阅读说明：本技术 用于降低血清尿酸的组合物 (Composition for reducing serum uric acid ) 是由 J·霍格斯特 J·麦凯 E·约翰逊 于 2018-10-01 设计创作，主要内容包括：本披露提供可用于降低血清尿酸水平的包含维立诺雷、黄嘌呤氧化酶抑制剂、和达格列净的组合物,包含它们的配制品,以及使用这些组合物和配制品的方法。在一些实施例中,本文所述的方法和组合物用于治疗或预防与高尿酸血症有关的病症,诸如慢性肾病、心力衰竭、和痛风。(The present disclosure provides compositions comprising vilinolide, a xanthine oxidase inhibitor, and dapagliflozin useful for reducing serum uric acid levels, formulations comprising the same, and methods of using the compositions and formulations. In some embodiments, the methods and compositions described herein are used to treat or prevent conditions associated with hyperuricemia, such as chronic kidney disease, heart failure, and gout.)

1. A method of reducing serum uric acid levels in a subject in need thereof, the method comprising administering to the subject:

vilonolide or a pharmaceutically acceptable salt thereof;

xanthine oxidase inhibitors; and

dapagliflozin.

2. A method of treating or preventing a disorder associated with hyperuricemia in a subject in need thereof, the method comprising administering to the subject:

vilonolide or a pharmaceutically acceptable salt thereof;

xanthine oxidase inhibitors; and

dapagliflozin.

3. The method of claim 2, wherein the disorder is gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof.

4. The method of claim 2, wherein the disorder is gout.

5. The method of claim 2, wherein the disorder is chronic kidney disease.

6. The method of claim 2, wherein the condition is heart failure.

7. The method of any one of claims 1-6, wherein the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1-6, wherein the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof.

9. A method of treating or preventing chronic kidney disease in a subject in need thereof, the method comprising administering to the subject:

vilonolide or a pharmaceutically acceptable salt thereof;

allopurinol or a pharmaceutically acceptable salt thereof; and

dapagliflozin.

10. A method of treating or preventing heart failure in a subject in need thereof, the method comprising administering to the subject:

vilonolide or a pharmaceutically acceptable salt thereof;

allopurinol or a pharmaceutically acceptable salt thereof; and

dapagliflozin.

11. A method of reducing serum uric acid levels in a subject currently being treated with dapagliflozin, the method comprising administering to the subject:

vilonolide or a pharmaceutically acceptable salt thereof; and

xanthine oxidase inhibitors.

12. The method of claim 11, wherein the subject has diabetes.

13. The method of claim 11 or 12, wherein the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof.

14. The method of claim 11 or 12, wherein the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof.

15. A method of treating or preventing a disorder associated with hyperuricemia in a subject currently being treated with dapagliflozin, the method comprising administering to the subject:

vilonolide or a pharmaceutically acceptable salt thereof; and

xanthine oxidase inhibitors.

16. The method of claim 15, wherein the subject has diabetes.

17. The method of claim 15, wherein the disorder is gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof.

18. The method of claim 16, wherein the disorder is gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof.

19. The method of claim 15, wherein the disorder is gout.

20. The method of claim 16, wherein the disorder is gout.

21. The method of claim 15, wherein the disorder is chronic kidney disease.

22. The method of claim 16, wherein the disorder is chronic kidney disease.

23. The method of claim 15, wherein the condition is heart failure.

24. The method of claim 16, wherein the condition is heart failure.

25. The method of any one of claims 15-24, wherein the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 15-24, wherein the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof.

27. A method of treating or preventing chronic kidney disease in a subject with diabetes currently being treated with dapagliflozin, the method comprising administering to the subject:

vilonolide or a pharmaceutically acceptable salt thereof; and

allopurinol or a pharmaceutically acceptable salt thereof.

28. A method of treating or preventing heart failure in a diabetic patient currently being treated with dapagliflozin, the method comprising administering to the subject:

vilonolide or a pharmaceutically acceptable salt thereof; and

allopurinol or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising:

vilonolide or a pharmaceutically acceptable salt thereof;

xanthine oxidase inhibitors;

dapagliflozin; and

a pharmaceutically acceptable excipient or carrier.

30. The pharmaceutical composition of claim 29, wherein the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof.

31. The pharmaceutical composition of claim 29, wherein the xanthine oxidase inhibitor is allopurinol, or a pharmaceutically acceptable salt thereof.

32. A method of reducing serum uric acid levels in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 29-31.

33. A method of treating or preventing a disorder associated with hyperuricemia in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 29-31.

34. The method of claim 33, wherein the disorder is gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof.

35. The method of claim 33, wherein the disorder is gout.

36. The method of claim 33, wherein the disorder is chronic kidney disease.

37. The method of claim 33, wherein the condition is heart failure.

Background

Uric acid is a product of metabolic breakdown of purine nucleotides. Most uric acid dissolves in the blood and is transported to the kidney where it is excreted via glomerular filtration and tubular secretion. A large portion of uric acid is reabsorbed by the renal tubules. Uric acid concentrations in plasma above the normal range are called hyperuricemia. Hyperuricemia has been associated with chronic kidney disease and renal insufficiency and has been identified as an independent risk factor for reduced renal function. See Levy, g.d. et al j.rheum [ rheumatology journal ] 2014; 41(5): 955; X.Su et al PLoS ONE [ public science library, integrated ] 2017; 12(11): e0187550. hyperuricemia has also been associated with cardiovascular disease and heart failure. See m.li et al sci.rep. [ scientific report ] 2016; 6: 19520. accordingly, there is a need for therapeutic methods and compositions for reducing serum uric acid levels that can be used in therapeutic and prophylactic methods, e.g., to treat or prevent conditions associated with hyperuricemia, such as chronic kidney disease and heart failure.

Disclosure of Invention

In some embodiments, the present disclosure provides methods of reducing serum uric acid levels in a subject in need thereof, the methods comprising administering to the subject: URAT1 inhibitors; xanthine oxidase inhibitors; and SGLT2 inhibitors. In some embodiments, disclosed herein is a method of reducing serum uric acid levels in a subject in need thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; xanthine oxidase inhibitors; and dapagliflozin. In some embodiments, disclosed herein is a method of treating or preventing a disorder associated with hyperuricemia in a subject in need thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; xanthine oxidase inhibitors; and dapagliflozin. In some embodiments, the disorder is gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof. In some embodiments, the disorder is gout. In some embodiments, the disorder is chronic kidney disease. In some embodiments, the disorder is heart failure. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a method of treating or preventing chronic kidney disease in a subject in need thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; allopurinol or a pharmaceutically acceptable salt thereof; and dapagliflozin. In some embodiments, disclosed herein is a method of treating or preventing heart failure in a subject in need thereof, comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; allopurinol or a pharmaceutically acceptable salt thereof; and dapagliflozin. In some embodiments, disclosed herein is a method of reducing serum uric acid levels in a subject currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; and xanthine oxidase inhibitors. In some embodiments, the subject has diabetes. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a method of treating or preventing a disorder associated with hyperuricemia in a subject currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; and xanthine oxidase inhibitors. In some embodiments, the subject has diabetes. In some embodiments, the disorder is gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof. In some embodiments, the disorder is gout. In some embodiments, the disorder is chronic kidney disease. In some embodiments, the disorder is heart failure. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a method of treating or preventing chronic kidney disease in a subject having diabetes currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; and allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a method of treating or preventing heart failure in a diabetic patient currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; and allopurinol or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides pharmaceutical compositions comprising effective amounts of URAT1 inhibitor, XOI, and SGLT2 inhibitor. In some embodiments, disclosed herein is a pharmaceutical composition comprising: vilonolide or a pharmaceutically acceptable salt thereof; xanthine oxidase inhibitors; dapagliflozin; and a pharmaceutically acceptable excipient or carrier. In some embodiments, the xanthine oxidase inhibitor is febuxostat, or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a method of reducing serum uric acid levels in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition disclosed herein. In some embodiments, disclosed herein is a method of treating or preventing a disorder associated with hyperuricemia in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition disclosed herein. In some embodiments, the disorder is gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof. In some embodiments, the disorder is gout. In some embodiments, the disorder is chronic kidney disease. In some embodiments, the disorder is heart failure.

Detailed Description

Definition of

The terms "patient," "subject," or "individual" are used interchangeably. As used herein, they refer to individuals suffering from disorders and the like. Neither of these terms require that the individual be under the care and/or supervision of a medical professional.

As used herein, the term "treating" and other grammatical equivalents includes alleviating, eliminating, or ameliorating a disease or disorder or one or more symptoms thereof, ameliorating the underlying metabolic cause of a symptom, inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, causing regression of a disease or disorder, alleviating a condition caused by a disease or disorder, or terminating a symptom of a disease or disorder.

As used herein, the term "administering" or the like refers to a method that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds, compositions, and methods described herein.

As used herein, the term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refers to a sufficient amount of at least one administered agent or compound that will alleviate one or more symptoms of the disease or disorder being treated to some extent. The result can be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein that is required to provide a clinically significant reduction in disease. The appropriate "effective" amount may vary from subject to subject. In any individual case, a suitable "effective" amount may be determined using techniques such as dose escalation studies.

As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not eliminate the biological activity or properties of the compounds described herein and is relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of a composition in which it is contained.

As used herein, the term "pharmaceutically acceptable salt" refers to salts of the free acids and bases of a particular compound that retain biological effectiveness and are not biologically or otherwise undesirable. The compounds described herein may have acidic or basic groups and thus may react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. These salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. In some embodiments, for example, vilonolide is provided as a base addition salt, such as a sodium salt.

As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one active ingredient in admixture with at least one pharmaceutically acceptable chemical component, such as, but not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, excipients, and the like.

As used herein, the terms "co-administration," "combined administration," and grammatical equivalents thereof, are intended to encompass administration of the active ingredients to a single individual, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, in the same or different pharmaceutical compositions, and at the same or different times of administration. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in one composition in which all active ingredients are present.

Method of treatment

In some embodiments, the present disclosure provides methods of reducing serum uric acid levels in a subject in need thereof, the methods comprising administering to the subject: URAT1 inhibitors; xanthine oxidase inhibitors; and SGLT2 inhibitors. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is rasidone or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or allopurinol, or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, or engagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the subject is a human. In some embodiments, the subject has diabetes. In some embodiments, the subject does not have diabetes.

In some embodiments, the present disclosure provides a method of reducing serum uric acid levels in a subject currently being treated with an SGLT2 inhibitor, the method comprising administering to the subject: URAT1 inhibitors; and xanthine oxidase inhibitors. In some embodiments, the subject has diabetes. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is rasidone or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or allopurinol, or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, or engagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the subject is a human. In some embodiments, the present disclosure provides a method of reducing serum uric acid levels in a subject currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; and xanthine oxidase inhibitors. In some embodiments, the subject has diabetes. In some embodiments, the subject does not have diabetes.

Active ingredient

URAT1 inhibitors

The level of urate anions in the blood is regulated in part by urate transporters. In particular cases, the urate transporter is URAT 1. In some cases, a single nucleotide polymorphism of the gene expressing URAT1 is significantly associated with increased or decreased reabsorption of uric acid by the kidney, which results in hyperuricemia and hypouricemia, respectively.

Disclosed herein is the use of URAT1 inhibitors in combination therapy for reducing urate. In some embodiments, the URAT1 inhibitor is rascinod, voronoi, or a pharmaceutically acceptable salt thereof. In particular embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof.

Voronolide is the common name for 2- [3- (4-cyanonaphthalen-1-yl) pyridin-4-yl ] sulfanyl-2-methylpropanoic acid, having the following chemical structure:

in some embodiments, the pharmaceutically acceptable salt of vilonolide is the sodium salt of vilonolide, i.e., 2- [3- (4-cyanonaphthalen-1-yl) pyridin-4-yl]Sodium sulfanyl-2-methylpropionate. In some embodiments, a crystalline solvate of voronoi is administered in a method disclosed herein or used in a composition disclosed herein. In some embodiments, the crystalline solvate of voronoi disclosed in U.S. patent No. 7,919,598 is applied in a method disclosed herein or used in a composition disclosed herein. In some embodiments, the crystalline voronoi: (2S) -1, 2-propanediol: h₂O (1: 1) is administered in a method disclosed herein or used in a composition disclosed herein.

Xanthine oxidase inhibitors

Xanthine oxidase can catalyze the oxidation of hypoxanthine to xanthine and further catalyze the oxidation of xanthine to uric acid. In some embodiments, disclosed herein is the use of a Xanthine Oxidase Inhibitor (XOI) in a combination therapy to reduce urate. In some embodiments, the XOI is a purine analog, such as allopurinol, oxypurinol, or mercaptopurine. In other embodiments, the XOI is another molecule, such as febuxostat or topirostat. In some embodiments, the XOI is allopurinol or febuxostat. In some embodiments, the XOI is febuxostat.

In embodiments, the XOI is allopurinol.

Sodium-glucose transporter, subtype 2(SGLT2) inhibitor

In some cases, glucose reabsorption in the kidney is regulated by members of the sodium glucose co-transporter family, which are sodium-dependent glucose transporters. In some cases, glucose reabsorption in the kidney is regulated by sodium-glucose transporter subtype 2(SGLT 2). In some cases, inhibition of SGLT2 results in diabetes. In certain cases, inhibition of SGLT2 results in altered uric acid transport activity in the renal tubules caused by diabetes. In some cases, inhibitors of SGLT2 may reduce serum uric acid levels.

In some embodiments, disclosed herein is the use of an SGLT2 inhibitor in a combination therapy for reducing urate. In some embodiments, the SGLT2 inhibitor is gliflozin. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, engagliflozin, egagliflozin, rigagliflozin etabonate, segagliflozin etabonate, soagliflozin, or togagliflozin. In particular embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, or engagliflozin. In a particular embodiment, the SGLT2 inhibitor is dapagliflozin, having the following chemical structure:

hyperuricemia-related disorders

Hyperuricemia is an abnormally high level of uric acid in the blood. Hyperuricemia may be asymptomatic. In certain instances, hyperuricemia is associated with at least one other disease or disorder. In certain instances, hyperuricemia is associated with gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof. In some embodiments, the disorder is gout. In some embodiments, the disorder is chronic kidney disease. In some embodiments, the disorder is heart failure.

In some embodiments, the present disclosure provides methods of treating or preventing a disorder associated with hyperuricemia in a subject in need thereof, the methods comprising administering to the subject: URAT1 inhibitors; xanthine oxidase inhibitors; and SGLT2 inhibitors. In some embodiments, the disorder is gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof. In some embodiments, the disorder is gout. In some embodiments, the disorder is chronic kidney disease. In some embodiments, the disorder is heart failure. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is rasidone or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or allopurinol, or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, or engagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the subject is a human.

In some embodiments, the present disclosure provides a method of treating or preventing a disorder associated with hyperuricemia in a subject currently being treated with an SGLT2 inhibitor, the method comprising administering to the subject: URAT1 inhibitors; and xanthine oxidase inhibitors. In some embodiments, the disorder is gout, gout recurrence, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, lesch-nyhan syndrome, keli-seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof. In some embodiments, the disorder is gout. In some embodiments, the disorder is chronic kidney disease. In some embodiments, the disorder is heart failure. In some embodiments, the subject has diabetes. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is rasidone or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or allopurinol, or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, or engagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the subject is a human.

In some embodiments, the present disclosure provides a method of treating or preventing a disorder associated with hyperuricemia in a subject currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; and allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has diabetes. In some embodiments, the present disclosure provides a method of treating or preventing a disorder associated with hyperuricemia in a subject currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject: vilonolide or a pharmaceutically acceptable salt thereof; and febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has diabetes.

Renal disease

In some cases, disclosed herein is a method of treating or preventing a renal disease in a subject in need thereof, the method comprising administering to the subject: URAT1 inhibitors; xanthine oxidase inhibitors; and SGLT2 inhibitors. In some embodiments, the kidney disease is acute kidney disease, acute kidney failure, chronic kidney disease, chronic kidney failure, or diabetic nephropathy. In some embodiments, the kidney disease is chronic kidney disease. In some embodiments, the kidney disease is diabetic nephropathy. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is rasidone or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or allopurinol, or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, or engagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the subject is a human.

In some embodiments, the present disclosure provides a method of treating or preventing chronic kidney disease in a subject having diabetes currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject voronoi or a pharmaceutically acceptable salt thereof; and allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating or preventing chronic kidney disease in a subject having diabetes currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject voronoi or a pharmaceutically acceptable salt thereof; and febuxostat or a pharmaceutically acceptable salt thereof.

Cardiovascular diseases

In some cases, disclosed herein is a method of treating or preventing a cardiovascular disease in a subject in need thereof, the method comprising administering to the subject: URAT1 inhibitors; xanthine oxidase inhibitors; and SGLT2 inhibitors. In some embodiments, the cardiovascular disease is coronary heart disease or heart failure. In some embodiments, the cardiovascular disease is heart failure. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is rasidone or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or allopurinol, or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, or engagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the subject is a human.

In some embodiments, the present disclosure provides a method of treating or preventing heart failure in a subject having diabetes currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject voronoi or a pharmaceutically acceptable salt thereof; and allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating or preventing heart failure in a subject having diabetes currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject voronoi or a pharmaceutically acceptable salt thereof; and febuxostat or a pharmaceutically acceptable salt thereof.

Gout

In another aspect, disclosed herein is a method of treating or preventing gout in a subject in need thereof, the method comprising administering to the subject: URAT1 inhibitors; xanthine oxidase inhibitors; and SGLT2 inhibitors. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is rasidone or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or allopurinol, or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is febuxostat. In some embodiments, the xanthine oxidase inhibitor is allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the xanthine oxidase inhibitor is allopurinol. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, or engagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol or pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is febuxostat; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof; the xanthine oxidase inhibitor is allopurinol; and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the subject is a human.

In some embodiments, the present disclosure provides a method of treating or preventing gout in a subject having diabetes currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject voriconazole, or a pharmaceutically acceptable salt thereof; and allopurinol or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating or preventing gout in a subject having diabetes currently being treated with dapagliflozin or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject voriconazole, or a pharmaceutically acceptable salt thereof; and febuxostat or a pharmaceutically acceptable salt thereof.

Administration of drugs

The amount of active ingredient or ingredients administered in the methods disclosed herein will depend, first of all, on the patient being treated. The daily dosage is usually determined by the prescribing physician and will generally vary with the age, sex, diet, body weight, general health, genetics, individual response, severity of the individual's symptoms, the precise indication or condition being treated, the severity of the indication or condition being treated, the time of administration, the route of administration, the distribution of the composition, the rate of excretion, drug combination, and the discretion of the prescribing physician. In view of such factors as those described above, the amount and frequency of administration of the compounds described herein, and if applicable other therapeutic agents and/or therapies, will be adjusted according to the judgment of the attending physician (physician). Thus, the amount of the pharmaceutical composition to be administered may vary widely.

In some embodiments, the methods comprise administering between 1mg and 20mg of voronoi or a pharmaceutically acceptable salt thereof; between 100mg and 600mg allopurinol; and between about 1mg and 20mg dapagliflozin. In some embodiments, the methods comprise administering between 5mg and 15mg of voronoi or a pharmaceutically acceptable salt thereof; between 100mg and 400mg allopurinol; and between about 5mg and 15mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 100mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 200mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 400mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 100mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 200mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 400mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof; about 300mg of allopurinol; and about 10mg dapagliflozin.

In some embodiments, the methods comprise administering between 1mg and 20mg of voronoi or a pharmaceutically acceptable salt thereof per day; between 100mg and 600mg allopurinol per day; and between about 1mg and 20mg of dapagliflozin per day. In some embodiments, the methods comprise administering between 5mg and 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; between 100mg and 400mg allopurinol per day; and between about 5mg and 15mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 100mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 200mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 400mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 100mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 200mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 400mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 300mg allopurinol per day; and about 10mg of dapagliflozin per day.

In some embodiments, the methods described herein comprise administering between 1mg and 20mg of voronoi or a pharmaceutically acceptable salt thereof; between 10mg and 200mg of febuxostat; and between about 1mg and 20mg dapagliflozin. In some embodiments, the methods comprise administering between 5mg and 15mg of voronoi or a pharmaceutically acceptable salt thereof; between 40mg and 100mg febuxostat; and between about 5mg and 15mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 40mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 40mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 5mg dapagliflozin. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof; about 80mg of febuxostat; and about 10mg dapagliflozin.

In some embodiments, the methods described herein comprise administering between 1mg and 20mg of voronoi or a pharmaceutically acceptable salt thereof per day; between 10mg and 200mg febuxostat per day; and between about 1mg and 20mg of dapagliflozin per day. In some embodiments, the methods comprise administering between 5mg and 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; between 40mg and 100mg febuxostat per day; and between about 5mg and 15mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 40mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 40mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 5mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg of febuxostat; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; about 80mg febuxostat per day; and about 10mg of dapagliflozin per day.

In some embodiments, the methods described herein comprise administering a combination of a URAT1 inhibitor (e.g., voronoi or a pharmaceutically acceptable salt thereof) and a xanthine oxidase inhibitor. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof. In some embodiments, the URAT1 inhibitor is vilinolide or a pharmaceutically acceptable salt thereof, and the xanthine oxidase inhibitor is febuxostat. In some embodiments, the URAT1 inhibitor is voronoi or a pharmaceutically acceptable salt thereof, and the xanthine oxidase inhibitor is allopurinol.

In some embodiments, the methods comprise administering between 1mg and 20mg of voronoi or a pharmaceutically acceptable salt thereof; and between 100mg and 600mg allopurinol. In some embodiments, the methods comprise administering between 5mg and 15mg of voronoi or a pharmaceutically acceptable salt thereof; and between 100mg and 400mg allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 100mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 200mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 400mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 100mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 200mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 400mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof; and about 300mg of allopurinol.

In some embodiments, the methods comprise administering between 1mg and 20mg of voronoi or a pharmaceutically acceptable salt thereof per day; and between 100mg and 600mg allopurinol per day. In some embodiments, the methods comprise administering between 5mg and 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; and between 100mg and 400mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 100mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 200mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 400mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 100mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 200mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 400mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 300mg allopurinol per day.

In some embodiments, the methods described herein comprise administering between 1mg and 20mg of voronoi or a pharmaceutically acceptable salt thereof; and between 10mg and 200mg of febuxostat. In some embodiments, the methods comprise administering between 5mg and 15mg of voronoi or a pharmaceutically acceptable salt thereof; and between 40mg and 100mg of febuxostat. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 40mg of febuxostat. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 40mg of febuxostat. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof; and about 80mg of febuxostat.

In some embodiments, the methods described herein comprise administering between 1mg and 20mg of voronoi or a pharmaceutically acceptable salt thereof per day; and between 10mg and 200mg febuxostat per day. In some embodiments, the methods comprise administering between 5mg and 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; and between 40mg and 100mg febuxostat per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 40mg febuxostat per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 40mg febuxostat per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 2mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 3mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 4mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 5mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 6mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 7mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 7.5mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg of febuxostat. In some embodiments, the methods comprise administering about 8mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 9mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 10mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 11mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 12mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 13mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 14mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day. In some embodiments, the methods comprise administering about 15mg of voronoi or a pharmaceutically acceptable salt thereof per day; and about 80mg febuxostat per day.

In some embodiments, as a result of the combination therapy, lower amounts of the components (e.g., the URAT1 inhibitor, XOI, and/or SGLT2 inhibitor) may be administered and still have a therapeutic or prophylactic effect.

Pharmaceutical composition

The present disclosure provides pharmaceutical compositions comprising the active ingredients described herein for use in the methods described herein. In some embodiments, the pharmaceutical composition comprises an effective amount of URAT1 inhibitor, XOI, and optionally an SGLT2 inhibitor. In some embodiments, the pharmaceutical composition comprises an effective amount of a URAT1 inhibitor, XOI, and optionally an SGLT2 inhibitor, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition can be used to treat or prevent a disorder disclosed herein. In some embodiments, the pharmaceutical composition is for treating a disorder in a human.

Formulations

The pharmaceutical compositions described herein may also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use may optionally be prepared according to known methods, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or uncoated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water-soluble taste-masking material (such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose), or a time-delay material (such as ethyl cellulose, or cellulose acetate butyrate) may be suitably used.

Formulations for oral use may also exist in the following forms: hard capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft capsules wherein the active ingredient is mixed with a water-soluble carrier, such as polyethylene glycol, or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide (for example lecithin), or a condensation product of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or a condensation product of ethylene oxide with a long chain aliphatic alcohol (for example heptadecaethylene-5-oxycetanol), or a condensation product of ethylene oxide with a partial ester derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides (for example polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical composition may contain other ingredients, such as flavoring agents, binders, excipients, and the like, if desired. Thus for oral administration, tablets containing various excipients, such as citric acid, may be employed with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are commonly used for tableting purposes. Solid compositions of a similar type may also be used in soft and hard-filled gelatin capsules. Thus, preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and emulsifying or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof, if desired.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients (for example sweetening, flavoring and coloring agents) may also be present. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil (for example olive oil or arachis oil), or a mineral oil (for example liquid paraffin) or a mixture of these. Suitable emulsifying agents may be naturally-occurring phosphatides (e.g. soy bean lecithin), and esters or partial esters derived from fatty acids and hexitol anhydrides (e.g. sorbitan monooleate), and condensation products of the said partial esters with ethylene oxide (e.g. polyoxyethylene sorbitan monooleate). The emulsion may also contain sweetening agents, flavouring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidants.

Dosage forms

For convenience, the total daily dose may be divided and administered in portions during the day, if desired. Thus, the total daily dose may be subdivided into unit doses containing appropriate amounts of the active components, e.g., effective amounts of URAT1 inhibitor, XOI, and optionally SGLT2 inhibitor ("active ingredients") to achieve the desired purpose. The unit dosage form may be prepared by any method well known in the art of pharmacy. In general, unit dosage forms can be prepared similar to the formulations described herein.

The dosage form may, for example, be in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained release formulation, solution, or suspension. The dosage form may comprise a pharmaceutically acceptable carrier or excipient and, as active ingredients, a URAT1 inhibitor, XOI, and optionally a SGLT2 inhibitor as described herein. In addition, they may include other drugs or agents, carriers, adjuvants, and the like. In some embodiments, these active ingredients are administered in separate dosage units. In some embodiments, for example, each active ingredient is administered in a separate tablet. In other embodiments, these active ingredients are administered in a single dosage unit. For example, all active ingredients may be administered in the same tablet. In some embodiments, the unit dosage form comprises, for example, three separate tablets (each comprising one active ingredient), two tablets (wherein one tablet comprises two active ingredients and the other tablet comprises the third active ingredient), or a single tablet (which comprises all active ingredients).

Reagent kit

The present disclosure further provides kits for use in the methods described herein. These kits comprise a compound or composition described herein in a container, and optionally instructions directing the use of the kit according to the various methods and means described herein. In some embodiments, such kits also include information indicative of or determining the activity and/or advantages of the composition, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these, and/or information describing dosing, administration, side effects, drug interactions, or other information useful to a health care provider. In some embodiments, such information is based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. In some embodiments, the kits described herein can be provided, sold, and/or promoted to healthcare providers, including physicians, nurses, pharmacists, prescribing personnel, and the like. In some embodiments, the kit is sold directly to the consumer.

Examples of the invention

Example 1: study to evaluate the effect of intensive uric acid lowering (UA) therapy with Verinolide, febuxostat, dapagliflozin on urinary excretion of UA

This study was a randomized, placebo-controlled, double-blind, two-way crossover study on asymptomatic hyperuricemia patients. The core study consisted of a screening phase, two treatment phases (vilinolide + febuxostat + dapagliflozin/placebo), and a follow-up.

Study type: intervention (clinical trial)

Actual recruitment: 36 participants

Assignment: random

Intervention mode: cross distribution

Masking: double (participants, outcome assessors) [ unless otherwise required by the study findings, pharmacokinetic experts will remain blind during the study. After all patients have completed the study, obtained the final bioanalytical results and all necessary study data are considered clear, the pharmacokinetic specialist will not blindly perform the final PK analysis. This may occur prior to the database locking. ]

The main purpose: treatment of

Detailed Description

This study was a randomized, placebo-controlled, double-blind, two-way crossover study in asymptomatic hyperuricemia patients to evaluate the effect of intensive Uric Acid (UA) lowering therapy with vilinolide, febuxostat, dapagliflozin on urinary excretion of UA. 36 asymptomatic hyperuricemia patients aged between 18 and 65 years (inclusive) were enrolled in both study centers for this study. 24 patients were enrolled and completed the study. Due to insufficient urine sampling, 12 additional patients were included to ensure sufficient sample size (at least 20 evaluable patients) to evaluate the effect of potentiation of UA on urinary excretion by voronoi, febuxostat and dapagliflozin. There were 24 completers available in the interim analysis, which would provide a total sample size of 36 evaluable patients.

Prior to any study-specific assessments, potential patients provided informed consent. Each patient had the following referenced visits:

a screening period of up to 28 days;

two treatment periods from day-2 to day 1 and from day 6 to day 8, wherein the patient resides in a clinical department; and

follow-up was performed within 14 to 28 days after the first administration of study drug (IMP) in treatment phase 2.

On day-2 of treatment period 1, patients were randomized (1: 1) to 1 of 2 treatment orders (AB or BA). Each randomly grouped patient received a fixed dose of 2 treatments (1 treatment per treatment period) per day orally for 7 consecutive days.

Treatment A: verinolide + febuxostat + dapagliflozin

Treatment B: verinolide + febuxostat + placebo

For each treatment period, baseline measurements were taken. On day 1, after completion of all dosing and all assessments, patients received the instruction to administer IMP once daily at home from day 2 to day 6, and were assigned IMP for home dosing. The patient returned to the clinical department on day 6 and remained in the clinical department from day 6 to day 8.

Treatment period 1 and treatment period 2 are separated by an elution period of 7 to 21 days.

Patients returned to the clinical department for follow-up 14 to 28 days after day 1 of treatment period 2.

Group and intervention

Primary outcome measure

1. On day 7, the effects of vilinolide, febuxostat, and dapagliflozin on urinary excretion of Uric Acid (UA) [ time range: during treatment periods 1 and 2: day-1 and day 7 ].

On day 7 of treatment (day 1 is the first day of treatment), differences in changes in subjects were assessed in the first 8 hours relative to baseline UA excretion peak (maximum UA excretion in an interval of the first 8 hours measured in milligrams [ mg ]).

On day-1: baseline urine was collected from-24 to-12 hours per hour on day 7, followed by a single 12 hour urine collection from-12 to 0 hours (0 hours being the dosing time on day 1): urine collection was performed from 0 to 12 hours (inclusive) per hour, followed by a single pooled collection from 12 to 24 hours after study treatment dosing.

Secondary outcome measure

1. Effects of vilinolide, febuxostat, and dapagliflozin on urinary excretion of serum uric acid (sUA) 7 days after treatment [ time frame: at screening and treatment periods 1 and 2: day-1 and day 7 ].

Assessing the UA-lowering potentiation of vilonolide, febuxostat, and dapagliflozin by assessing the level of sUA 7 days after treatment. During screening: an assessment of sUA. During the treatment period: always in the morning and after 10 hours of overnight fasting.

2. Dosing interval (24 hours) plasma concentration time curve area under (AUC τ) assessment of vilinolide and its major metabolites, febuxostat, and dapagliflozin [ time range: during treatment periods 1 and 2: day 7 (15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, and 24 hours before and after administration) ]

Evaluation of AUC after single oral fixed dose of vilinolide + febuxostat + dapagliflozin/placebo_T

3. Maximum observed plasma concentrations (C) of vilonolide and its major metabolites, febuxostat, and dapagliflozin_max) Evaluation [ time range: during treatment periods 1 and 2: day 7 (15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, and 24 hours before and after administration)]

Evaluation of C after a single oral dose of vilinolide + febuxostat + dapagliflozin/placebo_max

4. The number of participants who produced Adverse Events (AE) due to vilonolide, febuxostat, and dapagliflozin [ time frame: at screening time (day-28), treatment period 1 (day-2), treatment periods 1 and 2 (days-1, 6, 7 and 8) and follow-up/early withdrawal visit (EDV) (day 23) ]

Assessment of renal and overall safety and tolerability of intensive UA-lowering therapy with voronoi, febuxostat, and dapagliflozin. AE will be collected from the start of screening throughout the treatment period to follow-up (including follow-up). From informed consent, severe adverse events will be recorded.

5. Systolic blood pressure [ SBP ] [ time range: at screening time (day-28), treatment periods 1 and 2 (days-1 and 7) and follow-up/EDV (day 23) ]

Evaluation of SBP as a measure of safety and tolerability.

6. Diastolic pressure [ DBP ] [ time horizon: at screening time (day-28), treatment periods 1 and 2 (days-1 and 7) and follow-up/EDV (day 23) ]

Evaluating DBP as a measure of safety and tolerability.

7. Pulse rate [ time range: at screening time (day-28), treatment periods 1 and 2 (days-1 and 7) and follow-up/EDV (day 23) ]

Evaluate pulse as a measure of safety and tolerability.

8. Hematology laboratory evaluations [ time range: at screening (day-28), treatment periods 1 (days-2, -1 (FPG only) and 7), treatment periods 2 (days-1, 1 (FPG only) and 7) and follow-up/EDV (day 23) ]

Evaluation of hematology-hematology counts [ White Blood Cells (WBC), Red Blood Cells (RBC), Hematocrit (HCT), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC) ], categorical absolute counts (neutrophils, lymphocytes, eosinophils, basophils, platelets and reticulocytes), hemoglobin (Hb) counts and hemoglobin A1c (HbA 1c only at screening visit) as measures of safety and tolerability variables. Fasting samples, pre-breakfast (food) and pre-dose (if applicable) collections.

9. Laboratory evaluation of clinical chemistry [ time range: at screening (day-28), treatment periods 1 (days-2, -1 (FPG only) and 7), treatment periods 2 (days-1, 1 (FPG only) and 7) and follow-up/EDV (day 23) ]

Evaluation of clinical chemistry (sodium, potassium, Blood Urea Nitrogen (BUN), creatinine, albumin, calcium, phosphate, UA, liver enzymes, total and unbound bilirubin; cystatin-C and estimated glomerular filtration rate (eGFR) (glucose-fasting, performed only at screening) as a measure of safety and tolerance.

10. Laboratory evaluation of urinalysis [ time range: at screening time (day-28) and follow-up/EDV (day 23) ]

Assessment of urinalysis (glucose, protein, blood, UA, sodium, pH, creatinine and cystatin-C) as a measure of safety and tolerability variables. If the urinalysis is positive for protein or blood, microscopic examination will be performed to assess RBC, WBC, casts [ cells, particles, clear ].

Qualification of

Age eligible for study: age 18 to 99 years old (adult, elderly)

Gender eligible for study: all are

Healthy volunteers: is free of

Standard of merit

And (3) inclusion standard:

18 to 65 years old

Asymptomatic hyperuricemia (sUA >6.0mg/dL)

A body mass index of between 18 and 35kg/m2 (inclusive) and a body weight of at least 50kg and not more than 150kg

Women must be non-pregnant and would like to use an acceptable method of contraception post-menopausal or during the study.

Exclusion criteria:

history of any clinically significant disease or disorder that puts the patient at risk or affects the study outcome or ability to participate in the study during the course of the study

At screening eGFR <45 mL/min/1.73m 2

HbA1c > 8% type 2 diabetes

Diabetic ketoacidosis, hypertonic nonketotic coma, gout, or alcoholism or drug abuse

Being treated with an SGLT2 inhibitor, a URAT1 inhibitor, and/or a xanthine oxidase inhibitor

Positive detection of hepatitis B, hepatitis C or HIV

Use of any drug within 2 weeks prior to first administration of study drug

Results

Subjects (n-24) were enrolled as males, with an average age of 43 years. At Baseline (BL) (D-2), the median Body Mass Index (BMI) and eGFR were 29kg/m²And 85mL/min/1.73m²Average (SD) sUA 445.3(60.8) μmol/L. BL levels of serum creatinine (sCr) and blood sodium (sNa) were (Grp1/Grp2) 93.8/95.8. mu. mol/L and 138/139mmol/L, respectively. The peak uric acid (uUA) was available to 13 subjects, and 24-hour urine was available to all patients. After dapagliflozin treatment, the subject showed no increase (mg/h) in the uUA excretion peak of D7; grp1-5.33(-15.04, 4.37), Grp2-7.20(-16.91, 2.51); the average difference was 1.87(-7.63, 11.36). Likewise, there was no difference in total 24h ua excretion. After dapagliflozin treatment, a significant reduction in the subject's sUA levels is shown; the average difference between D7 (Grp1 and Grp2) was-76.35(-104.02，-48.68)μmol/L(p<0.01). No difference between groups was observed at sCr or sNa. 9 AEs from 8 subjects (Grp1 n-5; Grp2, n-4) were mild and were not within the group. Dapagliflozin does not affect the pharmacokinetics of vilinolide or febuxostat.

Conclusion

Hyperuricosuric excretion can damage the renal tubules due to high concentrations of uric acid crystals. The effect of dapagliflozin administered in combination with vilonolide and febuxostat on the excretion of sUA and urinary UA (UA) in hyperuricemic patients was examined. The addition of dapagliflozin to the enhanced UA reduction strategy with vilinolide and febuxostat additionally reduced sUA without increasing uUA excretion or causing sCr changes, indicating that the combination therapy of dapagliflozin, vilinolide, and febuxostat did not adversely affect renal function.

While certain embodiments of the claims have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that in some instances various alternatives to the embodiments described herein may be employed in practicing the invention.

It is intended that the methods and structures within the scope of these claims and their equivalents be covered thereby. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described or claimed. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.