Pharmaceutical composition for preventing, treating or relieving uric acid metabolic disorder and application thereof

Abstract

The invention provides a pharmaceutical composition for preventing, treating or relieving uric acid metabolic disorder and application, the pharmaceutical composition comprises a xanthine oxidase inhibitor and a URAT1 inhibitor, and the xanthine oxidase inhibitor is selected from teguxostat or febuxostat; the URAT1 inhibitor is selected from the group consisting of dotenod, Velnod, Lesinurad, Ruzinurad, SAP-001, ABP-671, SHR4640 and the like. The pharmaceutical composition provided by the invention can effectively reduce the concentration of uric acid in serum of a patient with hyperuricemia, so that the hyperuricemia is effectively prevented, treated or relieved. Compared with a single drug and the sum thereof, the combined drug composition can effectively inhibit serum uric acid, serum creatinine and urea nitrogen.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical use technology, specifically relating to pharmaceutical compositions and uses for the prevention, treatment or relief of uric acid metabolism disorders (especially hyperuricemia or gout). Background Technology

[0003] Hyperuricemia, caused by excessive production or insufficient excretion of uric acid, is considered a contributing factor to several diseases that seriously affect quality of life. For example, hyperuricemia is considered a trigger for gout (the most common form of inflammatory arthritis), characterized by severe joint pain and tenderness caused by the accumulation of urate crystals. Most uric acid dissolves in the blood and is transported to the kidneys, where it is excreted through glomerular filtration and tubular secretion. A significant portion of uric acid is reabsorbed by the renal tubules.

[0004] The level of urate anions in the blood is partially regulated by urate transporters such as URAT1. In some cases, single nucleotide polymorphisms in genes expressing URAT1 are significantly associated with increased or decreased renal reabsorption of uric acid, leading to hyperuricemia and hypouricemia, respectively.

[0005] Verinurad, chemically named 2-((3-(4-cyanonathi-1-yl)pyridin-4-yl)thio)-2-methylpropionic acid, with the structure shown in Formula I, is a new generation of superior URAT1 inhibitor developed by Ardea Biosciences based on the antiviral drug REDA806. It can effectively promote uric acid excretion, thereby treating gout patients with hyperuricemia.

[0006]

[0007] Dotinurad (Dotinurad), chemically named (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxide-3(2H)-benzothiazolyl) methyl ketone, with the structure shown in Formula II, is an oral tablet jointly developed by Fuji Yakuhin Pharmaceutical and Mochida Pharmaceutical in Japan for the treatment of certain types of hyperuricemia and gout. This drug is a urate reabsorption inhibitor that targets and inhibits the activity of the urate reabsorption transporter (URAT1). By selectively inhibiting the urate reabsorption transporter (URAT1) in the kidneys, it inhibits urate reabsorption and lowers uric acid levels in the blood.

[0008] SAP-001, chemically named 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione, with the structural formula shown in Formula III, is an oral, small-molecule URAT1 inhibitor developed by Shanton Pharma for once-daily uric acid-lowering treatment of refractory gout. Currently in clinical trials, it belongs to the xanthine class of compounds. Early trials have shown potent uric acid-lowering capabilities. (The primary objective of this trial was to reduce serum uric acid levels in patients resistant to standard xanthine oxidase inhibitors (such as allopurinol or febuxostat), while secondary endpoints included safety, tolerability, and gout attack frequency.)

[0009] ABP-671 (lingdolinurad), chemically named (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methyl ketone, with the structural formula shown in Formula V, is a drug developed by JW Pharmaceutical (Chong Kun Dang Pharmaceutical Co., Ltd., South Korea) for the treatment of gout. By inhibiting URAT1, ABP-671 can prevent the reabsorption of uric acid and promote its excretion through urine.

[0010] Uric acid is the final product of purine metabolism in the human body. Xanthine oxidase is a key enzyme in purine metabolism, which oxidizes hypoxanthine to xanthine, and further oxidizes xanthine to uric acid. Therefore, xanthine oxidase inhibitors can lower uric acid levels in the body by inhibiting uric acid production, thereby achieving a therapeutic goal.

[0011] Febuxostat (trade name: Uloric, Takeda North America) is a non-purine selective xanthine oxidase inhibitor. It was launched in the European Union in May 2008, approved by the US FDA in March 2009, and entered the Chinese market in 2013 for the long-term treatment of hyperuricemia associated with gout. Related studies and clinical practice indicate that febuxostat also has certain adverse reactions: common adverse reactions include abnormal liver function (3.5%), diarrhea (2.7%), headache (1.8%), nausea (1.7%), and rash (1.5%).

[0012] Tigulixostat, chemically named 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, with the structure shown in Formula IV, is a selective xanthine oxidase (XO) inhibitor developed by LG Life Sciences in South Korea. This compound has shown significant uric acid-lowering effects in vitro and in vivo, and is currently in Phase III clinical trials, making it a promising investigational drug.

[0013] Because the use of xanthine oxidase inhibitors or URAT1 inhibitors alone in clinical practice still has significant limitations, and the number of patients with hyperuricemia and gout worldwide is increasing year by year, the clinical demand for anti-gout drugs has not yet been met. More effective methods, combinations and therapies are needed to lower uric acid in this population, which has very important clinical value. Summary of the Invention

[0014] To achieve the above-mentioned technical objectives, the present invention provides a pharmaceutical composition and its use for preventing, treating or alleviating uric acid metabolism disorders, especially hyperuricemia. It considers different mechanisms of action to achieve combined uric acid reduction, and can effectively reduce the serum uric acid concentration of patients with hyperuricemia at a much lower dose than that of single drug use, thereby effectively treating hyperuricemia; the uric acid reduction efficiency of the obtained pharmaceutical composition is significantly improved.

[0015] In a first aspect, a pharmaceutical composition is provided, comprising a xanthine oxidase inhibitor or a pharmaceutically acceptable salt thereof and a URAT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the xanthine oxidase inhibitor is selected from tegusostat or febuxostat; and the URAT1 is selected from dotinurad, verinurad, probenecid, lesinurad, sulfinpyrazone, benzbromarone, high-dose salicylic acid, losartan, amlodipine, atorvastatin, fenofibrate, and SAP-001. At least one of the following: ABP-671, SHR4640, HP501, ahalofenyl ester, AC-201, D-0120, JTT-552, KUX-1151, THDBH130, THDBH151, WXSH10493, Verinurad, Tynnerad, Mebaron, TD213, FCN-207, FCN-342, QJ-19-0002, HY-0902, ABP-601, ACQT1001, CDER167, HP520, JNS4, JPH367, KPH2f, NC-2700, AR882, XNW3009, YL-90148, epaminurad, and ruzinurad.

[0016] In some embodiments, the pharmaceutical composition comprises tegusoxostald and dotenord.

[0017] In some embodiments, the pharmaceutical composition includes tegusoxostat and virinod.

[0018] In some embodiments, the pharmaceutical composition comprises tegusoxostald and resinard.

[0019] In some embodiments, the pharmaceutical composition includes tegusoxostat and Ruzinurad.

[0020] In some embodiments, the pharmaceutical composition comprises tegusoxostald and SAP-001.

[0021] In some embodiments, the pharmaceutical composition comprises tegusoxostald and ABP-671.

[0022] In some embodiments, the pharmaceutical composition comprises tegusoxusta and SHR4640 (ruzinurad), with the structure of ).

[0023] In some embodiments, the pharmaceutical composition comprises tegusoxostald and HP501.

[0024] In some embodiments, the pharmaceutical composition comprises tegusoxostal and alhalfenoxate.

[0025] In some embodiments, the pharmaceutical composition includes tegusoxostat and AC-201.

[0026] In some embodiments, the pharmaceutical composition includes tegusoxostald and D-0120.

[0027] In some embodiments, the pharmaceutical composition comprises tegusoxostat and JTT-552.

[0028] In some embodiments, the pharmaceutical composition comprises tegusoxostat and KUX-1151.

[0029] In some embodiments, the pharmaceutical composition comprises tegusoxostat and THDBH130.

[0030] In some embodiments, the pharmaceutical composition comprises tegusoxostat and THDBH151.

[0031] In some embodiments, the pharmaceutical composition includes tegusoxostal and WXSH10493.

[0032] In some embodiments, the pharmaceutical composition includes tegusoxostat and Verinurad.

[0033] In some embodiments, the pharmaceutical composition comprises tegusoxostald and tyrinard.

[0034] In some embodiments, the pharmaceutical composition includes tegusoxostat and meparone.

[0035] In some embodiments, the pharmaceutical composition includes tegusoxostat and TD213.

[0036] In some embodiments, the pharmaceutical composition includes tegusoxostat and FCN-207.

[0037] In some embodiments, the pharmaceutical composition comprises tegusoxostat and FCN-342.

[0038] In some embodiments, the pharmaceutical composition comprises tegusoxostald and QJ-19-0002.

[0039] In some embodiments, the pharmaceutical composition comprises tegusoxostald and HY-0902.

[0040] In some embodiments, the pharmaceutical composition comprises tegusoxusta and ABP-601.

[0041] In some embodiments, the pharmaceutical composition comprises tegusoxostald and ACQT1001.

[0042] In some embodiments, the pharmaceutical composition includes tegusoxostat and CDER167.

[0043] In some embodiments, the pharmaceutical composition includes tegusoxostald and HP520.

[0044] In some embodiments, the pharmaceutical composition comprises tegusoxostat and JNS4.

[0045] In some embodiments, the pharmaceutical composition includes tegusoxostat and JPH367.

[0046] In some embodiments, the pharmaceutical composition comprises tegusoxostat and KPH2f.

[0047] In some embodiments, the pharmaceutical composition includes tegusoxostat and NC-2700.

[0048] In some embodiments, the pharmaceutical composition includes tegusoxostat and AR882.

[0049] In some embodiments, the pharmaceutical composition includes tegusoxostat and XNW3009.

[0050] In some embodiments, the pharmaceutical composition comprises tegusoxostald and YL-90148.

[0051] In some embodiments, the pharmaceutical composition includes tegusoxostat and epaminurad.

[0052] In some embodiments, the pharmaceutical composition includes febuxostat and dotenorode.

[0053] In some embodiments, the pharmaceutical composition includes febuxostat and virinod.

[0054] In some embodiments, the pharmaceutical composition includes febuxostat and resinard.

[0055] In some embodiments, the pharmaceutical composition includes febuxostat and Ruzinurad.

[0056] In some embodiments, the pharmaceutical composition includes febuxostat and SAP-001.

[0057] In some embodiments, the pharmaceutical composition includes febuxostat and ABP-671.

[0058] In some embodiments, the pharmaceutical composition includes febuxostat and SHR4640.

[0059] In some embodiments, the pharmaceutical composition includes febuxostat and HP501.

[0060] In some embodiments, the pharmaceutical composition comprises febuxostat and alhalfen ester.

[0061] In some embodiments, the pharmaceutical composition includes febuxostat and AC-201.

[0062] In some embodiments, the pharmaceutical composition includes febuxostat and D-0120.

[0063] In some embodiments, the pharmaceutical composition includes febuxostat and JTT-552.

[0064] In some embodiments, the pharmaceutical composition includes febuxostat and KUX-1151.

[0065] In some embodiments, the pharmaceutical composition includes febuxostat and THDBH130.

[0066] In some embodiments, the pharmaceutical composition includes febuxostat and THDBH151.

[0067] In some embodiments, the pharmaceutical composition includes febuxostat and WXSH10493.

[0068] In some embodiments, the pharmaceutical composition includes febuxostat and Verinurad.

[0069] In some embodiments, the pharmaceutical composition includes febuxostat and tylenol.

[0070] In some embodiments, the pharmaceutical composition includes febuxostat and meparone.

[0071] In some embodiments, the pharmaceutical composition includes febuxostat and TD213.

[0072] In some embodiments, the pharmaceutical composition includes febuxostat and FCN-207.

[0073] In some embodiments, the pharmaceutical composition includes febuxostat and FCN-342.

[0074] In some embodiments, the pharmaceutical composition comprises febuxostat and QJ-19-0002.

[0075] In some embodiments, the pharmaceutical composition includes febuxostat and HY-0902.

[0076] In some embodiments, the pharmaceutical composition includes febuxostat and ABP-601.

[0077] In some embodiments, the pharmaceutical composition includes febuxostat and ACQT1001.

[0078] In some embodiments, the pharmaceutical composition includes febuxostat and CDER167.

[0079] In some embodiments, the pharmaceutical composition includes febuxostat and HP520.

[0080] In some embodiments, the pharmaceutical composition comprises febuxostat and JNS4.

[0081] In some embodiments, the pharmaceutical composition includes febuxostat and JPH367.

[0082] In some embodiments, the pharmaceutical composition includes febuxostat and KPH2f.

[0083] In some embodiments, the pharmaceutical composition includes febuxostat and NC-2700.

[0084] In some embodiments, the pharmaceutical composition includes febuxostat and AR882.

[0085] In some embodiments, the pharmaceutical composition includes febuxostat and XNW3009.

[0086] In some embodiments, the pharmaceutical composition includes febuxostat and YL-90148.

[0087] In some embodiments, the pharmaceutical composition includes febuxostat and epaminurad.

[0088] In some embodiments, the molar ratio of the xanthine oxidase inhibitor to the URAT1 inhibitor in the pharmaceutical composition is (1-20):(1-20). Preferably, the ratios are 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, or any two of the above values ​​forming any range.

[0089] In some embodiments, the mass ratio of the xanthine oxidase inhibitor to the URAT1 inhibitor in the pharmaceutical composition is (1-200):(1-20). Preferably, the ratios are 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, and 15:1. The range can be any two of the following ratios: 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 75:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 200:1, and any two of the above ratios.

[0090] In some embodiments, the pharmaceutical composition is tegusoxusta and dotenorode, with a molar ratio of (15-200):1, preferably 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 75:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 200:1, or any two of the above values ​​forming any one of the ranges.

[0091] In some embodiments, the pharmaceutical composition is tegusoxustal and dotenorazole in a mass ratio of (15-200):1, preferably 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 75:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 200:1, or any two of the above values ​​forming any one of the ranges.

[0092] In some embodiments, the pharmaceutical composition is tegusoxusta and ricinard in a mass ratio of (1-10):1, preferably 1:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, or any two of the above values ​​forming any one of the ranges.

[0093] In some embodiments, the pharmaceutical composition is tegusoxusta and Verinurad in a mass ratio of (1-50):1, preferably 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, 50:1, or any two of the above values ​​forming any one of the ranges.

[0094] In some embodiments, the pharmaceutical composition is tegusoxusta and ruzinurad in a mass ratio of (15-200):1, preferably 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 75:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 200:1, or any two of the above values ​​forming any one of the ranges.

[0095] In some embodiments, the pharmaceutical composition is tegusoxusta and virinod in a molar ratio of (15-20):1, preferably 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, or any two of the above values ​​forming a range.

[0096] In some embodiments, the pharmaceutical composition is febuxostat and dotenoroxetine in a mass ratio of (15-200):1, preferably 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 75:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 200:1, or any two of the above values ​​forming any one of the ranges.

[0097] In some embodiments, the pharmaceutical composition is febuxostat and retinoic acid in a mass ratio of (1-10):1, preferably 1:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, or any two of the above values ​​forming any one of the ranges.

[0098] In some embodiments, the pharmaceutical composition is febuxostat and Verinurad in a mass ratio of (1-50):1, preferably 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, 50:1, or any two of the above values ​​forming any one of the ranges.

[0099] In some embodiments, the pharmaceutical composition is febuxostat and ruzinurad in a mass ratio of (15-200):1, preferably 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 75:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 200:1, or any two of the above values ​​forming any one of the ranges.

[0100] In some embodiments, the pharmaceutical composition comprises a first formulation formed of a xanthine oxidase inhibitor and a pharmaceutically acceptable carrier, and a second formulation formed of a URAT1 inhibitor and a pharmaceutically acceptable carrier; or comprises a combination formulation formed of a xanthine oxidase inhibitor, a URAT1 inhibitor, and a pharmaceutically acceptable carrier.

[0101] In some embodiments, the pharmaceutical composition comprises a xanthine oxidase inhibitor or a pharmaceutically acceptable salt thereof at a dose of 0.5 mg / day to 400 mg / day. Preferably, the dose comprises 0.5 mg / day, 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, etc. The dosage ranges are 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, and any two of the above values. In some embodiments, the dosage of tegusostat in the pharmaceutical composition is 0.5 mg / day to 300 mg / day, for example, 50 mg / day to 300 mg / day. In some embodiments, the dosage of febuxostat in the pharmaceutical composition is 0.5 mg / day to 120 mg / day, for example, 20 mg / day to 80 mg / day.

[0102] In some embodiments, the pharmaceutical composition comprises a dose of 0.5 mg / day to 400 mg / day of an URAT1 inhibitor or a pharmaceutically acceptable salt thereof. Preferably, the dose comprises 0.5 mg / day, 1 mg / day, 1.5 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, etc. The dosage ranges are 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, and any two of the above values. In some embodiments, the dosage of dotenorad in the pharmaceutical composition is 0.1 mg / day to 120 mg / day, for example, 0.5 mg / day to 4 mg / day. In some embodiments, the dosage of virinodide in the pharmaceutical composition is 0.1 mg / day to 120 mg / day, for example, 2.5 mg / day to 24 mg / day. In some embodiments, the dosage of ABP-671 in the pharmaceutical composition is 0.1 mg / day to 120 mg / day, for example, 1 mg / day to 2 mg / day. In some embodiments, the dosage of SAP-001 in the pharmaceutical composition is 0.1 mg / day to 200 mg / day, for example, 5 mg / day to 120 mg / day. In some embodiments, the dosage of SHR4640 in the pharmaceutical composition is 0.1 mg / day to 200 mg / day, for example, 1 mg / day to 10 mg / day.

[0103] In some embodiments, the pharmaceutical composition can reduce the blood uric acid concentration of a patient receiving the pharmaceutical composition to below 4-6 mg / dL, preferably 4 mg / dL, 5 mg / dL, 6 mg / dL, or any two of the above values ​​forming a range.

[0104] In some embodiments, the pharmaceutical composition is formulated as a liquid or solid dosage form, including oral solid dosage forms (such as tablets, capsules, etc.), oral liquid dosage forms, injections, lyophilized powder injections, large-volume parenteral solutions, patches, ointments, creams, sprays, gels, soft capsules, or suppositories.

[0105] In some embodiments, the pharmaceutically acceptable carrier refers to a drug carrier conventional in the pharmaceutical field, selected from at least one of fillers, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, polymeric framework materials, film-forming materials, wetting agents, pigments, fragrances, solvents, surfactants, flavoring agents, buffers, isotonic modifiers, antioxidants, antibacterial agents, and analgesics.

[0106] In some embodiments, the filler may be selected from, but is not limited to, at least one of lactose, sucrose, starch, microcrystalline cellulose, sorbitol, or calcium phosphate.

[0107] In some embodiments, the lubricant may be selected from, but is not limited to, at least one of magnesium stearate.

[0108] In some embodiments, the polymeric backbone material may be selected from, but is not limited to, at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, carnauba wax, hydrogenated vegetable oil, or acrylic resin.

[0109] In some embodiments, the film-forming material may be selected from, but is not limited to, hydroxypropyl methylcellulose, polyvinylpyrrolidone, or acrylic resin, etc.

[0110] In some embodiments, the adhesive may be selected from, but is not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, polyvinyl acetate, povidone, polyvinylpyrrolidone, copovidone, polyethylene glycol, sodium lauryl sulfate, light anhydrous silicate, synthetic aluminum silicate, silicate derivatives such as calcium silicate or magnesium aluminosilicate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, pregelatinized starch, gums such as gum arabic, gelatin, cellulose derivatives such as ethyl cellulose, and mixtures thereof.

[0111] In some embodiments, the disintegrant includes one or more of substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, croscarmellose sodium, and microcrystalline cellulose.

[0112] In some embodiments, the lubricant includes one or more of magnesium stearate, talc, calcium stearate, sodium stearate fumarate, polyethylene glycol 4000, and polyethylene glycol 6000.

[0113] In some embodiments, the diluent includes one or more of powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, sodium chloride, starch, and sorbitol. In a second aspect, the invention provides the use of the pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of uric acid metabolism disorders.

[0114] In some embodiments, the pharmaceutical composition comprises tegusoxostald and dotenord.

[0115] In some embodiments, the pharmaceutical composition includes tegusoxostat and virinod.

[0116] In some embodiments, the pharmaceutical composition may be administered as a monotherapy alone, or may be given in combination with one or more other substances and / or additionally. The combined application method of the present invention can be achieved by administering the individual components of the treatment simultaneously, sequentially, or individually.

[0117] In some embodiments, the specific functions of the pharmaceutical composition include simultaneously inhibiting uric acid production and promoting uric acid excretion; improving damage caused by renal tubular dilation, alleviating the progression of renal fibrosis, and thereby reducing kidney damage.

[0118] In some embodiments, the uric acid metabolism disorder includes, but is not limited to, hyperuricemia, gout, recurrent gout attacks, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, nephropathy, chronic kidney disease, kidney stones, kidney failure, kidney injury, renal fibrosis, diabetic nephropathy, arthritis, urinary tract stones, polycythemia, myeloid metaplasia, Kelley-Seegmiller syndrome, lead poisoning, hyperparathyroidism, psoriasis, or sarcoidosis.

[0119] Compared with the prior art, one of the above technical solutions has the following advantages or beneficial effects: The pharmaceutical composition provided by the present invention can be effectively used to treat or prevent patients with hyperuricemia. It can not only effectively improve the efficiency of lowering uric acid and significantly reduce the serum uric acid level of patients with hyperuricemia, but also maintain a low blood uric acid concentration for a long time.

[0120] Compared to the combined effects of the T and D groups (monotherapy), the D+T group showed a 4-fold, 3.5-fold, and 2.9-fold increase in the inhibition of serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN), respectively. In the D+T group, dotenorode and tegusostat exhibited a synergistic effect.

[0121] Compared to the combined effects of the T and V groups (monotherapy), the V+T group showed a 3.8-fold, 3.8-fold, and 4.5-fold increase in the inhibition of serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN), respectively. There was a synergistic effect between velinord and tegusostat in the V+T group.

[0122] Compared to the combined D+F and V+F groups, the D+T and V+T groups showed better uric acid-lowering effects and also exhibited renal protective effects. Compared to the L and T groups using single-drug therapy, the combined L+T group effectively controlled serum uric acid, creatinine, and blood urea nitrogen. Furthermore, there were statistically significant differences, with the optimal dose ratio of domenolide and tegusostat in the L+T group demonstrating a superior effect.

[0123] Compared to existing drug combinations, the drug composition provided by this invention can effectively regulate the blood uric acid concentration in patients with hyperuricemia, improving efficacy while taking effect more quickly.

[0124] Terminology Explanation Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0125] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0126] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0127] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0128] In the following content, all numbers disclosed herein, whether or not they use words such as "approximately" or "about," are approximate values. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%. Whenever a number with a value of N is disclosed, any numbers with values ​​of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% will be explicitly disclosed, where "+ / -" indicates addition or subtraction.

[0129] The terms “patient,” “subject,” and “individual” are used interchangeably. As used in this specification, they refer to individuals suffering from the disease. Individuals with symptoms, etc. None of the terms used require that "patient," "subject," or "individual" be under the care and / or supervision of a medical professional.

[0130] As used in this invention, the term "treatment" and other grammatical equivalents refer to the relief, reduction, or improvement of a disease or ailment or one or more symptoms thereof, the improvement of the underlying metabolic cause of the symptoms, or the inhibition of the disease or ailment, for example, preventing the development of the disease or ailment, alleviating the disease or ailment, resulting in the inhibition of the disease or ailment, alleviating the ailment caused by the disease or ailment, or terminating the symptoms of the disease or ailment.

[0131] As used herein, the terms "administration," "dosing," etc., refer to methods that can be used to facilitate the delivery of a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), and local and rectal administration. Those skilled in the art to which this invention pertains are familiar with administration techniques that can be used with the compounds, compositions, methods, etc., described herein. Furthermore, the pharmaceutical compositions of this invention are administered to the subject once daily at approximately the same time.

[0132] As used in this specification, the terms "effective amount," "therapeutic effective amount," and "pharmaceutical effective amount" refer to the amount of at least one drug or compound administered that is sufficient to alleviate, to a certain extent, one or more symptoms of the disease or ailment being treated. For therapeutic purposes, an "effective amount" is the amount of a composition comprising compounds as disclosed in this specification that is necessary to provide clinically significant disease relief. Appropriate "effective" amounts can vary between individuals. An appropriate "effective" amount for any individual can be determined using techniques such as dose escalation studies.

[0133] As used in this specification, the term "pharmaceutical composition" means a composition comprising at least one pharmaceutically acceptable chemical component, such as at least one excipient component, such as, but not limited to, a carrier, stabilizer, diluent, dispersant, suspending agent, and thickener.

[0134] As used in this specification, the term "pharmaceutically acceptable salt" means a salt that retains the bioavailability of the specified compound's free acid and free base without being biologically or otherwise undesirable. The compounds described in this specification may have acidic or basic groups and therefore can react with many inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts.

[0135] The term "pharmaceuticalally acceptable" refers to a substance that is acceptable to patients from a pharmacological / toxicological point of view in terms of composition, formulation, safety, etc., and "pharmaceuticalally acceptable carrier" refers to a medium that does not interfere with the bioactivity of the active ingredient and is non-toxic to the subject after administration.

[0136] As used in this specification, the terms “co-administered” and “combined administered” and their equivalents are intended to include the administration of two or more active ingredients to a single individual. Each active ingredient may be included independently in a preparation (or formulation), and in such cases, may be administered at the same or different times via the same or different routes of administration. Specific substances that can be co-administered or combined administered will be described later.

[0137] Specific diseases associated with hyperuricemia include gout, recurrent gout attacks, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, heart failure, Lesch-Niehan syndrome, Kelley-Sigmüller syndrome, nephropathy, chronic kidney disease, kidney stones, kidney failure, diabetic nephropathy, joint inflammation, arthritis, urinary tract stones, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, and hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. In particular, urate crystals produced in the body are known to be a direct cause of chronic arthritis, urinary tract stones, kidney disease, recurrent acute arthritis, bursitis, and gout attacks. Gout is often associated with obesity, diabetes, hypertension, and cardiovascular disease. Furthermore, with the increase in blood uric acid concentration due to increased protein-rich diets in recent years, the number of gout patients is also increasing; therefore, controlling blood uric acid concentration is crucial to preventing the formation of urate crystals.

[0138] When this composition is used as a medicine for the prevention and / or treatment of diseases, it can be safely administered orally or parenterally to mammals such as humans, mice, rats, rabbits, dogs, and cats. The dosage of the composition can be appropriately determined based on the type of disease, age, sex, weight, severity of symptoms, and method of administration. For example, when administered orally to patients with gout or hyperuricemia, the composition can be administered once or several times daily.

[0139] Dosage conversion: Calculated based on a rat weight of 150g and a human weight of 60kg.

[0140] HED(mg / kg)=Animal NOAEL(mg / kg)×(Weight animal [kg] / Weight human [kg]) (1-0.67) In this invention, the dose of dotenord in rats was 1.3 mg, which is 2.7 times the maximum human dose of 4 mg; the dose of verinurad in rats was 1.5 mg, which is equivalent to 12 mg in humans (the maximum dose used in combination in clinical trials); the dose of febuxostat in rats was 20 mg, which is twice the maximum human therapeutic dose of 80 mg; and the dose of tigulixostat in rats was 24 mg, which is equivalent to 200 mg in the maximum human therapeutic dose group in clinical studies. Attached Figure Description

[0141] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0142] Figure 1 This is a comparison chart of the changes in serum uric acid levels in each experimental group in Example 1.

[0143] Figure 2 This is a comparison chart of the changes in serum creatinine levels in each experimental group in Example 1.

[0144] Figure 3 This is a comparison chart of the changes in urea nitrogen content in each experimental group in Example 1.

[0145] Figure 4 The figure shows the experimental results of Example 2.

[0146] Figure 5 The graph shows the results of the combined use of retinoic acid and tegusostat in Experiment 1 of Example 3.

[0147] Figure 6 The graph shows the results of the combined use of dotenorazole and tegusostat in Experiment 2 of Example 3.

[0148] Figure 7 The graph shows the results of the combined use of Verinurad and tegusostat in Experiment 3 of Example 3.

[0149] Figure 8 The graph shows the results of the combined use of ruzinurad and tegusostat in Experiment 4 of Example 3. Detailed Implementation

[0150] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and techniques have also been described in many publications.

[0151] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0152] All drugs were prepared into a suspension using CMC-Na before administration to animals via gavage.

[0153] Instruments: UA, Cr, BUN: Fully automated biochemical analyzer, Siemens ADVIA2400.

[0154] Animals: SPF-grade male SD rats were purchased from the Experimental Animal Center of Xuzhou Medical University; Pharmaceuticals: Potassium oxazine was purchased from Shanghai Yuanye Biotechnology Co., Ltd.; Tigulixostat was purchased from Shanghai Huayuan Biochemical Technology Co., Ltd.; Febuxostat was purchased from Teijin Co., Ltd. (trade name: Febuxostat, specification 20mg / tablet); Dotenoroxetine was purchased from Eisai Pharmaceutical Co., Ltd. (trade name: Dotenoroxetine, specification 1mg / tablet); Verinurad was purchased from Shanghai Huayuan Biochemical Technology Co., Ltd.; ABP-671 was purchased from Shanghai Huayuan Biochemical Technology Co., Ltd.; SAP-001 was synthesized according to the method of Example 2 of patent CN107206002A; SHR4640 was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0155] Example 1 To explore the efficacy of combination therapy of tegusostat and URAT1 inhibitor in the treatment of hyperuricemic rats. I. Experimental Objective The purpose of this study was to investigate the effects of teguxostat and URAT1 inhibitors on uric acid metabolism in hyperuricemic rats by observing changes in serum uric acid concentration before and after treatment.

[0156] II. Materials and Methods 1. Laboratory animals Eight-week-old male Sprague-Dawley rats were selected and housed in pairs in isolation cages for one week to acclimatize before grouping. The animals were housed in a controlled environment with a temperature of 20-25°C and humidity of 35-55%. Throughout the study, the rats had free access to standard rodent feed and deionized water.

[0157] 2. Research Design Model establishment: Rats were divided into a blank control group, a model group, and a hyperuricemia treatment group, with 10 rats in each group. The model group and the hyperuricemia treatment group were administered potassium oxonate by gavage at a dose of 750 mg / kg / day for 7 days to establish the model. Successful model establishment was defined as the detection of serum uric acid levels. When the serum uric acid level was significantly higher than that of rats fed a normal diet, the model was considered to have been successfully established.

[0158] Grouping and Dosage: After successful modeling, the participants were randomly divided into a blank group, a model group, and a drug-treated group. The distribution of the drug-treated groups is shown in Table 1 below. Table 1 Distribution of drug administration groups

[0159] All treatment groups were given the modeling agent 4 hours after administration of the corresponding drug via gavage, with a gavage volume of 1 ml / 100 g, administered after meals (pd).

[0160] All oral medications should be prepared into a corresponding suspension using 0.5% CMC-Na solution before use.

[0161] Study Design: The modeling experiment was conducted during the first week of the study period. The treatment period began on day 8, with the corresponding drug administered by gavage 4 hours after the modeling agent was applied daily. During the treatment period, the control group and the model group were administered the corresponding volume of 0.5% CMC-NA by gavage. Animals were removed from their cages for drug administration and then immediately returned to their original cages. Rats had free access to standard feed and deionized water.

[0162] At the end of the third week of the experiment, participants fasted for 12 hours, and blood was collected from the abdominal aorta. The serum was separated by centrifugation, and the changes in serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN) levels were measured.

[0163] Drug solution Preparation of molding agent: Dissolve an appropriate amount of potassium oxonate in distilled water to make a solution.

[0164] Both the blank control group and the model group were given 0.5% CMC-NA solution.

[0165] Positive control group: Based on the different drugs administered as shown in Table 1, the groups were D, V, F, T, D+F, D+T, and S. Research groups: V+F group, V+T group, S+T group.

[0166] Indicator Collection After blood samples were collected, they were left at room temperature for 1 hour until the blood had completely coagulated. Then, they were centrifuged at 3500 rpm and 4°C for 10 minutes. The serum was then centrifuged again under the same conditions for 5 minutes. Finally, 0.2 mL of serum was collected, and the changes in serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN) were detected using a Beckman Coulter AU480 biochemical analyzer.

[0167] Statistical analysis Continuous data in all datasets for each group are expressed as mean ± standard deviation. One-way ANOVA was used to compare the experimental groups, followed by Tukey's post-hoc test for corrected multiple comparisons and pairwise comparisons between groups. Results are as follows: Figures 1-3 As shown in Figure 1 and Table 2.

[0168] Table 2. Detection of relevant parameters in serum

[0169] Conclusion Analysis: As can be seen from the data in Table 2, after 3 weeks of continuous medication, serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN) in both the D+T and V+T groups were effectively relieved and controlled.

[0170] Compared to the single-drug groups F, T, D, and V, the combined application of the D+F, V+F, D+T, and V+T groups effectively controlled serum uric acid, creatinine, and blood urea nitrogen. Compared to the combined single-drug application of groups T and D, the D+T group showed a 4-fold, 3.5-fold, and 2.9-fold increase in the inhibition of serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN), respectively, with a synergistic effect between dolinodine and tegusostat in the D+T group. Compared to the combined single-drug application of groups T and V, the V+T group showed a 3.8-fold, 3.8-fold, and 4.5-fold increase in the inhibition of serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN), respectively, with a synergistic effect between dolinodine and tegusostat in the V+T group. Compared to single-component administration, the combined application of the pharmaceutical compositions of this invention achieves a technical effect of 1+1>2.

[0171] Compared to the combined use of the D+F and V+F groups, the D+T and V+T groups showed better uric acid-lowering effects and also had a kidney-protective effect.

[0172] Example 2 To explore the efficacy of teguxostat 300 mg combined with a URAT1 inhibitor in the treatment of hyperuricemia in rats.

[0173] The experimental materials, methods, and procedures are as described in Example 1. The drug administration groups and dosages are shown in Table 3 below. Table 3. Dosage and administration groupings

[0174] The statistical analysis method is as described in Example 1, and the results are as follows: Figure 4 As shown in Figure 4 and Table 4: Table 4 Results

[0175] Conclusion Analysis: As can be seen from the data in Table 4, after 3 weeks of continuous medication, serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN) in both the D+T and V+T groups were effectively relieved and controlled.

[0176] Compared to the single-drug groups F, T, D, and V, the combined application of the D+F, V+F, D+T, and V+T groups effectively controlled serum uric acid, creatinine, and blood urea nitrogen. Compared to the combined single-drug application of groups T and D, the D+T group showed a 5-fold, 4.1-fold, and 4-fold increase in the inhibition of serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN), respectively, with a synergistic effect between dolinodine and tegusostat in the D+T group. Compared to the combined single-drug application of groups T and V, the V+T group showed a 5-fold, 4.3-fold, and 5.2-fold increase in the inhibition of serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN), respectively, with a synergistic effect between dolinodine and tegusostat in the V+T group. Compared to single-component administration, the combined application of the pharmaceutical compositions of this invention achieves a technical effect of 1+1>2.

[0177] Compared to the combined use of the D+F and V+F groups, the D+T and V+T groups showed better uric acid-lowering effects and also had a kidney-protective effect.

[0178] Example 3 This study explored the effects of different ratios of xanthine oxidase inhibitors and URAT1 inhibitors in the treatment of hyperuricemic rats. Four experiments were conducted to investigate the combination of tegusostat with lesinurad, dotenorad, verinurad, and ruzinurad. The optimal ratio was determined by exploring the effect of the human dose ratio (mass ratio) of the two inhibitors on lowering uric acid. The control group and the model group were still administered 0.5% CMC-Na solution by gavage.

[0179] Experiment 1 The experimental materials, methods, and procedures were as described in Example 1. Using a rat dose of 150g and an adult dose of 60kg, the human dose of retinoic acid (L) was 200mg, converted to a rat dose of 24.5mg / kg / day, and the human dose of tegusostat (T) was 300mg, converted to a rat dose of 36.8mg / kg / day. The L+T group was administered at a human dose ratio of retinoic acid:tegusostat of 1:1.5. The dosing groups and dosages are shown in Table 5 below. Table 5. Dosage Grouping and Dosage Information

[0180] The statistical analysis method is as described in Example 1, and the results are as follows: Figure 5 As shown in Figure 6 and Table 6: Table 6 Experimental Results

[0181] Conclusion Analysis: The data in the table show that after 3 weeks of continuous medication, serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN) in the L+T group were effectively relieved and controlled.

[0182] Compared to the L and T groups treated with single drugs, the L+T group effectively controlled serum uric acid, creatinine, and blood urea nitrogen. Furthermore, there were statistically significant differences, with the L+T group exhibiting an advantageous dosage ratio of domenolide and tegusostat.

[0183] Experimental conclusion: Compared to pre-administration blood uric acid concentrations, the pharmaceutical composition of this invention effectively reduced blood uric acid concentrations in hyperuricemic mice. Through mass ratio experiments, it was found that the combination of tegusostat and dotenorode, and the combination of tegusostat and velinorode, exhibited very significant synergistic effects within the specified ratio range.

[0184] Experiment 2 The experimental materials, methods, and procedures were as described in Example 1. Using a 150g rat and a 60kg adult as the baseline, the human doses of dotenoroxetine (D) were 1mg and 4mg, respectively, converted to rat doses of 0.12 mg / kg / day and 0.49 mg / kg / day. The human doses of tegusostat (T) were 50mg, 75mg, 100mg, 150mg, and 300mg, respectively, converted to rat doses of 6.1mg / kg / day, 9.2mg / kg / day, 12.3mg / kg / day, 18.4mg / kg / day, and 36.8mg / kg / day. The four combination groups were administered at human dose ratios (mass ratios) of 1:50, 1:75, 1:100, and 1:150 for dotenoroxetine and tegusostat, respectively. The dosing groups and dosages are shown in Table 7 below. Table 7 Dosage Groups and Doses

[0185] The statistical analysis method is as described in Example 1, and the results are as follows: Figure 6 As shown in Figure 8 and Table 8: Table 8 Experimental Results

[0186] Conclusion Analysis: As can be seen from the data in Table 8, after 3 weeks of continuous medication, serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN) in each combination group were effectively relieved and controlled.

[0187] Compared to the single-drug groups D and T, the combined D+T group effectively controlled serum uric acid, creatinine, and urea nitrogen at a 1:50 dosage ratio, with statistically significant differences. The control effect increased proportionally with the increase of the T dose, indicating a very significant synergistic effect in the human dosage ratio of the formulation.

[0188] Experiment 3 The experimental materials, methods, and procedures were as described in Example 1. Using a 150g rat and a 60kg adult as the baseline, the human doses of Verinurad (V) were 12mg and 24mg, respectively, converted to rat doses of 1.47mg / kg / day and 2.94mg / kg / day. The human doses of Tigusostat (T) were 50mg, 75mg, 100mg, 150mg, and 300mg, respectively, converted to rat doses of 6.1mg / kg / day, 9.2mg / kg / day, 12.3mg / kg / day, 18.4mg / kg / day, and 36.8mg / kg / day. The four combination groups were administered at human dose ratios (mass ratios) of 1:25 for dotenoradine and 1:25 for Tigusostat. The dosing groups and dosages are shown in Table 9 below. Table 9 Dosage Groups and Doses

[0189] The statistical analysis method is as described in Example 1, and the results are as follows: Figure 7 As shown in Figure 16 and Table 10: Table 10 Experimental Results

[0190] Conclusion Analysis: As can be seen from the data in Table 10, after 3 weeks of continuous medication, serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN) in each combination group were effectively relieved and controlled.

[0191] Compared to the single-drug groups V and T, the combined V+T group effectively controlled serum uric acid, creatinine, and urea nitrogen in a 6:25 dosage ratio, with statistically significant differences. The control effect increased proportionally with the increase of the T dose, indicating a very significant synergistic effect in the human dosage ratio of the formulation.

[0192] Experiment 4 The experimental materials, methods, and procedures were as described in Example 1. Using a rat dose of 150g and an adult dose of 60kg, the human doses of Ruzinurad (R) of 5mg and 10mg were converted to rat doses of 0.61mg / kg / day and 1.23mg / kg / day, respectively. The human dose of Tigoxostat (T) of 300mg was converted to a rat dose of 36.8mg / kg / day. The R+T groups were administered at human dose ratios (mass ratios) of 1:60 for Ruzinurad and 1:30 for Tigoxostat. The dosing groups and dosages are shown in the table below. Table 11 Dosage Groups and Doses

[0193] The statistical analysis method is as described in Example 1, and the results are as follows: Figure 8 As shown in Figure 16 and Table 12: Table 12 Experimental Results

[0194] Conclusion Analysis: The data in the table show that after 3 weeks of continuous medication, serum uric acid (UA), serum creatinine (CRE), and blood urea nitrogen (BUN) in each combination group were effectively relieved and controlled.

[0195] Compared to the single-drug R and T groups, the combined R+T group effectively controlled serum uric acid, creatinine, and urea nitrogen at a 1:60 dosage ratio, with statistically significant differences. As the dosages of both R and T increased simultaneously, the control effect increased proportionally. This demonstrates a very significant synergistic effect of the formulation in terms of human dosage ratio.

[0196] Example 4 In clinical studies, patients with hyperuricemia with serum uric acid concentrations of 600-650 μmol / L were given a combination of xanthine oxidase inhibitors and URAT1 inhibitors (e.g., a combination of teguxostat and dotenorode) once daily. After two weeks, serum uric acid concentrations decreased to normal or below normal levels, and no adverse reactions were observed in the patients who received the medication.

[0197] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises at least one of the following combinations: Lesinurad and verinurad, lesinurad and Ruzinurad, lesinurad and febuxostat, lesinurad and tompiromide, lesinurad and ABP-671, lesinurad and SAP-001, lesinurad and SHR4640, febuxostat and verinurad, febuxostat and Ruzinurad, febuxostat and tompiromide, febuxostat and ABP-671, febuxostat and SAP-001, or febuxostat and SHR4640.

2. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition comprises at least one of the following combinations: Lesinurad and verinurad, lesinurad and Ruzinurad, lesinurad and febuxostat, lesinurad and tompiromide, lesinurad and ABP-671, lesinurad and SAP-001, lesinurad and SHR4640, febuxostat and verinurad, febuxostat and Ruzinurad, febuxostat and tompiromide, febuxostat and ABP-671, febuxostat and SAP-001, or febuxostat and SHR4640.

3. The pharmaceutical composition according to claim 2, wherein The molar ratio of the xanthine oxidase inhibitor and the URAT1 inhibitor is (1-20):(1-20); or the mass ratio of the xanthine oxidase inhibitor and the URAT1 inhibitor is (1-200):(1-20).

4. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition comprises a first preparation of the xanthine oxidase inhibitor and a pharmaceutically acceptable carrier, and a second preparation of the URAT1 inhibitor and a pharmaceutically acceptable carrier; or a complex preparation of the xanthine oxidase inhibitor, the URAT1 inhibitor and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 1, wherein The pharmaceutical composition comprises the xanthine oxidase inhibitor or the pharmaceutically acceptable salt thereof at a dose of 0.5 mg / day-400 mg / day, and the URAT1 inhibitor or the pharmaceutically acceptable salt thereof at a dose of 0.5 mg / day-400 mg / day.

6. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition can reduce the blood uric acid concentration of the patient receiving the pharmaceutical composition to less than 4-6 mg / dL.

7. The pharmaceutical composition of claim 1, wherein, The pharmaceutically acceptable carrier is at least one selected from the group consisting of a filler, a binder, a disintegrant, a lubricant, a diluent, a solubilizer, a suspending agent, a wetting agent, a pigment, an essence, a solvent, a surfactant, a flavoring agent, a buffer, an isotonicity adjusting agent, an antioxidant, a bacteriostatic agent and an analgesic agent.

8. Use of the pharmaceutical composition of any one of claims 1-7 in the preparation of a medicament for preventing, treating or alleviating uric acid metabolism disorder.

9. Use according to claim 8, the pharmaceutical composition being administered alone as monotherapy or in addition to one or more other substances.

10. Use according to claim 8, characterized in that, The disorder of uric acid metabolism comprises hyperuricemia, gout, recurrent gout flares, gouty arthritis, high blood pressure, cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, kidney injury, kidney fibrosis, diabetic nephropathy, arthritis, urinary tract stones, polycythemia vera, myeloid metaplasia, Kelley-Seegmiller syndrome, lead poisoning, hyperparathyroidism, psoriasis, or sarcoidosis.

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