorph, for example, a manganese oxide in the form of a salt-type polymorph.

[0073] In some embodiments, the manganese oxide in polymorphic form is selected from one or more of α-form crystalline manganese oxide (e.g., salt-type α-form crystalline manganese oxide), β-form crystalline manganese oxide (e.g., salt-type β-form crystalline manganese oxide), γ-form crystalline manganese oxide (e.g., salt-type γ-form crystalline manganese oxide), δ-form crystalline manganese oxide (e.g., salt-type δ-form crystalline manganese oxide), λ-form crystalline manganese oxide (e.g., salt-type λ-form crystalline manganese oxide), ε-form crystalline manganese oxide (e.g., salt-type ε-form crystalline manganese oxide), R-form crystalline manganese oxide (e.g., salt-type R-form crystalline manganese oxide), amorphous manganese oxide (e.g., salt-type amorphous manganese oxide), α-form crystalline manganese oxyhydroxide (e.g., salt-type α-form crystalline manganese oxyhydroxide), β-form crystalline manganese oxyhydroxide (e.g., salt-type β-form crystalline manganese oxyhydroxide), and γ-form crystalline manganese oxyhydroxide (e.g., salt-type γ-form crystalline manganese oxyhydroxide).

[0074] In some embodiments, the manganese oxide in polymorphic form is α-form crystalline manganese oxide. In some embodiments, the α-form crystalline manganese oxide is α-form crystalline manganese oxide in the form of hollandite or cryptomelane.

[0075] In some embodiments, the manganese oxide in polymorphic form is β-form crystalline manganese oxide. In some embodiments, the β-form crystalline manganese oxide is β-form crystalline manganese oxide in the form of pyrolusite.

[0076] In some embodiments, the manganese oxide in polymorphic form is γ-form crystalline manganese oxide. In some embodiments, the γ-form crystalline manganese oxide is γ-form crystalline manganese oxide in the form of nsutite.

[0077] In some embodiments, the manganese oxide in the form of a polymorph is δ-form crystalline manganese oxide. In some embodiments, the δ-form crystalline manganese oxide is δ-form crystalline manganese oxide in one or more forms of birnessite, buserite, and bernardite.

[0078] In some embodiments, the manganese oxide in the form of a polymorph is λ-form crystalline manganese oxide.

[0079] In some embodiments, the manganese oxide in the form of a polymorph is ε-form crystalline manganese oxide.

[0080] In some embodiments, the manganese oxide in the form of a polymorph is R-form crystalline manganese oxide. In some embodiments, the R-form crystalline manganese oxide is R-form crystalline manganese oxide in the form of ramsdellite.

[0081] In some embodiments, the manganese oxide in the form of a polymorph is amorphous manganese oxide.

[0082] In some embodiments, the manganese oxide in the form of a polymorph is α-form crystalline manganese oxyhydroxide. In some embodiments, the α-form crystalline manganese oxyhydroxide is α-form crystalline manganese oxyhydroxide in the form of groutite.

[0083] In some embodiments, the manganese oxide in the form of a polymorph is β-form crystalline manganese oxyhydroxide. In some embodiments, the β-form crystalline manganese oxyhydroxide is β-form crystalline manganese oxyhydroxide in one or both forms of feitknechtite and hydrohausmannite.

[0084] In some embodiments, the manganese oxide in the form of a polymorph is γ-form crystalline manganese oxyhydroxide. In some embodiments, the γ-form crystalline manganese oxyhydroxide is γ-form crystalline manganese oxyhydroxide in the form of manganite.

[0085] In some embodiments, the manganese oxide is manganese oxide in the form of a salt-type polymorph.

[0086] In some embodiments, the manganese oxide in the form of a salt-type polymorph is selected from one or more of salt-type α-form crystalline manganese oxide, salt-type β-form crystalline manganese oxide, salt-type γ-form crystalline manganese oxide, salt-type δ-form crystalline manganese oxide, salt-type λ-form crystalline manganese oxide, salt-type ε-form crystalline manganese oxide, salt-type R-form crystalline manganese oxide, and salt-type amorphous manganese oxide.

[0087] In some embodiments, the manganese oxide in the form of a salt polymorph is salt-type α-form crystalline manganese oxide. In some embodiments, the salt-type α-form crystalline manganese oxide is selected from one or both of potassium-type α-form crystalline manganese oxide and hydrogen-type α-form crystalline manganese oxide. In some embodiments, the salt-type α-form crystalline manganese oxide is potassium-type α-form crystalline manganese oxide. In some embodiments, the potassium-type α-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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-form crystalline manganese oxide is hydrogen-type α-form crystalline manganese oxide.In some embodiments, hydrogen-type α-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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, hydrogen-type α-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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, hydrogen-type α-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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°.

[0088] In some embodiments, the manganese oxide in the form of a salt polymorph is salt-type β-form crystalline manganese oxide. In some embodiments, the salt-type β-form crystalline manganese oxide is selected from one or both of potassium-type β-form crystalline manganese oxide and hydrogen-type β-form crystalline manganese oxide. In some embodiments, the salt-type β-form crystalline manganese oxide is potassium-type β-form crystalline manganese oxide. In some embodiments, the potassium-type β-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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-form crystalline manganese oxide is hydrogen-type β-form crystalline manganese oxide. In some embodiments, the hydrogen-type β-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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-type β-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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°.

[0089] In some embodiments, the manganese oxide in the form of a salt polymorph is salt-type γ-form crystalline manganese oxide. In some embodiments, the salt-type γ-form crystalline manganese oxide is selected from one or both of ammonium-type γ-form crystalline manganese oxide and hydrogen-type γ-form crystalline manganese oxide. In some embodiments, the salt-type γ-form crystalline manganese oxide is ammonium-type γ-form crystalline manganese oxide. In some embodiments, the ammonium-type γ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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-type γ-form crystalline manganese oxide is hydrogen-type γ-form crystalline manganese oxide. In some embodiments, the hydrogen-type γ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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 hydrogen-type γ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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°.

[0090] In some embodiments, the manganese oxide in the form of a salt polymorph is a salt-type δ-form crystalline manganese oxide. In some embodiments, the salt-type δ-form 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-type δ-form crystalline manganese oxide, hydrogen-type δ-form crystalline manganese oxide, sodium-type δ-form crystalline manganese oxide, ammonium-type δ-form crystalline manganese oxide, calcium-type δ-form crystalline manganese oxide, magnesium-type δ-form crystalline manganese oxide, iron-type δ-form crystalline manganese oxide, divalent iron-type δ-form crystalline manganese oxide, zinc-type δ-form crystalline manganese oxide, lanthanum-type δ-form crystalline manganese oxide, bismuth-type δ-form crystalline manganese oxide, lithium-type δ-form crystalline manganese oxide, and silver-type δ-form crystalline manganese oxide. In some embodiments, the salt-type δ-form crystalline manganese oxide is potassium-type δ-form crystalline manganese oxide. In some embodiments, the potassium-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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 δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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 δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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 δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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 δ-form crystalline manganese oxide is hydrogen-type δ-form crystalline manganese oxide.In some embodiments, hydrogen-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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, hydrogen-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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, hydrogen-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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, hydrogen-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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, salt-type δ-form crystalline manganese oxide is sodium-type δ-form crystalline manganese oxide. In some embodiments, sodium-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing characteristic X-ray diffraction peaks at the following 2θ angles: 12.In some embodiments, the salt-type δ-form crystalline manganese oxide is magnesium-type δ-form crystalline manganese oxide. In some embodiments, the magnesium-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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 δ-form crystalline manganese oxide is iron-type δ-form crystalline manganese oxide. In some embodiments, the iron-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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 δ-form crystalline manganese oxide is divalent iron-type δ-form crystalline manganese oxide. In some embodiments, the divalent iron-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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-form crystalline manganese oxide is zinc-type δ-form crystalline manganese oxide. In some embodiments, the zinc-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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-form crystalline manganese oxide is lanthanum-type δ-form crystalline manganese oxide. In some embodiments, the lanthanum-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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 δ-form crystalline manganese oxide is bismuth-type δ-form crystalline manganese oxide.In some embodiments, bismuth-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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, salt-type δ-form crystalline manganese oxide is lithium-type δ-form crystalline manganese oxide. In some embodiments, lithium-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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, salt-type δ-form crystalline manganese oxide is silver-type δ-form crystalline manganese oxide. In some embodiments, silver-type δ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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°.

[0091] In some embodiments, manganese oxide in the form of a salt-type polymorph is salt-type λ-form crystalline manganese oxide. In some embodiments, salt-type λ-form crystalline manganese oxide is selected from one or both of lithium-type λ-form crystalline manganese oxide and hydrogen-type λ-form crystalline manganese oxide. In some embodiments, salt-type λ-form crystalline manganese oxide is lithium-type λ-form crystalline manganese oxide. In some embodiments, salt-type λ-form crystalline manganese oxide is hydrogen-type λ-form crystalline manganese oxide. In some embodiments, hydrogen-type λ-form crystalline manganese oxide is characterized by its powder X-ray diffraction pattern showing 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°.

[0092] In some embodiments, the manganese oxide in the form of a salt polymorph is salt form ε - form crystalline manganese oxide. In some embodiments, the salt form ε - form crystalline manganese oxide is selected from one or both of potassium form ε - form crystalline manganese oxide and hydrogen form ε - form crystalline manganese oxide. In some embodiments, the salt form ε - form crystalline manganese oxide is potassium form ε - form crystalline manganese oxide. In some embodiments, the potassium form ε - form crystalline manganese oxide is characterized by its powder X - ray diffraction pattern showing 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 form ε - form crystalline manganese oxide is hydrogen form ε - form crystalline manganese oxide. In some embodiments, the hydrogen form ε - form crystalline manganese oxide is characterized by its powder X - ray diffraction pattern showing 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°.

[0093] In some embodiments, the manganese oxide in the form of a salt polymorph is salt form R - form crystalline manganese oxide. In some embodiments, the salt form R - form crystalline manganese oxide is hydrogen form R - form crystalline manganese oxide. In some embodiments, the hydrogen form R - form crystalline manganese oxide is characterized by its powder X - ray diffraction pattern showing 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°.

[0094] In some embodiments, the manganese oxide in the form of a salt-type polymorph is a salt-type amorphous manganese oxide. In some embodiments, the salt-type amorphous manganese oxide is selected from one or both of potassium-type amorphous manganese oxide and hydrogen-type amorphous manganese oxide. In some embodiments, the salt-type amorphous manganese oxide is potassium-type amorphous manganese oxide. In some embodiments, the potassium-type amorphous manganese oxide is characterized in that its powder X-ray diffraction pattern does not exhibit distinct characteristic X-ray diffraction peaks. In some embodiments, the salt-type amorphous manganese oxide is hydrogen-type amorphous manganese oxide. In some embodiments, the hydrogen-type amorphous manganese oxide is characterized in that its powder X-ray diffraction pattern does not exhibit distinct characteristic X-ray diffraction peaks.

[0095] The insoluble manganese-containing compound (e.g., manganese oxide) according to the present disclosure exhibits high uric acid clearance ability in an artificial intestinal fluid (SIF) assay. The artificial intestinal fluid (SIF) assay can be performed using methods known to those skilled in the art. For example, in some embodiments, the artificial intestinal fluid (SIF) assay is performed in SIF with a uric acid 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 SIF has a pH of about 6.8 ± 0.2, such as about 6.6, 6.7, 6.8, 6.9, or 7.0. In some embodiments, the SIF has a phosphate content of from about 10 mM to 100 mM, such as from about 10 mM to 100 mM, from about 20 mM to 90 mM, from about 30 mM to 80 mM, from about 40 mM to 60 mM, or about 50 mM. In some embodiments, the artificial intestinal fluid (SIF) assay is performed in SIF with a uric acid concentration of about 8.4 ± 0.2 mg / dL, a pH of about 6.8 ± 0.2, and a phosphate content of from about 10 mM to 100 mM. In some embodiments, the artificial intestinal fluid (SIF) assay is performed at a temperature of from about 25°C to 37°C, such as from 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 at a concentration of the insoluble manganese-containing compound from about 0.1 g / L to 2 g / L, such as from 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 1.0 g / L, 0.1 g / L to 1.1 g / L, 0.1 g / L to 1.2 g / L, 0.1 g / L to 1.3 g / L, 0.1 g / L to 1.4 g / L, 0.1 g / L to 1.5 g / L, 0.1 g / L to 1.6 g / L, 0.1 g / L to 1.7 g / L, 0.1 g / L to 1.8 g / L, 0.1 g / L to 1.9 g / L, 0.2 g / L to 2 g / L, 0.3 g / L to 2 g / L, 0.4 g / L to 2 g / L, 0.5 g / L to 2 g / L, 0.6 g / L to 2 g / L, 0.7 g / L to 2 g / L, 0.8 g / L to 2 g / L, 0.9 g / L to 2 g / L, 1.0 g / L to 2 g / L, 1.1 g / L to 2 g / L, 1.2 g / L to 2 g / L, 1.3 g / L to 2 g / L, 1.4 g / L to 2 g / L, 1.5 g / L to 2 g / L, 1.6 g / L to 2 g / L, 1.7 g / L to 2 g / L, 1.8 g / L to 2 g / L or 1.9 g / L to 2.0 g / L. In some embodiments, the simulated intestinal fluid (SIF) assay is performed under shaking conditions. The shaking rate 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 at a temperature from about 25° C. to 37° C., at a concentration of manganese oxide from about 0.1 g / L to 2 g / L and under shaking conditions, using a simulated intestinal fluid (SIF) having a concentration of uric acid of about 8.4±0.2 mg / dL. In some embodiments, the duration of the simulated intestinal fluid (SIF) assay is ≧5 minutes, such as ≧10 minutes, ≧15 minutes, ≧20 minutes, ≧25 minutes, ≧30 minutes, ≧35 minutes, ≧40 minutes, ≧45 minutes, ≧50 minutes, ≧55 minutes, ≧60 minutes, ≧90 minutes, ≧120 minutes, ≧180 minutes, ≧240 minutes, ≧300 minutes, ≧360 minutes, ≧420 minutes, ≧480 minutes, ≧520 minutes or ≧600 minutes.

[0096] In some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) has a uric acid clearance capacity of from about 50 mg / g to about 1000 mg / g as measured by an artificial intestinal fluid (SIF) assay.

[0097] In some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) has a uric acid clearance capacity of from about 100 mg / g to about 900 mg / g as measured by an artificial intestinal fluid (SIF) assay.

[0098] In some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) has a uric acid clearance capacity of from about 200 mg / g to about 800 mg / g as measured by an artificial intestinal fluid (SIF) assay.

[0099] For example, in some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) is from about 100 mg / g to about 1000 mg / g, from about 150 mg / g to about 1000 mg / g, from about 200 mg / g to about 1000 mg / g, from about 250 mg / g to about 1000 mg / g, from about 300 mg / g to about 1000 mg / g, from about 350 mg / g to about 1000 mg / g, from about 400 mg / g to about 1000 mg / g, from about 450 mg / g to about 1000 mg / g, from about 500 mg / g to about 1000 mg / g, from about 550 mg / g to about 1000 mg / g, from about 600 mg / g to about 1000 mg / g, from about 650 mg / g to about 1000 mg / g, from about 700 mg / g to about 1000 mg / g, from about 750 mg / g to about 1000 mg / g, from about 800 mg / g to about 1000 mg / g, from about 850 mg / g to about 1000 mg / g, from about 900 mg / g to about 1000 mg / g, from about 950 mg / g to about 1000 mg / g, from about 100 mg / g to about 900 mg / g, from about 150 mg / g to about 900 mg / g, from about 200 mg / g to about 900 mg / g, from about 250 mg / g to about 900 mg / g, from about 300 mg / g to about 900 mg / g, from about 350 mg / g to about 900 mg / g, from about 400 mg / g to about 900 mg / g, from about 450 mg / g to about 900 mg / g, from about 500 mg / g to about 900 mg / g, from about 550 mg / g to about 900 mg / g, from about 600 mg / g to about 900 mg / g, from about 650 mg / g to about 900 mg / g, from about 700 mg / g to about 900 mg / g, from about 750 mg / g to about 900 mg / g, from about 800 mg / g to about 900 mg / g, from about 850 mg / g to about 900 mg / g, from about 100 mg / g to about 800 mg / g, from about 150 mg / g to about 800 mg / g, from about 200 mg / g to about 800 mg / g, from about 250 mg / g to about 800 mg / g, from about 300 mg / g to about 800 mg / g, from about 350 mg / g to about 800 mg / g, from about 400 mg / g to about 800 mg / g, from about 450 mg / g to about 800 mg / g, from about 500 mg / g to about 800 mg / g, from about 550 mg / g to about 800 mg / g, from about 600 mg / g to about 800 mg / g, from about 650 mg / g to about 800 mg / g, from about 700 mg / g to about 800 mg / g, from about 750 mg / g to about 800 mg / g, from about 100 mg / g to about 700 mg / g,It has a uric acid clearance ability measured by an artificial intestinal fluid (SIF) assay of from about 150 mg / g to about 700 mg / g, from about 200 mg / g to about 700 mg / g, from about 250 mg / g to about 700 mg / g, from about 300 mg / g to about 700 mg / g, from about 350 mg / g to about 700 mg / g, from about 400 mg / g to about 700 mg / g, from about 450 mg / g to about 700 mg / g, from about 500 mg / g to about 700 mg / g, from about 550 mg / g to about 700 mg / g, from about 600 mg / g to about 700 mg / g, from about 650 mg / g to about 700 mg / g, from about 100 mg / g to about 600 mg / g, from about 150 mg / g to about 600 mg / g, from about 200 mg / g to about 600 mg / g, from about 250 mg / g to about 600 mg / g, from about 300 mg / g to about 600 mg / g, from about 350 mg / g to about 600 mg / g, from about 400 mg / g to about 600 mg / g, from about 450 mg / g to about 600 mg / g, from about 500 mg / g to about 600 mg / g, from about 550 mg / g to about 600 mg / g, from about 100 mg / g to about 500 mg / g, from about 150 mg / g to about 500 mg / g, from about 200 mg / g to about 500 mg / g, from about 250 mg / g to about 500 mg / g, from about 300 mg / g to about 500 mg / g, from about 350 mg / g to about 500 mg / g, from about 400 mg / g to about 500 mg / g, from about 450 mg / g to about 500 mg / g, from about 100 mg / g to about 400 mg / g, from about 150 mg / g to about 400 mg / g, from about 200 mg / g to about 400 mg / g, from about 250 mg / g to about 400 mg / g, from about 300 mg / g to about 400 mg / g, from about 350 mg / g to about 400 mg / g, from about 100 mg / g to about 300 mg / g, from about 150 mg / g to about 300 mg / g, from about 200 mg / g to about 300 mg / g, from about 250 mg / g to about 300 mg / g, from about 100 mg / g to about 200 mg / g, or from about 150 mg / g to about 200 mg / g.

[0100] The insoluble manganese-containing compounds (e.g., manganese oxide) according to the present disclosure also exhibit high uric acid clearance ability in the fasting state simulated intestinal fluid (FaSSIF) and / or fed state simulated intestinal fluid (FeSSIF) assays. The fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assays can be performed using methods known to those skilled in the art. In some embodiments, the fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is performed in FaSSIF or FeSSIF with a uric acid 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 fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is performed at a temperature from about 25°C to 37°C, such as from 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 fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is performed at a concentration of the insoluble manganese-containing compound from about 0.1 g / L to 2 g / L, such as from 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 1.0 g / L, 0.1 g / L to 1.1 g / L, 0.1 g / L to 1.2 g / L, 0.1 g / L to 1.3 g / L, 0.1 g / L to 1.4 g / L, 0.1 g / L to 1.5 g / L, 0.1 g / L to 1.6 g / L, 0.1 g / L to 1.7 g / L, 0.1 g / L to 1.8 g / L, 0.1 g / L to 1.9 g / L, 0.2 g / L to 2 g / L, 0.3 g / L to 2 g / L, 0.4 g / L to 2 g / L, 0.5 g / L to 2 g / L, 0.6 g / L to 2 g / L, 0.7 g / L to 2 g / L, 0.8 g / L to 2 g / L, 0.9 g / L to 2 g / L, 1.0 g / L to 2 g / L, 1.1 g / L to 2 g / L, 1.2 g / L to 2 g / L, 1.3 g / L to 2 g / L, 1.4 g / L to 2 g / L, 1.5 g / L to 2 g / L, 1.6 g / L to 2 g / L, 1.7 g / L to 2 g / L, 1.8 g / L to 2 g / L or 1.9 g / L to 2.0 g / L. In some embodiments, the fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is performed under shaking conditions. The shaking frequency can be, for example, ≧50 rpm, ≧l00 rpm, ≧150 rpm, ≧200 rpm, ≧250 rpm, ≧300 rpm or higher. In some embodiments, the fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is performed at a temperature of about 25°C to 37°C, at a concentration of manganese oxide from about 0.1 g / L to 2 g / L and under shaking conditions, using a fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) having a concentration of uric acid of about 8.4 ± 0.2 mg / dL.In some embodiments, the duration of the fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is ≧5 minutes, for example ≧10 minutes, ≧15 minutes, ≧20 minutes, ≧25 minutes, ≧30 minutes, ≧35 minutes, ≧40 minutes, ≧45 minutes, ≧50 minutes, ≧55 minutes, ≧60 minutes, ≧90 minutes, ≧120 minutes, ≧180 minutes, ≧240 minutes, ≧300 minutes, ≧360 minutes, ≧420 minutes, ≧480 minutes, ≧520 minutes or >600 minutes.

[0101] In some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a fasting state simulated intestinal fluid (FaSSIF) assay.

[0102] In some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) has a uric acid clearance capacity of about 200 mg / g to about 800 mg / g as measured in a fed state simulated intestinal fluid (FeSSIF) assay.

[0103] For example, in some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) has a uric acid clearance capacity measured in a fasted state simulated intestinal fluid (FaSSIF) assay of from about 250 mg / g to about 800 mg / g, from about 300 mg / g to about 800 mg / g, from about 350 mg / g to about 800 mg / g, from about 400 mg / g to about 800 mg / g, from about 450 mg / g to about 800 mg / g, from about 500 mg / g to about 800 mg / g, from about 550 mg / g to about 800 mg / g, from about 600 mg / g to about 800 mg / g, from about 650 mg / g to about 800 mg / g, from about 700 mg / g to about 800 mg / g, from about 750 mg / g to about 800 mg / g, from about 200 mg / g to about 700 mg / g, from about 250 mg / g to about 700 mg / g, from about 300 mg / g to about 700 mg / g, from about 350 mg / g to about 700 mg / g, from about 400 mg / g to about 700 mg / g, from about 450 mg / g to about 700 mg / g, from about 500 mg / g to about 700 mg / g, from about 550 mg / g to about 700 mg / g, from about 600 mg / g to about 700 mg / g, from about 650 mg / g to about 700 mg / g, from about 200 mg / g to about 600 mg / g, from about 250 mg / g to about 600 mg / g, from about 300 mg / g to about 600 mg / g, from about 350 mg / g to about 600 mg / g, from about 400 mg / g to about 600 mg / g, from about 450 mg / g to about 600 mg / g, from about 500 mg / g to about 600 mg / g, from about 550 mg / g to about 600 mg / g, from about 200 mg / g to about 500 mg / g, from about 250 mg / g to about 500 mg / g, from about 300 mg / g to about 500 mg / g, from about 350 mg / g to about 500 mg / g, from about 400 mg / g to about 500 mg / g, from about 450 mg / g to about 500 mg / g, from about 200 mg / g to about 400 mg / g, from about 250 mg / g to about 400 mg / g, from about 300 mg / g to about 400 mg / g, from about 350 mg / g to about 400 mg / g, from about 200 mg / g to about 300 mg / g, or from about 250 mg / g to about 300 mg / g.In some embodiments, the insoluble manganese-containing compound has a uric acid clearance ability measured in a fed-state simulated intestinal fluid (FeSSIF) assay of from about 250 mg / g to about 800 mg / g, from about 300 mg / g to about 800 mg / g, from about 350 mg / g to about 800 mg / g, from about 400 mg / g to about 800 mg / g, from about 450 mg / g to about 800 mg / g, from about 500 mg / g to about 800 mg / g, from about 550 mg / g to about 800 mg / g, from about 600 mg / g to about 800 mg / g, from about 650 mg / g to about 800 mg / g, from about 700 mg / g to about 800 mg / g, from about 750 mg / g to about 800 mg / g, from about 200 mg / g to about 700 mg / g, from about 250 mg / g to about 700 mg / g, from about 300 mg / g to about 700 mg / g, from about 350 mg / g to about 700 mg / g, from about 400 mg / g to about 700 mg / g, from about 450 mg / g to about 700 mg / g, from about 500 mg / g to about 700 mg / g, from about 550 mg / g to about 700 mg / g, from about 600 mg / g to about 700 mg / g, from about 650 mg / g to about 700 mg / g, from about 200 mg / g to about 600, from about 250 mg / g to about 600 mg / g, from about 300 mg / g to about 600 mg / g, from about 350 mg / g to about 600 mg / g, from about 400 mg / g to about 600 mg / g, from about 450 mg / g to about 600 mg / g, from about 500 mg / g to about 600 mg / g, from about 550 mg / g to about 600 mg / g, from about 200 mg / g to about 500 mg / g, from about 250 mg / g to about 500 mg / g, from about 300 mg / g to about 500 mg / g, from about 350 mg / g to about 500 mg / g, from about 400 mg / g to about 500 mg / g, from about 450 mg / g to about 500 mg / g, from about 200 mg / g to about 400 mg / g, from about 250 mg / g to about 400 mg / g, from about 300 mg / g to about 400 mg / g, from about 350 mg / g to about 400 mg / g, from about 200 mg / g to about 300 mg / g or from about 250 mg / g to about 300 mg / g.

[0104] In some embodiments, the drug is an oral formulation.

[0105] In some embodiments, the oral formulation is a solid oral formulation. In some embodiments, the solid oral formulation is a powder, granule, tablet, capsule, pill or lozenge. In some embodiments, the oral formulation is a liquid oral formulation.

[0106] In some embodiments, the drug does not contain additional therapeutic agents.

[0107] In some embodiments, the drug comprises an effective amount of an insoluble manganese-containing compound (e.g., manganese oxide). In some embodiments, the drug 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 drug comprises from about 3 mg to about 3000 mg, from about 3 mg to about 2500 mg, from about 3 mg to about 2000 mg, from about 3 mg to about 1500 mg, from about 3 mg to about 1000 mg, from about 3 mg to about 900 mg, from about 3 mg to about 800 mg, from about 3 mg to about 700 mg, from about 3 mg to about 600 mg, from about 3 mg to about 500 mg, from about 3 mg to about 400 mg, from about 3 mg to about 300 mg, from about 3 mg to about 200 mg, from about 5 mg to about 3000 mg, from about 5 mg to about 2500 mg, from about 5 mg to about 2000 mg, from about 5 mg to about 1500 mg, from about 5 mg to about 1000 mg, from about 5 mg to about 900 mg, from about 5 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 drug comprises an insoluble manganese-containing compound of 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.

[0108] 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.

[0109] 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 having one or more of gouty urolithiasis, gouty nephropathy, and diabetes. In some embodiments, the mammal is a mammal in which gouty urolithiasis is observed. In some embodiments, the mammal is a mammal having at least one of gouty nephropathy, such as nephritis, pyelonephritis, hydronephrosis, uric acid nephrolithiasis, renal insufficiency, renal failure, and uremia. In some embodiments, the mammal is a mammal having diabetes.

[0110] In some embodiments, the digestive tract is the 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 the 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.

[0111] In some embodiments, the disease or disorder associated with an increase in uric acid level in the blood and / or the digestive tract is at least one selected from the group consisting of: gout, gout complications, hyperuricemia, high uric acid levels that typically do not reach the levels diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related disorders, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle spasm, local swelling, joint pain, malignant disease, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, non-alcoholic fatty liver disease, stroke, hemolytic anemia, congenital genetic errors of metabolism, poisoning, epididymitis and orchitis, and blood, bone marrow, or solid organ transplantation.

[0112] In some embodiments, the gout is acute gout, chronic gout, or refractory gout.

[0113] In some embodiments, the gout complications are at least one of gouty arthritis, gouty urolithiasis, and gouty nephropathy.

[0114] In some embodiments, gouty nephropathy is at least one of nephritis, pyelonephritis, hydronephrosis, uric acid nephrolithiasis, renal insufficiency, kidney failure, and uremia.

[0115] In some embodiments, 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.

[0116] In some embodiments, hyperuricemia is primary hyperuricemia or secondary hyperuricemia.

[0117] In some embodiments, secondary hyperuricemia is at least one of drug-related hyperuricemia and hyperuricemia associated with other medical conditions.

[0118] In some embodiments, conditions related to diabetes are at least one of diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, diabetic macrovascular disease, diabetic microvascular disease, diabetic foot lesions, and diabetic ketoacidosis.

[0119] In some embodiments, malignant tumors are hematological malignancies.

[0120] In some embodiments, hematological malignancies are at least one of leukemia and multiple myeloma. In some embodiments, leukemia is acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, or chronic myeloid leukemia.

[0121] In some embodiments, non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

[0122] In some embodiments, poisoning is at least one of chloroform poisoning, carbon tetrachloride poisoning, and lead poisoning.

[0123] In some embodiments, the inborn genetic error of metabolism is Lesch-Nyhan syndrome.

[0124] In some embodiments, 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% higher than 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 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% higher than 240 μmol / L. In some embodiments, 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% higher than 260 μmol / L. In some embodiments, 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% higher than 280 μmol / L. In some embodiments, 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% higher than 300 μmol / L.In some embodiments, 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% higher than 320 μmol / L. In some embodiments, 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% higher than 340 μmol / L. In some embodiments, 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% higher than 360 μmol / L. In some embodiments, 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% higher than 380 μmol / L. In some embodiments, 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% higher than 400 μmol / L. In some embodiments, 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% higher than 420 μmol / L.

[0125] In some embodiments, the blood and / or serum uric acid level of the subject decreases after administration of the drug as compared to that before administration of the drug.

[0126] In some embodiments, the blood and / or serum uric acid level of the subject decreases 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 as compared to that before administration of the drug.

[0127] In still further some embodiments, the blood and / or serum uric acid level of the subject is from 80 μmol / L to 460 μmol / L, from 100 μmol / L to 450 μmol / L, from 150 μmol / L to 440 μmol / L, from 200 μmol / L to 430 μmol / L, from 210 μmol / L to 420 μmol / L, from 80 μmol / L to 380 μmol / L, from 100 μmol / L to 370 μmol / L or from 150 μmol / L to 360 μmol / L after administration of the drug.

[0128] In some embodiments, the blood and / or serum uric acid level of the subject decreases after 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 of administration of the drug at an effective amount as compared to that before administration of the drug.

[0129] In a second aspect, the present disclosure provides the use of the manganese-containing compounds described herein in the preparation of a drug for adsorbing uric acid in the digestive tract of a mammal.

[0130] In some embodiments, the manganese-containing compound is an insoluble manganese-containing compound.

[0131] Other embodiments of this aspect may refer to those detailed in the above first aspect.

[0132] In a third aspect, the present disclosure provides a pharmaceutical composition for preventing and / or treating an increase in uric acid levels in the blood and / or gastrointestinal tract of a mammalian subject, or a disease or disorder associated with an increase in uric acid levels in the blood and / or gastrointestinal tract, the pharmaceutical composition comprising an insoluble manganese-containing compound and a pharmaceutically acceptable additive.

[0133] In some embodiments, the pharmaceutical composition is an oral formulation.

[0134] In some embodiments, the oral formulation is a solid oral formulation. In some embodiments, the solid oral formulation is a powder, granule, tablet, capsule, pill or lozenge. In some embodiments, the oral formulation is a liquid oral formulation.

[0135] In some embodiments, the pharmaceutical composition does not contain an additional therapeutic agent.

[0136] 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 from about 3 mg to about 3000 mg, from about 3 mg to about 2500 mg, from about 3 mg to about 2000 mg, from about 3 mg to about 1500 mg, from about 3 mg to about 1000 mg, from about 3 mg to about 900 mg, from about 3 mg to about 800 mg, from about 3 mg to about 700 mg, from about 3 mg to about 600 mg, from about 3 mg to about 500 mg, from about 3 mg to about 400 mg, from about 3 mg to about 300 mg, from about 3 mg to about 200 mg, from about 5 mg to about 3000 mg, from about 5 mg to about 2500 mg, from about 5 mg to about 2000 mg, from about 5 mg to about 1500 mg, from about 5 mg to about 1000 mg, from about 5 mg to about 900 mg, from about 5 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 an insoluble manganese-containing compound of 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.

[0137] In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 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 pharmaceutical composition to a 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% higher than 240 μmol / L. In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 260 μmol / L. In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 280 μmol / L. In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 300 μmol / L.In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 320 μmol / L. In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 340 μmol / L. In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 360 μmol / L. In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 380 μmol / L. In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 400 μmol / L. In some embodiments, prior to administration of the pharmaceutical composition to a 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% higher than 420 μmol / L.

[0138] In some embodiments, the blood and / or serum uric acid level of the subject decreases after administration of the pharmaceutical composition as compared to that before administration of the pharmaceutical composition.

[0139] In some embodiments, the blood and / or serum uric acid level of the subject decreases 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 as compared to that before administration of the pharmaceutical composition.

[0140] Still further, in some embodiments, the blood and / or serum uric acid level of the subject is from 80 μmol / L to 460 μmol / L, from 100 μmol / L to 450 μmol / L, from 150 μmol / L to 440 μmol / L, from 200 μmol / L to 430 μmol / L, from 210 μmol / L to 420 μmol / L, from 80 μmol / L to 380 μmol / L, from 100 μmol / L to 370 μmol / L or from 150 μmol / L to 360 μmol / L after administration of the pharmaceutical composition.

[0141] In some embodiments, the blood and / or serum uric acid level of the subject decreases after 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 of administration of the pharmaceutical composition in an effective amount as compared to that before administration of the pharmaceutical composition.

[0142] For other embodiments of this aspect, reference may be made to those detailed in the first aspect above.

[0143] In a fourth aspect, the present disclosure provides a kit comprising: (i) any of the pharmaceutical compositions according to the present disclosure, and (ii) instructions for use of the drug and / or a label of the drug.

[0144] As used throughout this text, the term "kit", which is alternatively also referred to as "medicine chest", refers to a commercially available form of a pharmaceutically acceptable formulation, as necessary, in the form of a unit dosage form of a pharmaceutical composition, for example, a package for use in a pharmaceutical composition. The package can be made from materials including, but not limited to, one or more of paper, glass, metal, and plastic. In the kit according to the present disclosure, the pharmaceutical composition can be placed in at least one container within the package. By way of 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 containing the pharmaceutical composition, the kit can optionally include one or more additional containers for containing pharmaceutically acceptable additives for diluting or suspending the pharmaceutical composition. Further, the kit according to the present disclosure also includes instructions for use of the drug and / or a label of the drug. For the purposes of the present disclosure, the "instructions for use of the drug" should be understood as a paper specification contained within the kit, which is intended to provide information about the components of the pharmaceutical composition, the route of administration, side effects, etc. Further, the "label of the drug" 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 the package, or which itself constitutes a part of the outer surface of the container and / or the packaging.

[0145] In a fifth aspect, the present disclosure provides a method for preventing and / or treating an increase in uric acid levels in the blood and / or gastrointestinal tract in a mammalian subject, or a disease or disorder associated with an increase in uric acid levels in the blood and / or gastrointestinal tract, the method comprising administering to a subject in need thereof an effective amount of an insoluble manganese-containing compound.

[0146] In a sixth aspect, the present disclosure provides a method for preventing and / or treating an increase in uric acid levels in the blood and / or gastrointestinal tract in a mammalian subject, or a disease or disorder associated with an increase in uric acid levels in the blood and / or gastrointestinal tract, the method comprising administering to a subject in need thereof an effective amount of an insoluble manganese-containing compound over an extended period of time.

[0147] In a seventh aspect, the present disclosure provides a method for maintaining uric acid levels in the blood in a mammalian subject, the method comprising administering to a subject in need thereof an effective amount of an insoluble manganese-containing compound over an extended period of time.

[0148] In some embodiments, the method maintains the blood and / or serum uric acid levels in the subject at blood and / or serum uric acid levels that do not cause, or are unlikely to cause, gout or gout complications. In some embodiments, the method maintains the blood and / or serum uric acid levels in the subject at from 80 μmol / L to 460 μmol / L, from 100 μmol / L to 450 μmol / L, from 150 μmol / L to 440 μmol / L, from 200 μmol / L to 430 μmol / L, from 210 μmol / L to 420 μmol / L, from 80 μmol / L to 380 μmol / L, from 100 μmol / L to 370 μmol / L or from 150 μmol / L to 360 μmol / L.

[0149] In some embodiments, the effective amount is from about 3 mg to about 3000 mg of an insoluble manganese-containing compound (such as manganese oxide) per day. In some embodiments, the effective amount is from about 3 mg to about 1500 mg of an insoluble manganese-containing compound per day. In some embodiments, the effective amount is from about 5 mg to about 500 mg of an insoluble manganese-containing compound per day. In some embodiments, the effective amount is from about 10 mg to about 200 mg of an insoluble manganese-containing compound per day. For example, in some embodiments, the effective amount is from about 3 mg to about 3000 mg of an insoluble manganese-containing compound, from about 3 mg to about 1500 mg of an insoluble manganese-containing compound, from about 3 mg to about 1000 mg of an insoluble manganese-containing compound, from about 3 mg to about 900 mg of an insoluble manganese-containing compound, from about 3 mg to about 800 mg of an insoluble manganese-containing compound, from about 3 mg to about 700 mg of an insoluble manganese-containing compound, from about 3 mg to about 600 mg of an insoluble manganese-containing compound, from about 3 mg to about 500 mg of an insoluble manganese-containing compound, from about 3 mg to about 400 mg of an insoluble manganese-containing compound, from about 3 mg to about 300 mg of an insoluble manganese-containing compound, from about 3 mg to about 200 mg of an insoluble manganese-containing compound, from about 5 mg to about 3000 mg of an insoluble manganese-containing compound, from about 5 mg to about 1500 mg of an insoluble manganese-containing compound, from about 5 mg to about 1000 mg of an insoluble manganese-containing compound, from about 5 mg to about 900 mg of an insoluble manganese-containing compound, from about 5 mg to about 800 mg of an insoluble manganese-containing compound, from about 5 mg to about 700 mg of an insoluble manganese-containing compound, from about 5 mg to about 600 mg of an insoluble manganese-containing compound, from about 5 mg to about 500 mg of an insoluble manganese-containing compound, from about 5 mg to about 400 mg of an insoluble manganese-containing compound, from about 5 mg to about 300 mg of an insoluble manganese-containing compound, from about 5 mg to about 200 mg of an insoluble manganese-containing compound, from about 10 mg to about 3000 mg of an insoluble manganese-containing compound, from about 10 mg to about 1500 mg of an insoluble manganese-containing compound,An insoluble manganese-containing compound of from about 10 mg to about 1000 mg per day, an insoluble manganese-containing compound of from about 10 mg to about 900 mg per day, an insoluble manganese-containing compound of from about 10 mg to about 800 mg per day, an insoluble manganese-containing compound of from about 10 mg to about 700 mg per day, an insoluble manganese-containing compound of from about 10 mg to about 600 mg per day, an insoluble manganese-containing compound of from about 10 mg to about 500 mg per day, an insoluble manganese-containing compound of from about 10 mg to about 400 mg per day, an insoluble manganese-containing compound of from about 10 mg to about 300 mg per day, or an insoluble manganese-containing compound of from about 10 mg to about 200 mg per day. In some embodiments, the pharmaceutical composition comprises from 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.,

[0150] In some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) is administered orally.

[0151] In some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) is formulated into an oral preparation.

[0152] In some embodiments, the oral preparation is a solid oral preparation. In some embodiments, the solid oral preparation is a powder, granule, tablet, capsule, pill or lozenge. In some embodiments, the oral preparation is a liquid oral preparation.

[0153] 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 from about 3 mg to about 3000 mg, from about 3 mg to about 2500 mg, from about 3 mg to about 2000 mg, from about 3 mg to about 1500 mg, from about 3 mg to about 1000 mg, from about 3 mg to about 900 mg, from about 3 mg to about 800 mg, from about 3 mg to about 700 mg, from about 3 mg to about 600 mg, from about 3 mg to about 500 mg, from about 3 mg to about 400 mg, from about 3 mg to about 300 mg, from about 3 mg to about 200 mg, from about 5 mg to about 3000 mg, from about 5 mg to about 2500 mg, from about 5 mg to about 2000 mg, from about 5 mg to about 1500 mg, from about 5 mg to about 1000 mg, from about 5 mg to about 900 mg, from about 5 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 oral formulation comprises an insoluble manganese-containing compound of 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.

[0154] In some embodiments, the insoluble manganese-containing compound (e.g., manganese oxide) is administered to the subject once, twice or more times a day. In some embodiments, the insoluble manganese-containing compound is administered to the subject once a day. In some embodiments, the insoluble manganese-containing compound is administered to the subject twice a day. In some embodiments, the insoluble manganese-containing compound is administered to the subject three times a day. In some embodiments, the insoluble manganese-containing compound is administered to the subject four times or more a day.

[0155] In some embodiments, an effective amount of an insoluble manganese-containing compound (e.g., manganese oxide) is administered to a subject in need thereof over an extended period of time. The insoluble manganese-containing compound (e.g., manganese oxide) according to the present disclosure, in view of its advantageous biological properties (including but not limited to low solubility and / or physiological inactivity), is administered to a subject in need thereof over an extended period (i.e., an extended period) to prevent and / or treat elevated uric acid levels in the blood and / or gastrointestinal tract in a mammalian subject, or diseases or disorders associated with elevated uric acid levels in the blood and / or gastrointestinal tract, adsorb uric acid in the gastrointestinal tract of a mammal, and / or maintain (normal or appropriate) uric acid levels in the blood of a mammalian subject. For example, in some embodiments, the administration lasts 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 (e.g., the entire duration of the subject's lifespan). 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 longer (e.g., the entire duration of the subject's lifespan).

[0156] The insoluble manganese-containing compound (e.g., manganese oxide) according to the present disclosure has an adsorption effect on uric acid that is not affected, substantially not affected, or not much affected by diet so that the insoluble manganese-containing compound and food can be ingested simultaneously or sequentially at certain time intervals. Thus, in some embodiments, the insoluble manganese-containing compound and food are ingested simultaneously or at intervals of less than 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes. In some embodiments, the insoluble manganese-containing compound is administered 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, or more after food intake. The food can be one or more of meat (e.g., pork, beef, chicken, lamb, fish, shrimp), vegetables, fruits, grains (e.g., rice and / or coarse grains), but is not limited thereto.

[0157] In some embodiments, prior to administration of the insoluble manganese-containing compound (e.g., manganese oxide) to a 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% higher than 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 insoluble manganese-containing compound to a 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% higher than 240 μmol / L. In some embodiments, prior to administration of the insoluble manganese-containing compound to a 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% higher than 260 μmol / L. In some embodiments, prior to administration of the insoluble manganese-containing compound to a 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% higher than 280 μmol / L. In some embodiments, prior to administration of the insoluble manganese-containing compound to a 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% higher than 300 μmol / L.In some embodiments, prior to administration of the insoluble manganese-containing compound 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% higher than 320 μmol / L. In some embodiments, prior to administration of the insoluble manganese-containing compound 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% higher than 340 μmol / L. In some embodiments, prior to administration of the insoluble manganese-containing compound 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% higher than 360 μmol / L. In some embodiments, prior to administration of the insoluble manganese-containing compound 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% higher than 380 μmol / L. In some embodiments, prior to administration of the insoluble manganese-containing compound 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% higher than 400 μmol / L.In some embodiments, prior to administration of the insoluble manganese-containing compound to a 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% higher than 420 μmol / L.

[0158] In some embodiments, the subject's blood and / or serum uric acid level decreases after administration of the insoluble manganese-containing compound (e.g., manganese oxide) as compared to before administration of the insoluble manganese-containing compound.

[0159] In some embodiments, the subject's blood and / or serum uric acid level decreases 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) as compared to before administration of the insoluble manganese-containing compound.

[0160] Still further, in some embodiments, the subject's blood and / or serum uric acid level is from 80 μmol / L to 460 μmol / L, from 100 μmol / L to 450 μmol / L, from 150 μmol / L to 440 μmol / L, from 200 μmol / L to 430 μmol / L, from 210 μmol / L to 420 μmol / L, from 80 μmol / L to 380 μmol / L, from 100 μmol / L to 370 μmol / L or from 150 μmol / L to 360 μmol / L after administration of the insoluble manganese-containing compound (e.g., manganese oxide).

[0161] In some embodiments, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 36, 48 hours, 3, 4, 5, 6, or 7 days after administration of an insoluble manganese-containing compound (e.g., manganese oxide) in an effective amount, the blood and / or serum uric acid levels of the subject are decreased compared to those before administration of the insoluble manganese-containing compound.

[0162] For other embodiments of this aspect, reference may be made to those detailed in the first aspect above.

[0163] In an eighth aspect, the present disclosure provides a pharmaceutical composition in which the amount of manganese oxide is sufficient to decrease the blood and / or serum uric acid levels by at least about 5% within 24 hours after administration of the pharmaceutical composition in a mammalian subject whose blood and / or serum uric acid levels are at least 10% higher than 360 μmol / L or 420 μmol / L.

[0164] In some embodiments, the particle size of the manganese oxide is ≧1 μm, for example, from 1 μm to 1 mm.

[0165] In some embodiments, the pharmaceutical composition is an oral formulation.

[0166] In some embodiments, the oral formulation is a solid oral formulation. In some embodiments, the solid oral formulation is a powder, granule, tablet, capsule, pill, or lozenge. In some embodiments, the oral formulation is a liquid oral formulation.

[0167] In some embodiments, the pharmaceutical composition does not contain an additional therapeutic agent.

[0168] In some embodiments, the pharmaceutical composition comprises an effective amount of 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 manganese oxide. For example, in some embodiments, the pharmaceutical composition comprises from about 3 mg to about 3000 mg, from about 3 mg to about 2500 mg, from about 3 mg to about 2000 mg, from about 3 mg to about 1500 mg, from about 3 mg to about 1000 mg, from about 3 mg to about 900 mg, from about 3 mg to about 800 mg, from about 3 mg to about 700 mg, from about 3 mg to about 600 mg, from about 3 mg to about 500 mg, from about 3 mg to about 400 mg, from about 3 mg to about 300 mg, from about 3 mg to about 200 mg, from about 5 mg to about 3000 mg, from about 5 mg to about 2500 mg, from about 5 mg to about 2000 mg, from about 5 mg to about 1500 mg, from about 5 mg to about 1000 mg, from about 5 mg to about 900 mg, from about 5 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 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.

[0169] In some embodiments, the blood and / or serum uric acid level in a 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% higher than 360 μMol / L or 420 μMol / L. In some embodiments, the blood and / or serum uric acid level in a 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% higher than 360 μMol / L. In some embodiments, the blood and / or serum uric acid level in a 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% higher than 420 μMol / L.

[0170] In some embodiments, the blood and / or serum uric acid level in a mammalian subject decreases by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% 24 hours after administration of the pharmaceutical composition.

[0171] For other embodiments of this aspect, reference may be made to those detailed in the first aspect above.

[0172] 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, the solid dosage unit comprising manganese oxide, the manganese oxide having a uric acid clearance capacity measured in a fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay that is at least about 100 mg / g higher than the uric acid clearance capacity of activated carbon measured under the same conditions.

[0173] In some embodiments, the uric acid clearance ability of manganese oxide measured in a fasting state artificial intestinal fluid (FaSSIF) or a fed state artificial intestinal fluid (FeSSIF) assay 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 ability of activated carbon measured under the same conditions.

[0174] The fasting state artificial intestinal fluid (FaSSIF) or fed state artificial intestinal fluid (FeSSIF) assay can be performed using methods known to those skilled in the art. In some embodiments, the fasting state artificial intestinal fluid (FaSSIF) or fed state artificial intestinal fluid (FeSSIF) assay is performed with FaSSIF or FeSSIF having a uric acid 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 fasting state artificial intestinal fluid (FaSSIF) or fed state artificial intestinal fluid (FeSSIF) assay is performed at a temperature from about 25°C to 37°C, such as from 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 fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is performed at a concentration of manganese oxide from about 0.1 g / L to 2 g / L, such as from 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 1.0 g / L, 0.1 g / L to 1.1 g / L, 0.1 g / L to 1.2 g / L, 0.1 g / L to 1.3 g / L, 0.1 g / L to 1.4 g / L, 0.1 g / L to 1.5 g / L, 0.1 g / L to 1.6 g / L, 0.1 g / L to 1.7 g / L, 0.1 g / L to 1.8 g / L, 0.1 g / L to 1.9 g / L, 0.2 g / L to 2 g / L, 0.3 g / L to 2 g / L, 0.4 g / L to 2 g / L, 0.5 g / L to 2 g / L, 0.6 g / L to 2 g / L, 0.7 g / L to 2 g / L, 0.8 g / L to 2 g / L, 0.9 g / L to 2 g / L, 1.0 g / L to 2 g / L, 1.1 g / L to 2 g / L, 1.2 g / L to 2 g / L, 1.3 g / L to 2 g / L, 1.4 g / L to 2 g / L, 1.5 g / L to 2 g / L, 1.6 g / L to 2 g / L, 1.7 g / L to 2 g / L, 1.8 g / L to 2 g / L or 1.9 g / L to 2.0 g / L. In some embodiments, the fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is performed under shaking conditions. The shaking rate can be, for example, ≧50 rpm, ≧100 rpm, ≧150 rpm, ≧200 rpm, ≧250 rpm, ≧300 rpm, or higher. In some embodiments, the fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is performed at a temperature of about 25°C to 37°C, at a concentration of manganese oxide from about 0.1 g / L to 2 g / L and under shaking conditions, using a fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) with a uric acid concentration of about 8.4 ± 0.2 mg / dL.In some embodiments, the duration of the fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF) assay is ≧5 minutes, such as ≧10 minutes, ≧15 minutes, ≧20 minutes, ≧25 minutes, ≧30 minutes, ≧35 minutes, ≧40 minutes, ≧45 minutes, ≧50 minutes, ≧55 minutes, ≧60 minutes, ≧90 minutes, ≧120 minutes, ≧180 minutes, ≧240 minutes, ≧300 minutes, ≧360 minutes, ≧420 minutes, ≧480 minutes, ≧520 minutes or ≧600 minutes.

[0175] For other embodiments of this aspect, reference may be made to those detailed in the above first and eighth aspects.

[0176] The features of the various embodiments described in the above aspects of the present disclosure can be combined without causing inconsistencies to obtain one or more additional embodiments within the spirit and / or scope of the present disclosure.

Examples

[0177] The present disclosure is described in more detail below using examples. Of course, the described examples are only a part of the present invention disclosed in the present disclosure, 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 invention. All equivalents or similar technical solutions obtained by those skilled in the art without creative efforts based on the disclosed examples shall be within the scope of protection of the present invention.

[0178] (Example 1) Preparation of Test Substances This example describes the sources or preparation methods (when not commercially available) of the various test substances used in the subsequent assays.

[0179] 1.1 Preparation of Control Substances In the examples of this application, "control substance" refers to a substance that does not belong to the category of manganese-containing compounds. Unless otherwise indicated, these materials are commercially available.

[0180] The following is a non-limiting enumeration of commercially available reference substances: (1) Zeolite molecular sieves including TS-1, NaY, 10X, ZSM-5, 4A, HY, 13X, zeolite, 5A, 3A and USY, (2) Prussian blue, (3) Activated carbon, namely medical activated carbon AST-120 (or "AST120", "KREMEZIN (registered trademark)") and medical charcoal capsules, and commercial activated carbons with specific surface areas of 600 m 2 / g, 720 m 2 / g, 1045 m 2 / g, 1400 m 2 / g, 1800 m 2 / g and 3500 m 2 / g, (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 (registered trademark) 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), (5) Metal-organic frameworks (MOFs) including ZIF-8, UIO66 and UIO66NH2, and (6) Montmorillonite.

[0181] Furthermore, some of the reference substances can be prepared by artificial synthesis. The preparation methods of various types of hydrotalcite used as reference substances in the embodiments of this application (note: the following "2-1", "3-1" and "4-1" refer to the magnesium-aluminum ratio) are listed as follows:

[0182] Preparation of 2-1 hydrotalcite 570 mg of magnesium chloride, 723 mg of aluminum chloride hexahydrate and 1.26 g of urea were weighed and dissolved in 10 mL of deionized water. The solution obtained above was transferred to a hydrothermal reactor and reacted at 160 °C for 6 hours. After natural cooling, the solid was collected by centrifugation at 1000 rpm, washed until neutral with water, and dried at 70 °C for 24 hours to obtain 2-1 hydrotalcite.

[0183] Preparation of 3-1 hydrotalcite 570 mg of magnesium chloride, 482 mg of aluminum chloride hexahydrate and 1.12 g of urea were weighed and dissolved in 10 mL of deionized water. The solution obtained above was transferred to a hydrothermal reactor and reacted at 160 °C for 6 hours. After natural cooling, the solid was collected by centrifugation at 1000 rpm, washed until neutral with water, and dried at 70 °C for 24 hours to obtain 3-1 hydrotalcite.

[0184] Preparation of 4-1 hydrotalcite 570 mg of magnesium chloride, 362 mg of aluminum chloride hexahydrate and 1.048 g of urea were weighed and dissolved in 10 mL of deionized water. The solution obtained above was transferred to a hydrothermal reactor and reacted at 160 °C for 6 hours. After natural cooling, the solid was collected by centrifugation at 1000 rpm, washed until neutral with water, and dried at 70 °C for 24 hours to obtain 4-1 hydrotalcite.

[0185] Preparation of CTAB (cetyltrimethylammonium bromide) hydrotalcite 82 mg of magnesium chloride, 104 mg of aluminum chloride hexahydrate, and 180 g of urea were weighed and dissolved in 15 mL of deionized water to prepare Solution 1. 131 mg of CTAB was weighed and dissolved in 9 mL of deionized water to prepare Solution 2. Solutions 1 and 2 were uniformly mixed, transferred to a hydrothermal reactor, and reacted at 160 °C for 6 hours. After natural cooling, the system was centrifuged at 1000 rpm, the obtained solid was separated, washed until neutral with water, and dried at 70 °C for 24 hours to obtain CTAB hydrotalcite.

[0186] 1.2 Preparation of Insoluble Manganese-Containing Compounds as Test Samples As test samples, the insoluble manganese-containing compounds used in the examples of this application include commercially available insoluble manganese-containing compounds, insoluble manganese-containing compounds in the form of natural minerals, and insoluble manganese-containing compounds that can be prepared by artificial synthesis methods.

[0187] The following is a non-limiting list of commercially available insoluble manganese-containing compounds: βM (β-form crystalline manganese oxide, lot: A0431349, 99%, 10 mesh, Acros), γM (γ-form crystalline manganese oxide, lot: G1804053, >90%, Aladdin), and λMLi (lithium-type λ-form crystalline manganese oxide, spinel LiMn2O4).

[0188] The following is a non-limiting list of insoluble manganese-containing compounds in the form of natural minerals: romanechite, pyrolusite, manganite (mainly composed of γ-form crystalline manganese oxyhydroxide), groutite (mainly composed of α-form crystalline manganese oxyhydroxide), phytochnite (mainly composed of β-form crystalline manganese oxyhydroxide), hydrohausmannite (mainly composed of β-form crystalline manganese oxyhydroxide), lithiophorite, carpholite, hausmannite, bixbyite, pyrochlore, green manganite.

[0189] For the purpose of use in the embodiments of this application, all the raw materials of the insoluble manganese-containing compound in the form of natural minerals were ground, sieved, and test samples with particle sizes ranging from 1 μM to 1 mm were obtained.

[0190] Furthermore, some test samples need to be prepared through artificial synthesis methods. The following lists the methods for preparing various forms of insoluble manganese-containing compounds used as test samples in the embodiments of this application. After the preparation was completed, the polymorphs of the products obtained by these methods were identified by powder X-ray diffraction using a multifunctional X-ray diffractometer D8 ADVANCE Da Vinci. The test conditions for the powder X-ray diffraction method are as follows: The X-ray generator uses a Cu target, the X-ray tube is a ceramic tube, the voltage is ≤40 kV, the current is ≤40 mA, the scan range is from 5° to 90°, the step size is 0.020435°, and the scan speed is 4° / S.

[0191] Preparation of potassium-type δ-form crystalline manganese oxide-1 (δΜ1K) Weighed 0.948 g of potassium permanganate, dissolved it in an appropriate amount of deionized water, and placed it on a magnetic stirrer to stir at room temperature to obtain a potassium permanganate solution. Weighed 0.169 g of manganese sulfate monohydrate, dissolved it in an appropriate amount of deionized water, and added it dropwise to the potassium permanganate solution (total water volume, 35 mL). After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes to form a homogeneous solution. The solution was transferred to a hydrothermal reactor and reacted at 160 °C for 12 hours. After natural cooling, the solid was collected by filtration, washed several times with water and several times with ethanol, and dried at 60 °C for 12 hours to obtain δΜ1K.

[0192] The powder X-ray diffraction pattern of δΜ1K exhibits 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 of the δ-form crystalline form.

[0193] Preparation of hydrogen-type δ-form crystalline manganese oxide-1 (δM1KH) δΜ1K was weighed and placed in a beaker. A dilute nitric acid solution was added at a ratio of 1 g of δΜ1K to 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred in a water bath at 60 °C for 90 minutes, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried in air at 60 °C for 12 hours to obtain δΜ1KH.

[0194] The powder X-ray diffraction pattern of δM1KH exhibits 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 δ-form crystalline birnessite.

[0195] Preparation of ammonium-type δ-form crystalline manganese oxide-1 (δM1KNH4) δΜ1K was weighed and placed in a beaker. δΜ1K was dispersed in a 1 M ammonium chloride solution at a ratio of 1 g / 100 mL. The beaker was stirred at room temperature for 4 hours, then heated in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried under vacuum at 60 °C overnight to obtain δM1KNH4.

[0196] The powder X-ray diffraction pattern of δM1KNH4 exhibits 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 δ-form crystalline birnessite.

[0197] Preparation of calcium-type δ-form crystalline manganese oxide-1 (δM1KCa) Weighed δΜ1K and placed it in a beaker. δΜ1K was dispersed in a 1 M calcium chloride solution at a ratio of 1 g / 100 mL. The beaker was stirred at room temperature for 4 hours, then placed in a hydrothermal reactor at 155 °C, and the system was reacted for 24 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried overnight at 60 °C under vacuum to obtain δM1KCa.

[0198] The powder X-ray diffraction pattern of δM1KCa exhibits 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 δ-form crystalline birnessite and buserite.

[0199] Preparation of magnesium-type δ-form crystalline manganese oxide-1 (δM1KMg) Weighed δΜ1K and placed it in a beaker. δΜ1K was dispersed in a 1 M magnesium chloride solution at a ratio of 1 g / 100 mL. The beaker was stirred at room temperature for 4 hours, then placed in a hydrothermal reactor at 155 °C, and the system was reacted for 24 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried overnight at 60 °C under vacuum to obtain δM1KMg.

[0200] The powder X-ray diffraction pattern of δM1KMg exhibits 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 δ-form crystalline buserite.

[0201] Preparation of iron-type δ-form crystalline manganese oxide-1 (δM1KFe3) δΜ1K was weighed and placed in a beaker. δΜ1K was dispersed in a 1 M iron(III) chloride solution at a ratio of 1 g / 100 mL. The beaker was stirred at room temperature for 4 hours, then placed in a hydrothermal reactor at 155 °C and the system was reacted for 24 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried overnight at 60 °C under vacuum to obtain δM1KFe3.

[0202] The powder X-ray diffraction pattern of δM1KFe3 exhibits 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 δ-form crystalline birnessite.

[0203] Preparation of divalent iron-type δ-form crystalline manganese oxide-1 (δM1KFe2) δΜ1K was weighed and placed in a beaker. δΜ1K was dispersed in a 1 M iron(II) chloride solution at a ratio of 1 g / 100 mL. The beaker was stirred at room temperature for 4 hours, then heated in a 60 °C water bath for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried overnight at 60 °C under vacuum to obtain δM1KFe2.

[0204] The powder X-ray diffraction pattern of δM1KFe2 exhibits 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 δ-form crystalline birnessite.

[0205] Preparation of zinc-type δ-form crystalline manganese oxide-1 (δM1KZn) δΜ1K was weighed and placed in a beaker. δΜ1K was dispersed in a 1 M zinc chloride solution at a ratio of 1 g / 100 mL. The beaker was stirred at room temperature for 4 hours, then heated in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried under vacuum at 60 °C overnight to obtain δM1KZn.

[0206] The powder X-ray diffraction pattern of δM1KZn exhibits 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 δ-form crystalline birnessite.

[0207] Preparation of Lanthanum-Type δ-Form Crystalline Manganese Oxide-1 (δM1KLa) δΜ1K was weighed and placed in a beaker. δΜ1K was dispersed in a 1 M lanthanum chloride solution at a ratio of 1 g / 100 mL. The beaker was stirred at room temperature for 4 hours, then heated in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried under vacuum at 60 °C overnight to obtain δM1KLa.

[0208] The powder X-ray diffraction pattern of δM1KLa exhibits 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 forms of δ-form crystalline birnessite and buserite.

[0209] Preparation of Bismuth-Type δ-Form Crystalline Manganese Oxide-1 (δM1KBi) Weighed δΜ1K and placed it in a beaker. A solution of bismuth nitrate in 0.7 M dilute nitric acid was added in the ratio of 1 g of δM1K / 100 mL of 0.7 M dilute nitric acid. The beaker was stirred at room temperature for 4 hours, then heated in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried overnight at 60 °C under vacuum to obtain δM1KBi.

[0210] The powder X-ray diffraction pattern of δM1KBi exhibits 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 δ-form crystalline manganite.

[0211] Preparation of Lithium-Type δ-Form Crystalline Manganese Oxide-1 (δM1KLi) Weighed δΜ1K and placed it in a beaker. δΜ1K was dispersed in a 1 M lithium chloride solution at a ratio of 1 g / 100 mL. The beaker was stirred at room temperature for 4 hours, then heated in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried overnight at 60 °C under vacuum to obtain δM1KLi.

[0212] The powder X-ray diffraction pattern of δM1KLi exhibits 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 δ-form crystalline manganite.

[0213] Preparation of Silver-Type δ-Form Crystalline Manganese Oxide-1 (δM1KAg) δΜ1K was weighed and placed in a beaker. δΜ1K was dispersed in a 1 M silver nitrate solution at a ratio of 1 g / 100 mL. The beaker was stirred in the dark at room temperature for 4 hours, then the solid was filtered off, washed with water, and dried under vacuum at room temperature overnight to obtain δM1KAg.

[0214] The powder X-ray diffraction pattern of δM1KAg exhibits 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 substantially coincide with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of δ-form crystalline birnessite.

[0215] Preparation of potassium-type δ-form crystalline manganese oxide-2 (δM2K) and hydrogen-type δ-form crystalline manganese oxide-2.1 (δM2KH) 9.65 g of potassium hydroxide was weighed and dissolved in 180 mL of deionized water. 20 mL of 30% hydrogen peroxide solution was measured and added to the above solution and mixed. Then the mixture was added dropwise with vigorous stirring to 100 mL of an aqueous manganese nitrate solution (containing 0.03 M manganese). After the dropwise addition was completed, the system was stirred at room temperature for an additional 1 hour for aging and then left standing for 10 minutes. The supernatant was decanted, the lower solid was centrifuged, washed with water and ethanol, and dried under vacuum at 80 °C overnight to obtain δΜ2K. The δΜ2K obtained above was taken out and put into a beaker. A dilute nitric acid solution was added at a ratio of 1 g of δM2K / 100 mL of 0.7 M dilute nitric acid solution. The beaker was stirred at room temperature for 4 hours, then heated in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried under vacuum at 60 °C overnight to obtain δM2KH.

[0216] The powder X-ray diffraction pattern of δM2K exhibits 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 substantially coincide with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of δ-form crystalline form of bernardite.

[0217] The powder X-ray diffraction pattern of δM2KH exhibits 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 substantially coincide with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of δ-form crystalline form of bernardite.

[0218] Preparation of Sodium-Type δ-Form Crystalline Manganese Oxide-2 (δM_{2}Na) and Hydrogen-Type δ-Form Crystalline Manganese Oxide-2.2 (δM_{2}NaH) 3.44 g of sodium hydroxide was weighed and dissolved in 90 mL of deionized water. 10 mL of 30% hydrogen peroxide solution was measured and added to the above solution and mixed. Then the mixture was added dropwise to 50 mL of an aqueous manganese nitrate solution (containing 0.03 M manganese) with vigorous stirring. After the dropwise addition was completed, the mixture was further stirred at room temperature for 1 hour for aging and then left standing for 10 minutes. The supernatant was decanted, the lower solid was centrifuged, washed with water, and dried under vacuum at room temperature overnight to obtain δM_{2}Na. The obtained δM_{2}Na was taken out and put into a beaker. A dilute nitric acid solution was added at a ratio of 1 g of δM_{2}Na / 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred in a water bath at 60 °C for 1.5 hours and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried under vacuum at 60 °C overnight to obtain δM_{2}NaH.

[0219] The powder X-ray diffraction pattern of δM2Na exhibits 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 with a δ-form crystal form.

[0220] The powder X-ray diffraction pattern of δM2NaH exhibits 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 with a δ-form crystal form.

[0221] Preparation of Potassium-Type δ-Form Crystalline Manganese Oxide-3 (δM3K) and Hydrogen-Type δ-Form Crystalline Manganese Oxide-3 (δM3KH) 2 g of potassium permanganate was weighed and dissolved in 500 mL of deionized water. Under vigorous stirring, 10 mL of absolute ethanol was added dropwise, and the system was stirred at room temperature and reacted for 6 hours. After standing for 30 minutes, the upper turbid solution was decanted, the lower solid was centrifuged, washed with water and ethanol, and dried overnight at 80 °C under vacuum to obtain δM3K. The δΜ3K obtained above was taken out and put into a beaker. A dilute nitric acid solution was added at a ratio of 1 g of δΜ3K / 100 mL of 0.7 M dilute nitric acid solution. The beaker was stirred at room temperature for 4 hours, then heated in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried overnight at 60 °C under vacuum to obtain δM3KH.

[0222] The powder X-ray diffraction pattern of δM3K exhibits 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 with a δ-form crystal form.

[0223] The powder X-ray diffraction pattern of δM3KH exhibits 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 substantially coincide with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of δ-form crystalline manganite.

[0224] Preparation of Potassium-Type δ-Form Crystalline Manganese Oxide-4 (δM4K) 0.75 g of potassium permanganate and 0.14 g of manganese sulfate monohydrate were weighed, dissolved in 40 mL of deionized water, placed on a magnetic stirrer, and stirred at room temperature for about 30 minutes to obtain a homogeneous solution. The solution was transferred to a 100 mL hydrothermal reactor and reacted at 140 °C for 24 hours. After natural cooling, the solid was collected by filtration using a sand core funnel, washed several times with deionized water, and dried using a freeze dryer for about 12 hours to obtain δM4K.

[0225] The powder X-ray diffraction pattern of δM4K exhibits 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 δM4K substantially coincide with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the form of δ-form crystalline manganite.

[0226] Preparation of Potassium-Type α-Form Crystalline Manganese Oxide-1 (αM1K) and Hydrogen-Type α-Form Crystalline Manganese Oxide-1 (αM1KH) 1.264 g of potassium permanganate was weighed and dissolved in 30 mL of deionized water. 0.507 g of manganese sulfate monohydrate was weighed and dissolved in 10 mL of deionized water. The manganese sulfate solution was added dropwise to the vigorously stirred potassium permanganate solution. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes to form a homogeneous solution. The solution was transferred to a hydrothermal reactor and reacted at 160 °C for 12 hours. After natural cooling, the solid was collected by filtration, washed several times with water, washed several times with ethanol, and dried overnight at 80 °C under vacuum to obtain αM1K. The αM1K obtained above was weighed and put into a beaker. Dilute nitric acid solution was added at a ratio of 1 g of αM1K / 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, and the solid was washed with water and dried at 60 °C under vacuum for 24 hours to obtain αM1KH.

[0227] The powder X-ray diffraction pattern of αM1K exhibits 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 α-form crystalline manganese oxide.

[0228] The powder X-ray diffraction pattern of αM1KH exhibits 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 α-form crystalline manganese oxide.

[0229] Preparation of Potassium-Type α-Form Crystalline Manganese Oxide-2 (αM2K) and Hydrogen-Type α-Form Crystalline Manganese Oxide-2 (αM2KH) 24 mmol of potassium permanganate was weighed and dissolved in 60 mL of deionized water. 8 mmol of manganese sulfate monohydrate was weighed and dissolved in 60 mL of deionized water. The manganese sulfate solution was added dropwise to the vigorously stirred potassium permanganate solution. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes to form a homogeneous solution. The solution was transferred to a hydrothermal reactor and reacted at 120 °C for 12 hours. After natural cooling, the solid was collected by filtration, washed several times with water and several times with ethanol, and dried overnight at 80 °C under vacuum to obtain αM2K. The αM2K obtained above was weighed and put into a beaker. Dilute nitric acid solution was added at a ratio of 1 g of αM2K / 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred at 60 °C in a water bath for 1.5 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried overnight at 60 °C under vacuum to obtain αM2KH.

[0230] The powder X-ray diffraction pattern of αM2K exhibits 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 α-form crystalline manganese oxide.

[0231] The powder X-ray diffraction pattern of αM2KH exhibits 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 α-form crystalline manganese oxide.

[0232] Preparation of Potassium-Type α-Form Crystalline Manganese Oxide-3 (αM3K) and Hydrogen-Type α-Form Crystalline Manganese Oxide-3 (αM3KH) 10 mmol of potassium permanganate was weighed and dissolved in 30 mL of 1.5 M sulfuric acid solution. 30 mmol of manganese sulfate monohydrate was weighed and dissolved in 30 mL of 1.5 M sulfuric acid solution. The manganese sulfate solution was added dropwise to the vigorously stirred potassium permanganate solution. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes to form a homogeneous solution. The solution was transferred to a hydrothermal reactor and reacted at 120 °C for 12 hours. After natural cooling, the solid was collected by filtration, washed several times with water, washed several times with ethanol, and dried overnight at 80 °C under vacuum to obtain αM3K. The αM3K obtained above was weighed and put into a beaker. Dilute nitric acid solution was added at a ratio of 1 g of αM3K / 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred in a water bath at 60 °C for 1.5 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried overnight at 60 °C under vacuum to obtain αM3KH.

[0233] The powder X-ray diffraction pattern of αM3K exhibits 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 α-form crystalline manganese oxide.

[0234] [[ID=�]]The powder X-ray diffraction pattern of αM3KH exhibits 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 α-form crystalline manganese oxide.

[0235] Preparation of potassium-type β-form crystalline manganese oxide (βMK) and hydrogen-type β-form crystalline manganese oxide-1 (βMKH) 1 mmol of potassium permanganate was weighed and dissolved in an appropriate amount of deionized water. 1.5 mmol of manganese sulfate monohydrate was weighed and dissolved in an appropriate amount of deionized water. The manganese sulfate solution was added dropwise to the vigorously stirred potassium permanganate solution. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes to form a homogeneous solution (total volume 40 mL). The solution was transferred to a hydrothermal reactor and reacted at 160 °C for 12 hours. After natural cooling, the solid was collected by filtration, washed several times with water, washed several times with ethanol, and dried overnight at 80 °C under vacuum to obtain βMK. The βMK obtained above was weighed and placed in a beaker. A dilute nitric acid solution was added at a ratio of 1 g of βMK / 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred in a water bath at 60 °C for 2 hours and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried at 60 °C under vacuum for 24 hours to obtain βMKH.

[0236] The powder X-ray diffraction pattern of βMK exhibits 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 identical to the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the β-form crystal form.

[0237] The powder X-ray diffraction pattern of βMKH exhibits 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 identical to the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the β-form crystal form.

[0238] Preparation of Hydrogen-Type β-Form Crystalline Manganese Oxide-2 (βMH) Manganese βM oxide was weighed and placed in a beaker. A dilute nitric acid solution was added at a ratio of 1 g of manganese βM oxide / 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried under vacuum at 60 °C for 12 hours to obtain βMH.

[0239] The powder X-ray diffraction pattern of βMH exhibits 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-form crystalline form.

[0240] Preparation of ammonium-type γ-form crystalline manganese oxide (γΜΝ) and hydrogen-type γ-form crystalline manganese oxide-1 (γΜΝΗ) 1.69 g of manganese sulfate monohydrate and 2.28 g of ammonium persulfate were weighed and dissolved in 40 mL of deionized water. A colorless and transparent homogeneous solution was formed after stirring at room temperature for 30 minutes. The solution was transferred to a hydrothermal reactor and reacted at 80 °C for 24 hours. After natural cooling, the solid was collected by filtration, washed several times with water, washed several times with ethanol, and dried under vacuum at 80 °C overnight to obtain γMN. The γMN obtained above was weighed and put into a beaker. A dilute nitric acid solution was added at a ratio of 1 g of γMN / 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried under vacuum at 60 °C for 24 hours to obtain γMNH.

[0241] The powder X-ray diffraction pattern of γMN exhibits 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 γMN are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of manganese oxide in the γ-form crystal form.

[0242] The powder X-ray diffraction pattern of γMNH exhibits 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-form crystal form.

[0243] Preparation of hydrogen-type γ-form crystalline manganese oxide-2 (γMH) γM manganese oxide was weighed and placed in a beaker. A dilute nitric acid solution was added at a ratio of 1 g of γM manganese oxide / 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred at 60 °C in a water bath for 2 hours, and then naturally cooled to room temperature. The system was filtered to obtain a solid, the solid was washed with water, and dried under vacuum at 60 °C for 12 hours to obtain γMH.

[0244] The powder X-ray diffraction pattern of γMH exhibits 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-form crystal form.

[0245] Preparation of hydrogen-type λ-form crystalline manganese oxide (λMLiH) Weighed 2 g of λΜLi (lithium-type λ-form crystalline manganese oxide, spinel LiMn2O4), dispersed it in an aqueous solution of 0.5 M sulfuric acid, and stirred it at room temperature for 1 hour. The resulting mixture was filtered, the solid was collected, washed 5 times with deionized water, and dried overnight in a drying oven at 80 °C to obtain λΜLiH.

[0246] The powder X-ray diffraction pattern of λMLiH exhibits 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 λ-form crystalline manganese oxide.

[0247] Preparation of potassium-type ε-form crystalline manganese oxide (εMK) and hydrogen-type ε-form crystalline manganese oxide (εMKH) Weighed 4 mmol of potassium permanganate, dissolved it in 20 mL of deionized water to prepare a 0.2 M potassium permanganate solution. Further, weighed 6 mmol of manganese sulfate monohydrate, dissolved it in 20 mL of deionized water to prepare a 0.3 M manganese sulfate solution. The manganese sulfate solution and the potassium permanganate solution were mixed and stirred at room temperature for 3 hours, and the solid was collected through filtration. The resulting solid was washed 5 times with water and dried in an oven at 60 °C for 12 hours to obtain εΜΚ. The εMK obtained above was weighed and put into a beaker. A dilute nitric acid solution was added at a ratio of 100 mL of 0.7 M dilute nitric acid solution per 1 g of εMK. The beaker was heated and stirred in a water bath at 60 °C for 2 hours, and then naturally cooled to room temperature. The solid was obtained through filtration, washed 5 times with water, and dried in an oven at 60 °C for 12 hours to obtain εMKH.

[0248] The powder X-ray diffraction pattern of 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 εMK are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of ε-form crystalline manganese oxide.

[0249] The powder X-ray diffraction pattern of 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 substantially coincide with those in the powder X-ray diffraction pattern of manganese oxide in the ε-form crystal form.

[0250] Preparation of Potassium-Type Amorphous Manganese Oxide (AMK) and Hydrogen-Type Amorphous Manganese Oxide (AMKH) 1.58 g of potassium permanganate was weighed and dissolved in 60 mL of deionized water to prepare a potassium permanganate solution. Further, 2.28 g of oxalic acid was weighed and dissolved in 100 mL of deionized water to prepare an oxalic acid solution. The potassium permanganate solution was added dropwise to the oxalic acid solution under magnetic stirring. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours, and the solid was collected by filtration. The resulting solid was washed 5 times with water and 3 times with ethanol, and dried overnight at 60 °C in an oven to obtain AMK. The AMK obtained above was weighed and placed in a beaker. A dilute nitric acid solution was added at a ratio of 1 g of AMK / 100 mL of 0.7 M dilute nitric acid solution. The beaker was heated and stirred at 60 °C in a water bath for 2 hours, and then naturally cooled to room temperature. The solid was obtained by filtration, washed 5 times with water, and dried at 60 °C in an oven for 12 hours to obtain AMKH.

[0251] The powder X-ray diffraction patterns of AMK and AMKH do not show distinct characteristic X-ray diffraction peaks. This indicates that the powder X-ray diffraction patterns of AMK and AMKH basically coincide with those of amorphous manganese oxide.

[0252] Preparation of Hydrogen-Type R-Form Crystalline Manganese Oxide (RMH) Weighed 3g of λΜLi of 3g (lithium-type λ-form crystalline manganese oxide, spinel LiMn2O4), dispersed it in 15 mL of 2.5 M sulfuric acid aqueous solution, and stirred it at 80 °C for 2.5 hours. The precipitate was obtained by centrifugation, purified 4 times with ultrapure water, and dried overnight at 80 °C under vacuum to obtain RMH.

[0253] The powder X-ray diffraction pattern of RMH exhibits 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 RMH are substantially consistent with the characteristic X-ray diffraction peaks in the powder X-ray diffraction pattern of R-form crystalline manganese oxide.

[0254] (Example 2) In vitro performance evaluation In this example, the clearance of uric acid by the test substance (i.e., uric acid adsorbent) was tested under various in vitro mimicking conditions to compare the performance of the insoluble manganese-containing compound according to the present disclosure with that of the control substance.

[0255] The composition of the body's gastrointestinal fluid is extremely complex and varies widely under various conditions (e.g., in various parts of the stomach, small intestine, and large intestine) and before and after meals (fasting, feeding). Therefore, in order to mimic the gastrointestinal environment under different conditions, it is necessary to select different artificial gastrointestinal fluids. In this example, the uric acid clearance ability of each test substance in simulated intestinal fluid (SIF), fasting state simulated intestinal fluid (FaSSIF), fed state simulated intestinal fluid (FeSSIF), and food enzyme hydrolysate was determined respectively. SIF only mimics the general pH and main inorganic salt components of intestinal fluid, while FaSSIF and FeSSIF mimic the small intestinal fluid components (including inorganic and organic components) before and after meals. On the other hand, food enzyme hydrolysate better mimics the gastrointestinal porridge-like fluid after consuming various types of foods. As the complexity of the components of the above artificial liquids increases, the proximity to the real human gastrointestinal environment increases accordingly. The more the complexity of the components of the artificial liquid increases, the higher the clearance effect of the substance tested against uric acid due to interference from other components that weaken the clearance effect.

[0256] 2.1 Comparison between the control substance and the test substance regarding the uric acid clearance ability and clearance rate measured by the SIF assay The experimental method is as follows: A 500 μΜ solution of uric acid in SIF containing approximately 50 mM phosphate at pH 6.8 was freshly prepared (concentration 8.4 mg / dL). 8 mg of each adsorbent was weighed and a solution of uric acid in 4 mL of SIF (adsorbent concentration: 2 g / L) was added. The mixture was placed on a shaker and shaken at 200 rpm at 25 °C for 4 hours. Subsequently, 1 mL of each sample was pipetted, centrifuged at 10000 rpm for 5 minutes, the supernatant was taken, diluted 10-fold (90 μL of SIF + 10 μL of supernatant), placed in a 96-well plate, and the absorbance was measured at 291 nm using a microplate reader. A standard curve including 0, 12.5, 25, 50, 100 and 500 μΜ point values was newly created. The uric acid concentration C (μΜ) in the supernatant was calculated according to the standard curve, the uric acid clearance ability Q (mg / g) was calculated according to Equation 1, and the uric acid clearance rate (%) was calculated according to Equation 2. Equation 1: Q = 0.168×(500 - C)×4 / 8 Equation 2: Uric acid clearance rate = (500 - C) / 500×100%

[0257] The results are shown in Figure 1. Figure 1 shows that among various types of uric acid adsorbents, manganese oxides (δΜ1KH and αΜ3KH) and activated carbon (AST-120) have the best adsorption effect on uric acid under the conditions of the SIF assay.

[0258] 2.2 Comparison between various types of insoluble manganese-containing compounds and activated carbon adsorbents regarding the uric acid clearance rate measured by the SIF assay The experimental method is as follows: A 500 μM solution of uric acid in SIF containing approximately 50 mM phosphate at pH 6.8 was freshly prepared (concentration 8.4 mg / dL). Various types 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, romanechite, pyrolusite, manganite, groutite, phillipsite, hydrohausmannite, lithiophorite, carpholite, hausmannite, vicsite, pyrochlore and green manganite) and various types of activated carbon adsorbents (two types of medical activated carbon: medical charcoal capsules, AST-120, and commercial activated carbons with specific surface areas of 600 m 2 / g, 720 m 2 / g, 1045 m 2 / g, 1400 m 2 / g, 1800 m 2 / g and 3500 m 2 / g) were each weighed at 20 mg, a solution of uric acid in 10 mL of SIF (adsorbent concentration: 2 g / L) was added, the mixture was placed on a shaker, and shaken at 200 rpm at 25 °C for 1 hour. Then, 1 mL of each sample was pipetted and centrifuged at 10000 rpm for 5 minutes. The supernatant was diluted 10-fold (90 μL of SIF + 10 μL of supernatant) and placed in a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. A standard curve including 0, 12.5, 25, 50, 100 and 500 μM point values was newly created. 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 Equation 2.

[0259] The results are shown in Figure 2. Figure 2 shows that various types of insoluble manganese-containing compounds and various types of activated carbon have a specific clearance effect on uric acid under the conditions of the SIF assay. Among these, various commercially available insoluble manganese-containing compounds, insoluble manganese-containing compounds prepared according to the method of Example 1, and various activated carbon adsorbents were able to achieve a high uric acid clearance rate. Furthermore, it was also found that the uric acid clearance rate of potassium-type, sodium-type or ammonium-type manganese oxides changed after being converted to the corresponding hydrogen-type manganese oxides.

[0260] 2.3 Comparison between various types of insoluble manganese-containing compounds and activated carbon adsorbents in terms of uric acid clearance rate measured by SIF assay The experimental method is as follows: A 500 μM solution of uric acid in SIF containing about 50 mM phosphate at pH 6.8 was freshly prepared (concentration 8.4 mg / dL). Various types of adsorbents (δM1KH, αM3KH, δM2KH, βMKH, RMH, γMNH, λMLiH, AMKH and AST-120) were each weighed at 4 mg, and a solution of uric acid in 2 mL of SIF (concentration of adsorbent: 2 g / L) was added. At 25 °C, the mixture was placed on a shaker and shaken at 200 rpm for 10 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, and then shaken manually for 5 minutes. Then, the mixture was immediately filtered, the filtrate was diluted 10-fold (90 μL of SIF + 10 μL of filtrate), placed in a 96-well plate, and the absorbance was measured at 291 nm using a microplate reader. A standard curve including 0, 12.5, 25, 50, 100 and 500 μM point values was newly created. The uric acid concentration C (μM) in the supernatant was calculated according to the standard curve, the uric acid clearance rate (%) after mixing for various periods was calculated according to Equation 2, and a curve of uric acid clearance rate vs. mixing time was plotted.

[0261] The results are shown in Figure 3. Figure 3 shows that various insoluble manganese-containing compounds and activated carbon prepared according to the method of Example 1 have a relatively fast uric acid clearance rate, and all of them can effectively clear uric acid within 30 to 60 minutes, and most of the uric acid (≧80%) in the solution system can be cleared within 120 minutes.

[0262] 2.4 Comparison between various types of insoluble manganese-containing compounds and activated carbon adsorbents regarding uric acid clearance ability measured by SIF assay The experimental method is as follows: A 500 μΜ solution of uric acid in SIF containing about 50 mM phosphate at pH 6.8 was freshly prepared (concentration 8.4 mg / dL). Various 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, romanechite, pyrolusite, manganite, groutite, phillipsite, hydrohausmannite, lithiophorite, carpholite, hausmannite, bixbyite, pyrochlore, green manganese ore, medical charcoal capsules, AST-120, and commercial activated carbons with specific surface areas of 600 m 2 / g, 720 m 2 / g, 1045 m 2 / g, 1400 m 2 / g, 1800 m 2 / g and 3500 m 2 / g) were each weighed at 4 mg, and a solution of uric acid in 40 mL of SIF (adsorbent concentration: 0.1 g / L) was added. The mixture was placed on a shaker and shaken at 200 rpm at 37 °C for 4 hours. Then, 1 mL of each sample was pipetted and centrifuged at 10,000 rpm for 5 minutes. 100 μL of the supernatant was taken and placed in a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. A standard curve including 0, 100, 200, 300, 400, and 500 μM point values was newly created. The uric acid concentration C (μΜ) in the supernatant was calculated according to the standard curve, and the uric acid clearance ability Q (mg / g) was calculated according to Equation 3. Formula 3: Q = 0.168×(500 - C)×40 / 4

[0263] The results are shown in Figure 4. Figure 4 shows that various types of insoluble manganese-containing compounds and various types of activated carbon have a certain clearance effect on uric acid under the conditions of the SIF assay. Among all types of insoluble manganese-containing compounds, the lowest and highest clearance capacities are approximately 10 mg / g and approximately 800 mg / g, respectively, and among all types of activated carbon, the lowest and highest clearance capacities are approximately 20 mg / g and approximately 600 mg / g, respectively. Generally, insoluble manganese-containing compounds and activated carbon are similar with respect to uric acid clearance capacity under SIF assay conditions.

[0264] 2.5 Comparison of uric acid clearance capacity and clearance rate between insoluble manganese-containing compounds and activated carbon adsorbents, montmorillonite, and ion exchange resins in simple artificial intestinal fluid (SIF) and complex artificial intestinal fluids FaSSIF and FeSSIF assays Compared with SIF, FaSSIF and FeSSIF have more complex components closer to the actual situation in the body. Under such complex conditions, the clearance effect of the adsorbent on uric acid is more easily affected by the components of the complex environment. Therefore, this example compares the uric acid clearance capacity of various insoluble manganese-containing compounds measured by SIF, FaSSIF, and FeSSIF assays to examine the effect of the complex environment on the uric acid adsorption effect of the adsorbent, with the uric acid clearance capacity of activated carbon adsorbents, montmorillonite, and ion exchange resins.

[0265] Specifically, the examples are divided into two separate parts. In the first part, a comparison of the uric acid clearance ability between various insoluble manganese-containing compounds, activated carbon adsorbent (AST-120), and montmorillonite, measured by SIF, FaSSIF, or FeSSIF assay, was made. In the second part, δΜ4K, an exemplary insoluble manganese-containing compound, was compared with an ion exchange resin (sevelamer hydrochloride) regarding the uric acid clearance ability and clearance rate measured by SIF, FaSSIF, or FeSSIF assay.

[0266] The specific experimental method in the first part is as follows: A new 500 μΜ solution of uric acid (concentration 8.4 mg / dL) in SIF, FaSSIF, or FeSSIF was freshly prepared. The 500 μM uric acid solution obtained above was diluted with SIF, FaSSIF, or FeSSIF solution 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. Adsorbents (δΜ1KH, δΜ2KH, αΜ1KH, βΜΚΗ, γΜΝΗ, εΜΚΗ, RMH, AMKH, AST-120, and montmorillonite) were each weighed at 4 mg, and 40 mL of solutions with various uric acid concentrations (adsorbent concentration: 0.1 g / L) were added. At 37 °C, the mixture was placed on a shaker and shaken at 200 rpm for 4 hours. Then, 1 mL of each sample was pipetted and centrifuged at 10,000 rpm for 5 minutes. 100 μL of the supernatant was taken and placed in a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. A new standard curve containing 0, 100, 200, 300, 400, and 500 μM point values was made using SIF, FaSSIF, or FeSSIF. The uric acid concentration Ct (μM) in the supernatant was calculated according to the standard curve, and the uric acid clearance ability Q (mg / g) was calculated according to Equation 4. Equation 4: Q = 0.168 × (C0 - Ct) × 40 / 4

[0267] The specific experimental method in the second part is as follows: A new 500 μM solution of uric acid (concentration 8.4 mg / dL) in SIF, FaSSIF, or FeSSIF was freshly prepared. The 500 μM uric acid solution obtained above was diluted with SIF, FaSSIF, or FeSSIF solution 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 of adsorbents (δM4K and sevelamer hydrochloride) were each weighed and 40 mL of solutions with various uric acid concentrations (adsorbent concentration: 0.1 g / L) were added. At 37 °C, the mixture was placed on a shaker and shaken at 200 rpm for 4 hours. Then, 1 mL of each sample was pipetted and centrifuged at 10,000 rpm for 5 minutes. 100 μL of the supernatant was taken and placed in a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. A standard curve including 0, 100, 200, 300, 400, 500, 750, and 1000 μM point values was newly created using SIF, FaSSIF, or FeSSIF. The uric acid concentration Ct (μM) in the supernatant was calculated according to the standard curve, the uric acid clearance capacity Q (mg / g) was calculated according to Equation 4, and the uric acid clearance rate (%) was calculated according to Equation 5. Equation 5: Uric acid clearance rate = (C0 - Ct) / C0 × 100%

[0268] The results of the first part are shown in Figures 5, 6, and 7. Figures 5, 6, and 7 show that under the conditions of the SIF assay, the equilibrium uric acid clearance capacity reached 400 - 800 mg / g with various insoluble manganese-containing compounds, approximately 250 mg / g with activated carbon, and approximately 100 mg / g with montmorillonite. The equilibrium uric acid clearance capacity of δ-form manganese oxide was approximately 800 mg / g under the FaSSIF assay conditions, while those of activated carbon and montmorillonite were approximately 0 mg / g. Under the FeSSIF assay conditions, the equilibrium uric acid clearance capacity of δ-form manganese oxide slightly decreased but still reached approximately 600 mg / g, while those of activated carbon and montmorillonite were substantially 0 mg / g. This indicates that under various complex artificial intestinal fluid conditions, δ-form manganese oxide maintains a high uric acid adsorption effect, while the adsorption effects of activated carbon and montmorillonite on uric acid basically disappear.

[0269] The results of the second part are shown in Figures 8 to 13. Figures 8 and 9 show that the uric acid clearance ability of δΜ4K increases according to the concentration of uric acid under the SIF assay conditions. Under the condition of a uric acid concentration of 500 μΜ, the uric acid clearance ability and uric acid clearance rate of δΜ4K were approximately 800 mg / g and approximately 100% respectively, while the uric acid clearance ability and uric acid clearance rate of the ion exchange resin were only approximately 84 mg / g and approximately 10% respectively. Figures 10 and 11 show that the clearance effect of δΜ4K on uric acid under the FaSSIF assay conditions is the same as that under the SIF assay conditions. Specifically, under the condition of a uric acid concentration of 500 μΜ, the uric acid clearance ability and uric acid clearance rate of δΜ4K could still reach approximately 750 mg / g and approximately 90% respectively, while the uric acid clearance ability and uric acid clearance rate of the ion exchange resin were substantially 0 mg / g and 0% respectively. Figures 12 and 13 show that the clearance effect of δΜ4K on uric acid under the FeSSIF assay conditions is the same as that under the SIF assay conditions. Specifically, under the condition of a uric acid concentration of 500 μΜ, although the uric acid clearance ability and uric acid clearance rate of δΜ4K decreased slightly, they still reached approximately 700 mg / g and approximately 80% respectively, while the uric acid clearance ability and uric acid clearance rate of the ion exchange resin were still substantially 0 mg / g and approximately 0% respectively. This also shows that while δ-manganese oxide can maintain a high uric acid adsorption effect under various complex artificial intestinal fluid conditions, the uric acid adsorption effect of the ion exchange resin basically disappears under the same conditions.

[0270] 2.6 Comparison of the uric acid adsorption effect between various types of insoluble manganese-containing compounds and activated carbon adsorbents in the pork enzyme hydrolysis product assay Pork enzyme hydrolysate is rich in various organic molecules, such as peptides, amino acids, lipid molecules, carbohydrates and various vitamins, which have a strong interfering effect on the uric acid clearance effect of uric acid adsorbents. Therefore, this example further examines the effect of a complex environment on the uric acid adsorption effect of the adsorbent by comparing the uric acid clearance ability of various insoluble manganese-containing compounds with that of the activated carbon adsorbent in the pork enzyme hydrolysate assay.

[0271] The specific experimental method is as follows: Pork was heated and cooked, then stirred with a stirrer, and a mixed enzyme hydrolysate of α-amylase, amyloglucosidase, nuclease, pancreatic lipase and trypsin was added, and the system was enzymatically decomposed overnight at 37 °C to obtain pork enzyme hydrolysate. Uric acid (final concentration 500 μΜ) was added to the pork enzyme hydrolysate, and various types of adsorbents (final concentration 0.1 g / L) were added. At 37 °C, the system was placed on a shaker and shaken at 200 rpm for 4 hours. The supernatant was obtained by filtration. The uric acid concentration C (μΜ) in the supernatant was tested, and the clearance ability Q (mg / g) was calculated according to Equation 3.

[0272] The results are shown in Figure 14. Figure 14 shows that under the pork enzyme hydrolysate assay conditions, amorphous manganese hydroxide (AMKH) and δ-form manganese hydroxide (δM1KH and δM2KH) have the best adsorption effect on uric acid and still maintain a uric acid clearance ability exceeding 200 mg / g, while the uric acid clearance effect of activated carbon (AST-120 and medical charcoal capsules) is completely lost.

[0273] 2.7 Comparison of uric acid adsorption effects among various types of insoluble manganese-containing compound adsorbents in food enzyme hydrolysate assay Various food enzyme hydrolysates mimic human gastrointestinal chyme and have a strong interfering effect on the uric acid clearance effect of uric acid adsorbents. Therefore, this example further examines the effect of a complex environment on the uric acid adsorption effect of the adsorbent by comparing the uric acid clearance ability of various insoluble manganese-containing compounds in the food enzyme hydrolysate assay.

[0274] The specific experimental method is as follows: Pork, rice, and vegetables were heated and cooked separately, then stirred with a stirrer, fruits were directly stirred with a stirrer, and a mixed enzyme hydrolysate of α-amylase, amyloglucosidase, nuclease, pancreatic lipase, and trypsin was added. The system was enzymatically digested overnight at 37°C to obtain four kinds of food enzyme hydrolysates. Uric acid (final concentration of 500 μM) and various types of insoluble manganese-containing compounds (manganese oxide) (final concentration of 0.1 g / L) were added to each of the four food enzyme hydrolysates. The samples were placed on a shaker and shaken at 200 rpm at 37°C for 4 hours. The supernatant was obtained by filtration. The uric acid concentration C (μΜ) in the supernatant was tested, and the clearance ability Q (mg / g) was calculated according to Equation 3.

[0275] The results are shown in Figure 15. Figure 15 shows that under the assay conditions of the four food enzyme hydrolysates, all various types of manganese oxides maintained a high adsorption effect on uric acid. Among them, δ-form manganese oxide had the best effect, maintaining a uric acid clearance ability exceeding 200 mg / g in the enzyme hydrolysates of various foods.

[0276] 2.8 Comparison of the uric acid clearance ability of manganese oxide adsorbents of various salt types in the SIF assay The purpose of this example is to investigate the effect of the type of cation incorporated into the interatomic holes in the manganese oxide structure on the uric acid adsorption effect of the corresponding salt-type manganese oxide adsorbent.

[0277] The experimental method is as follows: A 500 μM solution of uric acid in SIF containing approximately 50 mM phosphate at pH 6.8 was freshly prepared (concentration 8.4 mg / dL). 4 mg of manganese oxide absorbents of various salt forms (δΜ1K, δΜ1KLi, δΜ1KH, δΜ1KNH4, δΜ1KCa, δΜ1KMg, δΜ1KFe2, δΜ1KFe3, δΜ1KZn, δΜ1KLa, δΜ1KBi, δΜ1KAg) were each weighed. A uric acid solution in 40 mL of SIF (absorbent concentration: 0.1 g / L) was added, and the mixture was placed on a shaker and shaken at 200 rpm at 37 °C for 4 hours. Then, 1 mL of each sample was pipetted and centrifuged at 10,000 rpm for 5 minutes. 100 μL of the supernatant was taken and placed in a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. A standard curve including 0, 100, 200, 300, 400, and 500 μM point values was freshly created. The uric acid concentration C (μΜ) in the supernatant was calculated according to the standard curve, and the uric acid clearance capacity Q (mg / g) was calculated according to Equation 3.

[0278] The results are shown in Figure 16. Figure 16 shows that under SIF assay conditions, manganese oxide adsorbents of various salt forms had a certain clearance effect on uric acid. Among all types of manganese oxide absorbents, the lowest clearance capacity was approximately 500 mg / g, and the highest clearance capacity was approximately 800 mg / g. Generally, under SIF assay conditions, manganese oxide absorbents of various salt forms had a similar ability to clear uric acid.

[0279] 2.9 Comparison of uric acid clearance capacity and uric acid clearance rate measured by SIF assay for various concentrations of insoluble manganese-containing compounds The experimental method is as follows: A 500 μM solution of uric acid in SIF containing approximately 50 mM phosphate at pH 6.8 was freshly prepared (concentration 8.4 mg / dL). 2, 2.4, 2.8, 3, 3.2, 3.6, 4, 6 or 8 mg of the insoluble manganese-containing compound (δM4K) was separately weighed and 40 mL of the uric acid solution in SIF was added to make the concentration of the adsorbent (Cx) 0.06, 0.07, 0.075, 0.08, 0.09, 0.1, 0.15 or 0.2 g / L, respectively. The mixture was placed on a shaker and shaken at 200 rpm at 37 °C for 4 hours. Then, 1 mL of each sample was pipetted and centrifuged at 10,000 rpm for 5 minutes. 100 μL of the supernatant was taken and placed in a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. A standard curve including 0, 100, 200, 300, 400 and 500 μM point values was newly created. The uric acid concentration C (μM) in the supernatant was calculated according to the standard curve, the uric acid clearance capacity Q (mg / g) was calculated according to Equation 6, and the uric acid clearance rate (%) was calculated according to Equation 2. Equation 6: Q = 0.168×(500 - C) / Cx

[0280] The results are shown in Figures 17 and 18, respectively. Figure 17 shows that adsorbents of various concentrations of δΜ4K have a specific clearance effect on uric acid under the conditions of the SIF assay, the lowest clearance capacity is about 400 mg / g, the highest clearance capacity is about 1100 mg / g, and the clearance capacity gradually decreases with the increase in the concentration of the adsorbent. Figure 18 shows that under the SIF assay conditions, the uric acid clearance rate of the δM4K adsorbent at various concentrations gradually increases with the gradual increase in the adsorbent concentration. When the adsorbent concentration reaches 0.1 g / L, the uric acid clearance rate reaches about 100%, and when the adsorbent concentration continues to increase, the uric acid clearance rate remains at about 100%.

[0281] 2.10 Cumulative uric acid clearance capacity measured in multiple SIF assays for insoluble manganese-containing compounds It is known that the content of uric acid in the intestinal tract is not constant. Specifically, the content of uric acid varies in different parts of the intestine and at different times, but generally ranges from 100 μM to 1300 μM. By performing multiple adsorption assays of the adsorbent in a low-concentration uric acid solution (for example, a 100 μM uric acid solution), the ability of the adsorbent to continuously adsorb uric acid under conditions of low uric acid content in the environment when passing through the intestinal tract can be reflected.

[0282] The experimental method is as follows: A 100 μΜ solution of uric acid in SIF containing about 50 mM phosphate with a pH of about 6.8 was freshly prepared (concentration 1.68 mg / dL). 4 mg of an insoluble manganese-containing compound (δΜ4K) was weighed, and a solution of uric acid in 40 mL of SIF (absorbent concentration: 0.1 g / L) was added. The mixture was placed in a shaker and shaken at 200 rpm at 37 °C for 0.5 hour, which was recorded as the first adsorption. The solid was then filtered off and placed in a new solution of 100 μΜ uric acid in 40 mL of SIF under the same shaking conditions for the second adsorption. Then the above procedure was repeated until a total of 12 adsorptions were completed. Thereafter, 1 mL of the filtrate was pipetted from the filtrate at each adsorption and centrifuged at 10,000 rpm for 5 minutes. 100 μL of the supernatant was taken and placed in a 96-well plate. The absorbance was measured at 291 nm using a microplate reader. A new standard curve was made including 0, 25, 50, 100, 200, and 500 μΜ point values. The uric acid concentration C (μΜ) in the supernatant was calculated according to the standard curve, the uric acid clearance capacity Q (mg / g) was calculated according to Equation 7, and the uric acid clearance rate (%) was calculated according to Equation 8. Equation 7: Q = 0.168×(100 - C)×40 / 4 Equation 8: Uric acid clearance rate = (100 - C) / 100×100%

[0283] The results are shown in Fig. 19. Fig. 19 shows that δΜ4K exhibited excellent uric acid clearance in multiple adsorption assays in solutions with low concentrations of uric acid in SIF. Specifically, in the first adsorption, the uric acid clearance ability of δM4K was approximately 170 mg / g, and the uric acid clearance rate was approximately 100%. With an increase in the number of adsorption times, the uric acid clearance ability of δΜ4K gradually decreased. Nevertheless, even at the 12th adsorption, the uric acid clearance ability of δΜ4K was still approximately 60 mg / g, and the cumulative uric acid clearance ability after a total of 12 adsorptions was approximately 1250 mg / g. The results indicate that δΜ4K could continuously adsorb uric acid at low uric acid concentrations and furthermore maintain an effective uric acid adsorption ability after multiple adsorptions.

[0284] (Example 3) Problems of size and solubility for manganese-containing compounds, and calculation of oral safe dosage Manganese is one of the essential trace elements in the normal body. As a component of many enzymes, manganese plays many important physiological roles. However, excessive intake of manganese may also cause damage to the body. For example, some manganese miners have been reported to suffer from severe neurological damage due to long-term inhalation of air with excessive manganese levels. Inhaled manganese can be directly transported into the brain tissue and may cause a permanent neurological disorder called "manganese poisoning". Insoluble inorganic manganese compounds, such as manganese oxide, are generally considered relatively safe in oral intake compared to inhalation, but there is still a risk of severe toxicity from excessive intake. For example, manganese oxide of nanometer size and slightly soluble manganese ions can enter the systemic circulation through the gastrointestinal tract and may become the main source of toxicity, and its toxicity mainly depends on the dose of absorbed manganese.

[0285] In this example, the applicant conducted an in vitro experiment mimicking the dissolution of manganese in gastrointestinal fluid, and measured the solubility of manganese oxides of various particle sizes of 1 micron and above (this size is designed to reduce the possibility of nano-form manganese-containing compounds being absorbed in the systemic circulation) in simulated intestinal fluid (SIF) (expressed as the value of the manganese dissolution amount of manganese oxide in SIF measured by the "Method for Manganese Dissolution Experiment" described below), and compared the dissolution of various types of manganese oxides. Since the amount of manganese-containing compound dissolved in gastrointestinal fluid basically determines the amount absorbed by the body, the applicant also calculated the safe dosage of these various types of manganese oxides when used orally in the human body based on the above results.

[0286] Method for Manganese Dissolution Experiment Various types of manganese oxides of various synthetic lots were dispersed in SIF at 2 g / L, incubated at 37 °C for 4 hours with a constant temperature shaker, and then filtered to obtain a filtrate. The manganese content in the filtrate was detected by inductively coupled plasma mass spectrometry (ICP-MS) to obtain the value of the manganese dissolution amount of manganese oxide in SIF, and this was designated as C mg / L.

[0287] Method for Calculating Safe Oral Dosage The oral safe dose was calculated based on the Tolerable Upper Intake Level (TUIL) of 0.16 mg / kg / day or 11 mg / day (recommended by the Agency for Toxic Substances and Disease Registry (ATSDR) of the United States). It is known that approximately 9 liters of fluid volume (V) passes through the gastrointestinal tract daily (Kvietys, P.R. and Granger, D.N. (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) for various types of manganese oxide and an additional uncertainty factor (UF) of 10, the calculation formula for the oral safe dose of various types of manganese oxide can be expressed as follows: Oral safe dose (g) = (TUIL × 2 g) / (C × V) / UF.

[0288] The amount of manganese dissolved in SIF for various types of manganese oxide measured in this example, and their respective estimated oral safe doses are as follows: [Table 1-1] [Table 1-2]

[0289] The above results indicate that all manganese oxides prepared by various methods have extremely low solubility in artificial intestinal fluid, which enables manganese oxide to be administered at extremely high oral safe doses without causing unacceptable side effects.

[0290] (Example 4) In vivo performance evaluation This example compares the uric acid-lowering properties of manganese oxide and a control substance in animals.

[0291] Specifically, the test substance and the control substance were administered to healthy rats, healthy mice, hyperuricemia model rats, and hyperuricemia model mice, and the effect of the test substance on the reduction of uric acid content in the body fluids of the animals was examined.

[0292] 4.1 Experiment in healthy rats Experimental method Male SD rats at 7 to 8 weeks of age were randomly divided into 5 groups of 6 rats each, which included 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, sterile water was forcibly administered orally to the blank group every day, and the other treatment groups were each administered a fixed dose of the test substance suspension. On days 0 and 7, the uric acid levels in the rat body fluids were measured.

[0293] Results After the administration of manganese oxide, the drug tolerance in the rats in each treatment group was good, and there were no adverse reactions. Manganese oxide can effectively reduce the uric acid content in the rat body fluids.

[0294] 4.2 Experiment in healthy mice Experimental method Male SD mice at 7 to 8 weeks of age were randomly divided into 5 groups of 6 mice each, which included 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, sterile water was forcibly administered orally to the blank group every day, and the other treatment groups were each administered a fixed dose of the test substance suspension. On days 0 and 7, the uric acid levels in the mouse body fluids were measured.

[0295] Results After administration of manganese oxide, the tolerance of the drug in the mice in each treatment group was good, and there were no adverse reactions. Manganese oxide can efficiently reduce the uric acid content in mouse body fluids.

[0296] 4.3 Experiment on Hyperuricemia Model Rats A hyperuricemia rat model was established as follows (see J. Agric. Food Chem. 2019, 67, 220 - 228): Animals were force-fed 450 mg / kg / day of oxonic acid potassium (physiological saline solution) + 100 mg / kg / day of adenine (physiological saline solution) for 7 days.

[0297] Experimental Method Male SD rats, 7 - 8 weeks old, were randomly divided into 9 groups of 6 rats each. These included a blank group (administered sterile water), a model group (administered only the inducer drug), an activated carbon control group (administered the inducer drug + activated carbon), a montmorillonite control group (administered the inducer drug + montmorillonite), an allopurinol control group (administered the inducer drug + allopurinol), a lesinurad control group (administered the inducer drug + lesinurad), a low-dose group (administered the inducer drug + low-dose manganese oxide), a medium-dose group (administered the inducer drug + medium-dose manganese oxide), and a high-dose group (administered the inducer drug + high-dose manganese oxide). The corresponding drugs were force-fed to the rats daily for 7 days. On the 7th day, the uric acid content in the body fluids of the hyperuricemia model rats was detected.

[0298] Results Under drug induction, the level of uric acid in rat body fluids increased. However, manganese oxide efficiently reduced the uric acid level in the body fluids of hyperuricemia model rats; at some doses, manganese oxide reduced the uric acid level better than or equally to allopurinol.

[0299] 4.4 Experiment on Hyperuricemia Model Mice 4.4.1 Experiment on Uricase Knockout (UOX KO) Mice Experimental Method Six- to eight-week-old uricase knockout (UOX KO) mice were selected. After one week of acclimation, urine and blood were collected to test urine uric acid and blood uric acid levels. Based on the criterion of no significant difference in blood uric acid levels among groups, the mice were randomly divided into five groups of nine mice each, which included a model group (administered sterile water), a positive control group (administered allopurinol), a low-dose group (administered low-dose manganese oxide), a medium-dose group (administered medium-dose manganese oxide), and a high-dose group (administered high-dose manganese oxide). The corresponding drugs were force-fed orally to the mice daily. After starting drug administration, the blood of the mice was collected every other week to prepare serum, and 24-hour urine was collected to detect the uric acid content in the urine using a uric acid assay kit.

[0300] Results UOX KO mice had high levels of uric acid in the blood and urine. Allopurinol was effective in reducing uric acid in UOX KO mice, and manganese oxide outperformed or equaled allopurinol in reducing uric acid at some doses.

[0301] 4.4.2 Experiment in oxonic acid potassium and adenine-induced hyperuricemia model mice Oteracil potassium and adenine are known to be model drugs capable of inducing hyperuricemia in mice. Specifically, oteracil potassium is a urate oxidase inhibitor that can inhibit 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 this example, healthy mice were randomly divided into 7 groups, and oteracil potassium and adenine were administered to 6 groups of mice (both were added to the basal diet of the mice), thereby establishing a mouse hyperuricemia model, and 1 group of healthy mice fed only the basal diet of the mice was used as the blank control group. The mice in the experimental groups were given the corresponding experimental substances according to the dosing regimens described in the following experimental methods. Six days after the start of the experiment, 24-hour urine samples were collected from each group of mice, and the uric acid content in the urine was detected using a uric acid assay kit to investigate the effects of various experimental substances on the amount of uric acid excreted in the urine of mice.

[0302] Experimental method Forty-two 6-week-old male KM mice were randomly divided into seven groups of six mice each, including a blank control group, a hyperuricemia model group, an allopurinol group, a febuxostat group, a δΜ1KH group, a δΜ2KH group, and a δΜ4K group. The control group was fed the basal diet of the mice from day 1 (i.e., the experimental day) to day 7 after the experiment started. For the other groups, to induce hyperuricemia, a modeled diet for mice (4.4 w / w% potassium oxonate and 0.44 w / w% adenine added to the basal diet of the mice) was fed. From day 1 to day 7 after the experiment started, the allopurinol group freely drank drinking water containing 50 mg / L allopurinol every day. The febuxostat group was given febuxostat (5 mg / kg / day) by forced oral administration every day. The δM1KH group, the δM2KH group, and the δM4K group were fed the diet of mice containing drugs every day (1.16 w / w% of δM1KH, δM2KH, or δM4K was added to the modeled diet of the mice, respectively). On day 6 after the experiment started, the mice were placed in metabolic cages, and urine was collected for 24 hours to analyze the uric acid level. One or two drops of 8 mol / L aqueous NaOH solution were added to the urine collection container to prevent urate precipitation. The uric acid level in the urine was measured using a uric acid assay kit (Solarbio, Beijing, China), and the amount of uric acid excreted through the urine in 24 hours was calculated based on the urine volume.

[0303] Results The results are shown in Figure 20. Figure 20 shows that the continuous 7-day administration of potassium oxonate and adenine to mice significantly increased the amount of uric acid excreted in the urine of the mice. The amount of uric acid excreted in the urine of the mice administered allopurinol or febuxostat respectively was also at a high level. In contrast, the amount of uric acid excreted in the urine significantly decreased in the mice receiving manganese oxide. Without being bound by any theory, the reason why manganese oxide (e.g., δ-form manganese oxide) significantly reduces uric acid excretion through urine is thought to be related to its effect of significantly increasing uric acid excretion through the digestive tract (via feces).

[0304] 4.4.3 Experiments on Uric Acid-Induced Hyperuricemia Model Mice Uric acid itself can also be used to establish a hyperuricemia model in mice. Specifically, after intraperitoneal injection, uric acid is 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 establish a model of hyperuricemia caused by parenteral causes. In this example, a mouse hyperuricemia model was established by intraperitoneal injection of uric acid into healthy mice (manganese oxide was force-fed to the experimental group, and uric acid was injected simultaneously), and blood was drawn from the mice at different time points after injection to prepare serum, and the uric acid content in the serum was tested to examine the effect of manganese oxide on the uric acid level in the blood of model mice with hyperuricemia caused by parenteral causes.

[0305] Experimental Method Eighteen 6-week-old male KM mice were randomly divided into three groups of 6 mice each, including a blank control group, a hyperuricemia model group, and a δM4K group. After one week of acclimation, at 9:00 am on the experimental day, the blank control group was force-fed pure water, the hyperuricemia model group was force-fed pure water, the δM4K group was force-fed 500 mg / kg δM4K, and they were fasted for 16 hours at night. At 8:00 am on the second day after the experiment started, 100 μL of blood was collected from each group of mice through the fundic venous plexus, and the serum was separated. The serum uric acid level was measured using a uric acid assay kit and recorded as the serum uric acid level at 0 minutes. At 9:00 am, the blank control group was force-fed pure water and intraperitoneally injected with normal saline, the hyperuricemia model group was force-fed pure water and intraperitoneally injected with a uric acid solution (uric acid dose 1000 mg / kg), the δM4K group was force-fed 500 mg / kg δM4K, and intraperitoneally injected with a uric acid solution (uric acid dose 1000 mg / kg). In each group of mice, 100 μL of blood was collected from the fundic venous plexus at 15 minutes, 30 minutes, 60 minutes, and 120 minutes after the injection of uric acid, the serum was separated, and the serum uric acid level was measured using a uric acid assay kit.

[0306] Results The results are shown in Figure 21. Figure 21 shows that after injecting uric acid into the peritoneal cavity of healthy mice, the serum uric acid level of the mice increased significantly. However, the administration of manganese oxide by forced oral administration can efficiently cancel out 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 forced oral administration, and the administration of manganese oxide by forced oral administration 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 the administration of manganese oxide (e.g., δ-form manganese oxide) by forced oral administration 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 parenteral causes.

[0307] 4.4.4 Experiments in potassium oxonate and hypoxanthine-induced hyperuricemia model mice Since hypoxanthine can be metabolized into uric acid in the body, it can also be used in combination with potassium oxonate as a model drug to induce hyperuricemia in mice. In this example, healthy mice were randomly divided into 7 groups, and a mouse hyperuricemia model was established by administering potassium oxonate and hypoxanthine (injected intraperitoneally together) to 6 groups of mice, and 1 group of healthy mice injected intraperitoneally with normal saline was used as the blank control group. The mice in the experimental groups were given the corresponding experimental substances according to the dosing regimens described in the following experimental methods. On the 8th day after the experiment started, blood was drawn from each group of mice, serum was prepared, and the uric acid content in the serum was tested to examine the effect of the experimental substances on the uric acid level in the blood of potassium oxonate and hypoxanthine-induced hyperuricemia model mice.

[0308] Experimental method Twenty-one 6-week-old male C57BL / 6J mice were randomly divided into 7 groups of 3 mice each, including a blank control group, a hyperuricemia model group, a benzbromarone group, an allopurinol group, a δΜ1KH group, a δΜ2KH group, and a δΜ4K group. From the 1st day (i.e., the experimental day) to the 8th day after the experiment started, normal saline was intraperitoneally injected into the blank control group at 9:00 am and 5:00 pm every day, and a modeling solution (100 mg / kg hypoxanthine + 100 mg / kg potassium oxonate) was intraperitoneally injected into the remaining groups at 9:00 am and 5:00 pm every day. The benzbromarone group was administered a benzbromarone solution (10 mg / kg) by forced oral administration at 10:00 am every day. The allopurinol group freely drank drinking water containing allopurinol (50 mg / L) every day, while the other groups freely drank normal drinking water. The δΜ1KH group, δΜ2KH group, and δΜ4K group freely consumed mouse diets containing δΜ1KH, δΜ2KH, and δΜ4K (1.14 w / w% of δΜ1KH, δΜ2KH, or δΜ4K was added to the mouse basal diet respectively) every day, and the other groups freely consumed the mouse basal diet. Four hours after the intraperitoneal injection at 9:00 am on the 8th day after the experiment started (i.e., 1:00 pm), 100 - 200 μL of blood was collected from the fundic vein of each group of mice, and serum was obtained by centrifugation. Serum uric acid levels were measured using a uric acid assay kit.

[0309] Results The results are shown in Figure 22. Figure 22 shows that after continuous administration of potassium oxonate and hypoxanthine to mice for 7 days, the serum uric acid levels of mice increased significantly. In contrast, the administration of benzbromarone, allopurinol, or manganese oxide significantly decreased the serum uric acid levels in mice. Among them, the ability of manganese oxide to decrease the serum uric acid levels in mice was better than that of benzbromarone and equivalent to that of allopurinol. The above results indicate that the administration of manganese oxide (such as δ-form manganese oxide) can significantly decrease the increase in blood uric acid levels in potassium oxonate and hypoxanthine-induced mice.

[0310] 4.4.5 Experiment in potassium oxonate and uric acid-induced hyperuricemia model mice Potassium oxonate is a uricase inhibitor that can inhibit the further metabolism of uric acid in mice, thereby increasing the concentration of uric acid in the blood of mice. Administration of uric acid by forced oral administration can increase the intestinal absorption of uric acid and also increase the uric acid level in the blood. In this example, healthy mice were randomly divided into 5 groups, and a mouse hyperuricemia model was established by administering potassium oxonate (via intraperitoneal injection) and uric acid (by forced oral administration) to healthy mice. One group of healthy mice that received intraperitoneal injection of normal saline and forced oral administration of SIF was used as the blank control group. The mice in the experimental groups were given the corresponding experimental substances according to the dosing regimens described in the following experimental methods. 60 minutes after completion of forced oral administration, blood was drawn from the mice to prepare serum, and the uric acid content in the serum was tested to examine the effect of the experimental substances on the uric acid levels in the blood of potassium oxonate and uric acid-induced hyperuricemia model mice.

[0311] Experimental method Thirty 6-week-old male KM mice were randomly divided into five groups of six mice each, including a blank control group, an oteracil potassium group, a hyperuricemia model group, a sevelamer hydrochloride group, and a δM4K group. In the blank control group, normal saline was first injected intraperitoneally, and then SIF was immediately administered by forced oral gavage. In the oteracil potassium group, an oteracil potassium solution (300 mg / kg) was first injected intraperitoneally, and then SIF was immediately administered by forced oral gavage. In the hyperuricemia model group, an oteracil potassium solution (300 mg / kg) was first injected intraperitoneally, and then immediately, an SIF solution containing uric acid (30 mg / kg) was administered by forced oral gavage to induce hyperuricemia. In the sevelamer hydrochloride group, an oteracil potassium solution (300 mg / kg) was first injected intraperitoneally, and then immediately, an SIF suspension containing uric acid and sevelamer hydrochloride (uric acid dose 30 mg / kg, sevelamer hydrochloride dose 50 mg / kg) was administered by forced oral gavage. In the δM4K group, an oteracil potassium solution (300 mg / kg) was first injected intraperitoneally, and then immediately, an SIF suspension containing uric acid and δM4K (uric acid dose 30 mg / kg, δM4K dose 50 mg / kg) was administered by forced oral gavage. The intraperitoneal injection and forced oral gavage operations for each mouse need to be continuously completed, that is, the intraperitoneal injection and forced oral gavage operations for the first mouse must be continuously completed, and then the corresponding operations for the second mouse are performed. In each mouse, 60 minutes after the completion of forced oral gavage, venous blood was collected into a micro blood collection tube and centrifuged at 3000 g for 15 minutes at 4°C. Serum uric acid levels were measured using a uric acid assay kit.

[0312] Results The results are shown in Figure 23. Figure 23 shows that the serum uric acid level in mice increased significantly after the administration of potassium oteracil or a combination of potassium oteracil and uric acid. The administration of sevelamer hydrochloride had little effect on the serum uric acid level in mice. In contrast, the administration of manganese oxide significantly decreased the serum uric acid level in mice. The above results indicate that the administration of manganese oxide (e.g., δ-form manganese oxide) can significantly reduce the increase in blood uric acid level in potassium oteracil- and uric acid-induced mice.

[0313] (Example 5) In vivo safety evaluation of manganese-containing compounds Experimental method In this example, healthy 8-week-old 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 normal saline), a low-dose group (administered 250 mg / kg / day of δM4K), a medium-dose group (administered 500 mg / kg / day of δM4K), a high-dose group (administered 1000 mg / kg / day of δM4K), and an ultra-high-dose group (administered 2000 mg / kg / day of δM4K), and then various experimental substances were administered orally by gavage to the mice in each group continuously for 14 days according to the dosing regimens mentioned above. During the experiment, the changes in body weight (g), food intake (g), and water intake (g) of the mice in each group were monitored over time. After the experiment, blood was drawn from the mice in each group for blood biochemical tests, and then the mice were sacrificed, and the heart, kidney, blood cells, spleen, liver, brain, lung, and body hair were separated, and the Mn content (mg / kg) in them was determined.

[0314] Results The results indicate that there were no abnormalities in the body weight, food intake, and water intake of the mice during the 14-day continuous administration of manganese oxide by forced oral administration. After the experiment, no significant differences were found in the blood biochemical indices (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 the Mn content in various tissues (excluding the liver) of the mice compared with the control group. Although a slight increase was observed in the liver Mn content compared with the control group, further studies found that the liver Mn content returned to the same level as the control group 7 days after drug withdrawal. This indicates that manganese oxide is rarely absorbed by mice and can be rapidly cleared without any accumulation effect in the body. In summary, the above results suggest that the oral administration of manganese oxide (e.g., δ-form manganese oxide) has high in vivo safety.

Claims

Claim 1 Use of an insoluble manganese-containing compound in the preparation of a drug for preventing and / or treating an increase in uric acid level in blood and / or the digestive tract in a mammalian subject, or a disease or disorder associated with an increase in uric acid level in blood and / or the digestive tract. Claim 2 The use according to claim 1, 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 when saturated in 1 mL of water as measured at about 37°C and about 1 atmosphere. Claim 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 when saturated in 1 mL of simulated intestinal fluid (SIF) as measured at about 37°C and about 1 atmosphere. Claim 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 when saturated in 1 mL of fasting simulated intestinal fluid (FaSSIF) as measured at about 37°C and about 1 atmosphere. Claim 5 The use according to any one of claims 1 to 4, wherein when the insoluble manganese-containing compound is saturated in 1 mL of fed-state artificial intestinal fluid (FeSSIF) measured at about 37 °C and about 1 atmosphere, it 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.

6. The use according to any one of claims 1 to 5, wherein the insoluble manganese-containing compound is a manganese-containing compound in which 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 enters the blood circulation by absorption in the gastrointestinal tract.

7. The use according to any one of claims 1 to 6, wherein the insoluble manganese-containing compound does not chemically interact with the 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 of the manganese-containing compound chemically interacts with the 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, for example, from 1 μm to 1 mm.

9. The use according to any one of claims 1 to 8, wherein the insoluble manganese-containing compound is selected from one or more of manganese oxide, manganese sulfide, manganese carbonate, manganese silicate, manganese borate, manganese ferricyanide, manganese oxalate, manganese selenite, manganese iodate, manganese tungstate and manganese phosphate, and solvates (such as hydrates) thereof.

10. The insoluble manganese-containing compound is manganese oxide or a solvate thereof (e.g., hydrate), and the manganese oxide is, for example: (1) manganese oxide composed of only manganese atoms and oxygen atoms, such as manganese monoxide, manganese dioxide, manganese trioxide monomanganese, manganese trioxide dimanganese, manganese pentoxide octoxide, manganese tetroxide trioxide, manganese heptoxide dioxide, manganese heptoxide dodecoxide, and manganese heptoxide tridecoxide; (2) manganese oxide composed of only manganese atoms, hydrogen atoms, and oxygen atoms, such as manganese oxyhydroxide and manganese hydroxide, or one or both of them; and (3) manganese oxide composed of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, such as salt-type manganese oxide, and is selected from one or more of them. The use according to any one of claims 1 to 9.

11. 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, divalent iron-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide. The use according to any one of claims 1 to 10.

12. The manganese oxide is manganese oxide in the form of a natural mineral, and the manganese oxide in the form of a natural mineral is selected from one or more of, for example, hollandite, cryptomelane, pyrolusite, nsutite, bernardite, buserite, bernardite, ramsdellite, romanechite, ramsdellite, hydrohausmannite, lithiophorite, calcoffite, hausmannite, bixbyite, pyrochlore, and green manganese ore. The use according to any one of claims 1 to 11.

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

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

15. The use according to any one of claims 1 to 14, wherein the insoluble manganese-containing compound has a uric acid clearance ability of about 50 mg / g to about 1000 mg / g as measured by an artificial 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 ability of about 100 mg / g to about 900 mg / g as measured by an artificial 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 ability of about 200 mg / g to about 800 mg / g as measured by an artificial 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 ability of about 200 mg / g to about 800 mg / g as measured by a fasting state artificial intestinal fluid (FaSIF) assay.

19. The use according to any one of claims 1 to 18, wherein the insoluble manganese-containing compound has a uric acid clearance ability of about 200 mg / g to about 800 mg / g as measured by a fed state artificial intestinal fluid (FeSIF) assay.

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

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 formulation is a powder, granule, tablet, capsule, pill or lozenge.

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

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

25. The use according to any one of claims 1 to 24, wherein the drug contains an insoluble manganese-containing compound of 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.

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 intestinal tract.

28. The use according to any one of claims 1 to 27, wherein the disease or disorder associated with an increase in uric acid level in the blood and / or the digestive tract is at least one selected from the group consisting of gout, gout complications, hyperuricemia, high uric acid levels that typically do not reach the levels diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related disorders, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle spasm, local swelling, joint pain, malignant disease, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, non-alcoholic fatty liver disease, stroke, hemolytic anemia, congenital genetic errors of metabolism, poisoning, epididymitis and orchitis, 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 urolithiasis 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 insufficiency, renal failure and uremia.

32. The use according to any one of claims 1 to 31, 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 to 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 related to other medical conditions.

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

36. The use according to any one of claims 1 to 35, wherein the malignant disease 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 to 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 congenital genetic error of metabolism is Lesch-Nyhan syndrome.

41. Before administration of the drug to the subject, the blood and / or serum uric acid level of the subject 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% higher than 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. The use according to any one of claims 1 to 40.

42. After administration of the drug, the blood and / or serum uric acid level of the subject 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% lower than that before administration of the drug. The use according to any one of claims 1 to 41.

43. After administration of the drug, the blood and / or serum uric acid level of the subject is from 80 μmol / L to 460 μmol / L, from 100 μmol / L to 450 μmol / L, from 150 μmol / L to 440 μmol / L, from 200 μmol / L to 430 μmol / L, from 210 μmol / L to 420 μmol / L, from 80 μmol / L to 380 μmol / L, from 100 μmol / L to 370 μmol / L or from 150 μmol / L to 360 μmol / L. The use according to any one of claims 1 to 42.

44. Use of a manganese-containing compound in the preparation of a drug for adsorbing uric acid in the digestive tract of a mammal. Claim 45 The use according to claim 44, wherein the manganese-containing compound is an insoluble manganese-containing compound. Claim 46 The use according to claim 44 or 45, wherein the insoluble manganese-containing compound has 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 when dissolved and saturated in 1 mL of water, measured at about 37°C and about 1 atmosphere. Claim 47 The use according to any one of claims 44 to 46, wherein the insoluble manganese-containing compound has 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 when dissolved and saturated in 1 mL of simulated intestinal fluid (SIF), measured at about 37°C and about 1 atmosphere. Claim 48 The use according to any one of claims 44 to 47, wherein the insoluble manganese-containing compound has 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 when dissolved and saturated in 1 mL of fasting simulated intestinal fluid (FaSSIF), measured at about 37°C and about 1 atmosphere. Claim 49 The use according to any one of claims 44 to 48, 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 when dissolved and saturated in 1 mL of fed-state artificial 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 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 of the insoluble manganese-containing compound is a manganese-containing compound that enters the blood circulation by absorption in the gastrointestinal tract.

51. The use according to any one of claims 44 to 50, wherein the insoluble manganese-containing compound does not chemically interact with surrounding substances or tissues in the body after administration, or 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 of the manganese-containing compound only chemically interacts with surrounding substances or tissues in the body.

52. The use according to any one of claims 44 to 51, wherein the particle size of the insoluble manganese-containing compound is ≧ 1 μm, for example, 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 (such as hydrates) thereof.

54. The insoluble manganese-containing compound is manganese oxide or a solvate thereof (e.g., hydrate), and the manganese oxide is, for example: (1) manganese oxide composed only of manganese atoms and oxygen atoms, such as manganese monoxide, manganese dioxide, manganese trioxide, dimanganese trioxide, manganese pentoxide octoxide, manganese tetroxide, manganese heptoxide, manganese heptoxide dodecoxide, and manganese heptoxide tridecoxide; (2) manganese oxide composed only of manganese atoms, hydrogen atoms, and oxygen atoms, such as manganese oxide hydroxide and manganese hydroxide; and (3) manganese oxide composed of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, such as salt-type manganese oxide, and is selected from one or more of them. The use according to any one of claims 44 to 53.

55. 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, divalent iron-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide. The use according to any one of claims 44 to 54.

56. The manganese oxide is manganese oxide in the form of a natural mineral, and the manganese oxide in the form of a natural mineral is selected from one or more of, for example, hollandite, cryptomelane, pyrolusite, nsutite, bernardite, buserite, bernardite, ramsdellite, romanechite, fulgurite, manganite, grautite, phytochroite, hydrohausmannite, lithiophyllite, carpholite, hausmannite, viksite, pyrochlore, and green manganese ore. The use according to any one of claims 44 to 55.

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

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

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

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

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

62. The use according to any one of claims 44 to 61, wherein the insoluble manganese-containing compound has a uric acid clearance ability of about 200 mg / g to about 800 mg / g as measured by a fasting state artificial intestinal fluid (FaSIF) assay.

63. The use according to any one of claims 44 to 62, wherein the insoluble manganese-containing compound has a uric acid clearance ability of about 200 mg / g to about 800 mg / g as measured by a fed state artificial intestinal fluid (FeSIF) assay.

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

65. The use according to any one of claims 44 to 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 to 65, wherein the solid oral formulation is a powder, granule, tablet, capsule, pill or lozenge.

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

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

69. The use according to any one of claims 44 to 68, wherein the drug contains 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.

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

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

72. A pharmaceutical composition for preventing and / or treating diseases or disorders associated with elevated uric acid levels in the blood and / or gastrointestinal tract of mammalian subjects, the pharmaceutical composition comprising an insoluble manganese-containing compound and a pharmaceutically acceptable additive.

73. The pharmaceutical composition according to claim 71, wherein the insoluble manganese-containing compound, when measured at about 37 °C and about 1 atmosphere and saturated in 1 mL of water, has 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 of a manganese-containing compound.

74. The pharmaceutical composition according to claim 72 or 73, wherein the insoluble manganese-containing compound, when measured at about 37 °C and about 1 atmosphere and saturated in 1 mL of simulated intestinal fluid (SIF), has 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 of a manganese-containing compound.

75. The pharmaceutical composition according to any one of claims 72 to 74, wherein the insoluble manganese-containing compound, when measured at about 37 °C and about 1 atmosphere and saturated in 1 mL of fasted simulated intestinal fluid (FaSSIF), has 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 of a manganese-containing compound.

76. The pharmaceutical composition according to any one of claims 72 to 75, 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 when saturated by dissolving in 1 mL of fed-state artificial intestinal fluid (FeSSIF) measured at about 37 °C and about 1 atmosphere.

77. The pharmaceutical composition according to any one of claims 72 to 76, wherein 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 of the insoluble manganese-containing compound is a manganese-containing compound that enters the blood circulation by absorption in the gastrointestinal tract.

78. The pharmaceutical composition according to any one of claims 72 to 77, wherein the insoluble manganese-containing compound does not chemically interact with surrounding substances or tissues in the body after administration, or 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 of the manganese-containing compound chemically interacts 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, for example, from 1 μm to 1 mm.

80. The pharmaceutical composition according to any one of claims 72 to 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 (such as hydrates) thereof.

81. The insoluble manganese-containing compound is manganese oxide or a solvate thereof (e.g., hydrate), and the manganese oxide is, for example: (1) manganese oxide consisting only of manganese atoms and oxygen atoms, such as manganese monoxide, manganese dioxide, manganese trioxide monomanganese, manganese trioxide dimanganese, manganese pentoxide octoxide, manganese tetroxide trioxide, manganese dioxide heptoxide, manganese heptoxide dodecaoxide, and manganese heptoxide tridecaoxide; (2) manganese oxide consisting only of manganese atoms, hydrogen atoms, and oxygen atoms, such as manganese oxyhydroxide and manganese hydroxide, or one or both of them; and (3) manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, such as salt-type manganese oxide, and is selected from one or more of them. The pharmaceutical composition according to any one of claims 72 to 80.

82. 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, divalent iron-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide. The pharmaceutical composition according to any one of claims 72 to 81.

83. The manganese oxide is manganese oxide in the form of a natural mineral, and the manganese oxide in the form of a natural mineral is selected from one or more of, for example, hollandite, cryptomelane, pyrolusite, enstatite, bernardite, buserite, bernardite, ramsdellite, romanechite, fulgurite, hydrohausmannite, lithiophorite, calcoffite, hausmannite, viksite, pyrochlore, and green manganese ore. The pharmaceutical composition according to any one of claims 72 to 82.

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

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

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

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

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

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

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

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

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

93. The pharmaceutical composition according to any one of claims 72 to 92, wherein the solid oral formulation is a powder, granule, tablet, capsule, pill or lozenge.

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

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

96. The pharmaceutical composition according to any one of claims 72 to 95, wherein the pharmaceutical composition contains 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 according to any one of claims 72 to 96, wherein the mammal is a human.

98. The pharmaceutical composition according to any one of claims 72 to 97, wherein the digestive tract is the intestinal tract.

99. The disease or disorder associated with an increase in uric acid level in the blood and / or digestive tract is: gout, gout complications, hyperuricemia, a high uric acid level that typically does not reach the level diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related disorders, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle spasm, local swelling, joint pain, malignant disease, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, non-alcoholic fatty liver disease, stroke, hemolytic anemia, congenital metabolic error, poisoning, epididymitis and orchitis, and at least one selected from the group consisting of blood, bone marrow or solid organ transplantation. The pharmaceutical composition according to any one of claims 72 to 98.

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

101. The pharmaceutical composition according to any one of claims 72 to 100, wherein the gout complication is at least one of gouty arthritis, gouty urolithiasis and gouty nephropathy.

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

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

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

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

107. The pharmaceutical composition according to any one of claims 72 to 106, wherein the malignant disease is a hematological malignant disease.

108. The pharmaceutical composition according to any one of claims 72 to 107, wherein the hematological malignant disease is at least one of leukemia and multiple myeloma.

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

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

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

112. Before administration of the pharmaceutical composition to the subject, the blood and / or serum uric acid level of the subject 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% higher than 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. The pharmaceutical composition according to any one of claims 72 to 111.

113. After administration of the pharmaceutical composition, the blood and / or serum uric acid level of the subject 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% compared to that before administration of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 72 to 112.

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

115. (i)A pharmaceutical composition according to any one of claims 72 to 114, and (ii)Instructions for use of the drug and / or a label of the drug A kit comprising.

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

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

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

119. The method according to any one of claims 116 to 118, wherein the method maintains the blood and / or serum uric acid level of the subject at from 80 μmol / L to 460 μmol / L, from 100 μmol / L to 450 μmol / L, from 150 μmol / L to 440 μmol / L, from 200 μmol / L to 430 μmol / L, from 210 μmol / L to 420 μmol / L, from 80 μmol / L to 380 μmol / L, from 100 μmol / L to 370 μmol / L or from 150 μmol / L to 360 μmol / L.

120. The method according to any one of claims 116 to 119, 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 when dissolved and saturated in 1 mL of water as measured at about 37 °C and about 1 atmosphere.

121. The method according to any one of claims 116 to 120, 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 when dissolved and saturated in 1 mL of simulated intestinal fluid (SIF) as measured at about 37 °C and about 1 atmosphere.

122. The method according to any one of claims 116 to 121, 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 when dissolved and saturated in 1 mL of fasted state simulated intestinal fluid (FaSSIF) as measured at about 37 °C and about 1 atmosphere.

123. The method according to any one of claims 116 to 122, 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 when saturated by dissolving in 1 mL of fed-state artificial intestinal fluid (FeSSIF) measured at about 37 °C and about 1 atmosphere.

124. The method according to any one of claims 116 to 123, wherein the insoluble manganese-containing compound is a manganese-containing compound in which 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 enters the blood circulation by absorption in the gastrointestinal tract.

125. The method according to any one of claims 116 to 124, wherein the insoluble manganese-containing compound does not chemically interact 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 of the manganese-containing compound chemically interacts with surrounding substances 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, for example, from 1 μm to 1 mm.

127. The method according to 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 ferricyanide, manganese oxalate, manganese selenite, manganese iodate, manganese tungstate and manganese phosphate, and solvates (such as hydrates) thereof.

128. The insoluble manganese-containing compound is manganese oxide or a solvate thereof (e.g., hydrate), and the manganese oxide is, for example: (1) manganese oxide consisting only of manganese atoms and oxygen atoms, such as manganese monoxide, manganese dioxide, manganese trioxide monomanganese, manganese trioxide dimanganese, manganese pentoxide octoxide, manganese tetroxide trioxide, manganese heptoxide dioxide, manganese heptoxide dodecoxide, and manganese heptoxide tridecoxide; (2) manganese oxide consisting only of manganese atoms, hydrogen atoms, and oxygen atoms, such as manganese oxide hydroxide and manganese hydroxide; and (3) manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, such as salt-type manganese oxide, and is selected from one or more of them. The method according to any one of claims 116 to 127.

129. 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, divalent iron-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type manganese oxide. The method according to any one of claims 116 to 128.

130. The manganese oxide is manganese oxide in the form of a natural mineral, and the manganese oxide in the form of a natural mineral is selected from one or more of, for example, hollandite, cryptomelane, pyrolusite, nsutite, bernardite, buserite, bernardite, ramsdellite, romanechite, shattuckite, manganite, grautite, fightoknechtite, hydrohausmannite, lithiophorite, calcoffanite, hausmannite, viksite, pyrochlore, and green manganese ore. The method according to any one of claims 116 to 129.

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

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

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

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

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

136. The method according to any one of claims 116 to 135, wherein the insoluble manganese-containing compound has a uric acid clearance ability of about 200 mg / g to about 800 mg / g as measured by a fasting artificial intestinal fluid (FaSIF) assay.

137. The method according to any one of claims 116 to 136, wherein the insoluble manganese-containing compound has a uric acid clearance ability of about 200 mg / g to about 800 mg / g as measured by a fed artificial intestinal fluid (FeSIF) assay.

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

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

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

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

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

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

144. The method according to any one of claims 116 to 143, wherein the oral preparation is a solid oral preparation or a liquid oral preparation.

145. The method according to any one of claims 116 to 144, wherein the solid oral preparation is a powder, granule, tablet, capsule, pill or lozenge.

146. The method according to any one of claims 116 to 145, wherein the oral preparation contains an effective amount of an insoluble manganese-containing compound.

147. The method according to any one of claims 116 to 146, wherein the oral preparation contains 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.

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

149. The method according to any one of claims 116 to 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 according to any one of claims 116 to 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 according to any one of claims 116 to 150, wherein the insoluble manganese-containing compound and the food are taken simultaneously or at intervals 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 according to any one of claims 116 to 151, wherein the insoluble manganese-containing compound is administered 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours or later after a meal.

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

154. The method according to any one of claims 116 to 153, wherein the digestive tract is the intestinal tract.

155. The method according to any one of claims 116 to 154, wherein the disease or disorder associated with an increase in uric acid level in the blood and / or gastrointestinal tract is at least one selected from the group consisting of gout, gout complications, hyperuricemia, high uric acid levels that typically do not reach levels diagnosed as hyperuricemia, cardiovascular disease, diabetes, diabetes-related disorders, insulin resistance, metabolic syndrome, hypothyroidism, hyperparathyroidism, obesity, inflammation, muscle spasm, local swelling, joint pain, malignant disease, tumor lysis syndrome, polycythemia vera, cognitive impairment, psoriasis, sarcoidosis, non-alcoholic fatty liver disease, stroke, hemolytic anemia, inborn errors of metabolism, poisoning, epididymitis and orchitis, and transplantation of blood, bone marrow or solid organs.

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

157. The method according to any one of claims 116 to 156, wherein the gout complications are at least one of gouty arthritis, gouty urolithiasis and gouty nephropathy.

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

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

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

162. The method according to any one of claims 116 to 161, wherein the conditions related to diabetes are at least one of diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, diabetic macrovascular disease, diabetic microvascular disease, diabetic foot lesions and diabetic ketoacidosis.

163. The method according to any one of claims 116 to 162, wherein the malignant disease is a hematological malignant disease.

164. The method according to any one of claims 116 to 163, wherein the hematological malignant disease is at least one of leukemia and multiple myeloma.

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

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

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

168. Before administration of the insoluble manganese-containing compound to the subject, the blood and / or serum uric acid level of the subject 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% higher than 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. The method according to any one of claims 116 to 167.

169. After administration of the insoluble manganese-containing compound, the blood and / or serum uric acid level of the subject 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% compared to that before administration of the insoluble manganese-containing compound. The method according to any one of claims 116 to 168.

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

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

172. The pharmaceutical composition according to claim 171, wherein the particle size of the manganese oxide is ≧1 μm, for example, from 1 μm to 1 mm.

173. The manganese oxide is selected from one or more of: (1) manganese oxides consisting only of manganese atoms and oxygen atoms, such as manganese monoxide, manganese dioxide, trimanganese monoxide, dimanganese trioxide, pentamanganese octoxide, manganese tritoxide, manganese heptoxide, heptamanganese dodecoxide, and heptamanganese tridecoxide; (2) manganese oxides consisting only of manganese atoms, hydrogen atoms, and oxygen atoms, such as manganese oxyhydroxide and manganese hydroxide; and (3) manganese oxides consisting of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, such as salt-type manganese oxides. The pharmaceutical composition according to claim 171 or 172.

174. The pharmaceutical composition according to any one of claims 171 to 173, wherein the manganese oxide salt type 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, divalent iron 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 according to any one of claims 171 to 174, wherein the manganese oxide is manganese oxide in the form of a natural mineral, and the manganese oxide in the form of a natural mineral is selected from one or more of, for example, hollandite, cryptomelane, pyrolusite, nsutite, bernardite, buserite, bernardite, ramsdellite, romanechite, fukuchilite, manganite, groutite, phillipsite, hydrohausmannite, lithiophorite, calcoffite, hausmannite, vicksite, pyrochlore and green manganese ore.

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

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

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

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

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

181. The pharmaceutical composition according to any one of claims 171 to 180, wherein the manganese oxide has a uric acid clearance ability of about 200 mg / g to about 800 mg / g as measured by a fasting state artificial intestinal fluid (FaSSIF) assay.

182. The pharmaceutical composition according to any one of claims 171 to 181, wherein the manganese oxide has a uric acid clearance ability of about 200 mg / g to about 800 mg / g as measured by a fed state artificial intestinal fluid (FeSSIF) assay.

183. The pharmaceutical composition according to any one of claims 171 to 182, wherein the pharmaceutical composition is an oral preparation.

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

185. The pharmaceutical composition according to any one of claims 171 to 184, wherein the solid oral preparation is a powder, granule, tablet, capsule, pill or lozenge.

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

187. The pharmaceutical composition according to any one of claims 171 to 186, wherein the pharmaceutical composition contains an effective amount of manganese oxide.

188. The pharmaceutical composition according to any one of claims 171 to 187, wherein the pharmaceutical composition contains 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 according to any one of claims 171 to 188, wherein the mammal is a human.

190. 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% higher than 360 μmol / L or 420 μmol / L, and the pharmaceutical composition according to any one of claims 171 to 189.

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

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

193. The manganese oxide has a uric acid clearance capacity 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 measured under the same conditions measured in a fasting state artificial intestinal fluid (FaSSIF) or fed state artificial intestinal fluid (FeSSIF) assay, and the pharmaceutical composition according to claim 192.

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

195. The particle size of the manganese oxide is ≧ 1 μm, for example 1 μm to 1 mm, and the pharmaceutical composition according to any one of claims 192 to 194.

196. The manganese oxide is: (1) manganese oxide consisting only of manganese atoms and oxygen atoms, such as manganese monoxide, manganese dioxide, trimanganese monoxide, dimanganese trioxide, pentamanganese octoxide, manganese tetroxide, manganese heptoxide, heptamanganese dodecoxide, and heptamanganese tridecoxide, and is selected from one or more of them; (2) manganese oxide consisting only of manganese atoms, hydrogen atoms, and oxygen atoms, such as manganese oxyhydroxide and manganese hydroxide, and is selected from one or both of them; and (3) manganese oxide consisting of manganese atoms, oxygen atoms, metal atoms, and optionally hydrogen atoms, such as salt-type manganese oxide, and is selected from one or more of them. The pharmaceutical composition according to any one of claims 192 to 195.

197. 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, divalent iron-type manganese oxide, zinc-type manganese oxide, lanthanum-type manganese oxide, bismuth-type manganese oxide, lithium-type manganese oxide, and silver-type R-form manganese oxide. The pharmaceutical composition according to any one of claims 192 to 196.

198. The manganese oxide is manganese oxide in the form of a natural mineral, and the manganese oxide in the form of a natural mineral is selected from one or more of, for example, hollandite, cryptomelane, pyrolusite, nsutite, bernardite, buserite, bernardite, ramsdellite, romanechite, fulgurite, hydrohausmannite, lithiophorite, calcoffite,hausmannite, vicsite, pyrochlore, and green manganese ore. The pharmaceutical composition according to any one of claims 192 to 197.

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

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

201. The pharmaceutical composition according to any one of claims 192 to 200, wherein the manganese oxide has a uric acid clearance ability of about 200 mg / g to about 800 mg / g as measured by a fasting state artificial intestinal fluid (FaSSIF) assay.

202. The pharmaceutical composition according to any one of claims 192 to 201, wherein the manganese oxide has a uric acid clearance ability of about 200 mg / g to about 800 mg / g as measured by a fed state artificial intestinal fluid (FeSSIF) assay.

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

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

205. The pharmaceutical composition according to any one of claims 192 to 204, wherein the pharmaceutical composition contains an effective amount of manganese oxide.

206. The pharmaceutical composition according to any one of claims 192 to 205, wherein the pharmaceutical composition contains 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 according to any one of claims 192 to 206, wherein the mammal is a human.

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