LXH-2301 pharmaceutical composition and application thereof in preparation of medicine for treating gout with hyperuricemia

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an LXH-2301 pharmaceutical composition and application of the LXH-2301 pharmaceutical composition in preparation of a medicine for treating gout with hyperuricemia. The LXH-2301 pharmaceutical composition disclosed by the invention comprises the following components: (a) LXH-2301 tablets with the specification of 0.5 g / tablet; (b) febuxostat tablets with the specification of 20 mg / tablet; wherein the LXH-2301 tablet is administered three times a day, two tablets are administered each time, the total dosage is 1.0 g, and the LXH-2301 tablet is combined with the febuxostat tablet for use. Patients suitable for the composition need to simultaneously meet the following screening standards: morning urine pHlt; and 6.0. The LXH-2301 pharmaceutical composition provided by the invention is applied to the preparation of medicines for treating gout with hyperuricemia, and the limitation of insufficient curative effect on patients with uric acid poor excretion type gout is solved; the problem of lack of prevention means for uric acid crystallization kidney injury is solved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a LXH-2301 pharmaceutical composition and use thereof in the preparation of a drug for treating gout with hyperuricemia. BACKGROUND

[0002] Gout and hyperuricemia are two closely related metabolic diseases, and there is a significant causal relationship in pathogenesis, pathological process and clinical outcome. Hyperuricemia refers to a pathological state of sustained abnormal elevation of blood uric acid level (male > 420 μmol / L, female > 360 μmol / L), which is a necessary biochemical basis for the occurrence of gout. Epidemiological data shows that there are 177 million hyperuricemia patients and more than 80 million gout patients in China, and there is a clear trend of youth, with 30-45 year-old young men as the main affected group, and the male incidence is 15 times that of women. The essence of this metabolic disease is the imbalance between uric acid production and excretion: on the one hand, excessive uric acid production is caused by excessive intake of purines or increased endogenous synthesis; on the other hand, the excretion efficiency is decreased due to kidney excretion dysfunction (such as reduced glomerular filtration and increased renal tubular reabsorption).

[0003] When the blood uric acid concentration exceeds the saturation point (> 6.8 mg / dL), monosodium urate (MSU) crystals will precipitate from the body fluid and deposit in the joints, soft tissues and kidneys, causing a series of crystal-related pathological reactions. Gout, as the most common clinical consequence of hyperuricemia, is essentially an aseptic inflammatory reaction triggered by MSU crystals: after the crystals are phagocytosed by macrophages, NOD-like receptor pyrin domain-associated protein (NLRP3 inflammasome) is activated, prompting the release of a large amount of pro-inflammatory factors such as interleukin-1β (IL-1β), recruiting neutrophil infiltration into the joint, leading to the typical symptoms of arthritis such as redness, swelling, heat and pain. It is worth noting that the harm of gout is far beyond the joint symptoms itself. Cohort studies have confirmed that within 60 days after acute attack, the risk of myocardial infarction and stroke in patients increases by 89%; the risk of venous thromboembolism increases by 131% within 30 days; and the risk of chronic kidney disease in repeated attackers is 10 times higher than that in the general population. This systemic damage is directly related to the persistent low-grade inflammatory state mediated by IL-1β, highlighting the central role of systemic anti-inflammatory therapy in the whole process of gout management.

[0004] The core of the treatment of acute gout is to quickly control inflammation and relieve joint pain. At present, the clinical treatment mainly relies on three categories of drugs, each of which has specific use scenarios and limitations: non-steroidal anti-inflammatory drugs (NSAIDs) as first-line drugs, which reduce prostaglandin synthesis by inhibiting cyclooxygenase (COX) to reduce redness, heat and pain. However, about 50% of patients have insufficient pain control, and there are contraindications such as gastrointestinal ulcers, kidney damage and cardiovascular risks. Colchicine exerts anti-inflammatory effects by inhibiting microtubule polymerization and neutrophil migration, and is suitable for use in the early stage of onset. However, its therapeutic window is narrow, and it is prone to cause adverse reactions such as diarrhea and bone marrow suppression, especially in patients with renal dysfunction, who should use it with caution. Glucocorticoids are used for patients who are intolerant to NSAIDs and colchicine, and can relieve symptoms through broad-spectrum anti-inflammatory effects. However, long-term or repeated use can lead to increased blood glucose, osteoporosis and increased risk of infection.

[0005] The core of the treatment of gout remission is to long-term control of blood uric acid level (target value <360 μmol / L, <300 μmol / L for patients with tophi), promote crystal dissolution, and prevent acute recurrence. At present, uric acid-lowering therapy (ULT) drugs are divided into two categories according to their mechanisms of action: uric acid synthesis inhibitors (allopurinol, febuxostat), and uric acid excretion promoters (benzbromarone, lesinurad). SUMMARY

[0006] The technical problem to be solved by the present application is to overcome the above-mentioned defects existing in the prior art, provide a LXH-2301 pharmaceutical composition, and apply it in the preparation of a drug for treating gout with hyperuricemia, solve the problem of gastrointestinal discomfort such as bloating and belching caused by traditional sodium bicarbonate gastric soluble tablets; solve the limitation of insufficient efficacy of single uric acid-lowering drug for uric acid excretion poor gout patients; solve the problem of ineffective or excessive treatment risk caused by lack of precise patient screening standards; and solve the problem of lack of prevention means for uric acid crystal-induced kidney damage.

[0007] The LXH-2301 pharmaceutical composition provided by the present application comprises:

[0008] (a) LXH-2301 tablets, with a specification of 0.5 g / tablet;

[0009] (b) febuxostat tablets, with a specification of 20 mg / tablet;

[0010] The LXH-2301 tablets are administered 3 times a day, 2 tablets each time, with a total dose of 1.0 g each time, in combination with febuxostat tablets.

[0011] The LXH-2301 tablets are released in the intestinal tract to avoid stomach irritation.

[0012] The patients suitable for the composition should meet the following screening criteria simultaneously: morning urine pH < 6.0; 24-hour uric acid excretion rate ≤ 600 mg·d-1; uric acid excretion fraction < 5.5%; fasting blood uric acid ≥ 420 μmol / L.

[0013] The use of the LXH-2301 pharmaceutical composition in the preparation of a drug for treating gout with hyperuricemia: the drug is used in combination, and the course of treatment is 14 days, febuxostat tablets are administered once a day, and LXH-2301 tablets are administered three times a day. LXH-2301 is a sodium bicarbonate enteric-coated tablet, which disintegrates in the intestine to release the drug, and can reduce the irritation to the stomach; sodium bicarbonate tablets are stomach tablets, which disintegrate in the stomach to release, the two dosage forms are different, the main components are the same, and the excipients are different, and LXH-2301 has an enteric-coated layer.

[0014] The target is to make the morning urine pH value of the patient reach 6.2-6.9, and reduce the 24-hour uric acid excretion amount.

[0015] The evaluation indexes of the combination include: the morning urine pH reaches 6.2-6.9 in the first week and the second week; the change amount of the 24-hour uric acid excretion amount and the uric acid excretion fraction compared with the baseline; the serum bicarbonate and serum uric acid level changes.

[0016] The combination is used to monitor the markers of kidney injury, including: urine albumin / creatinine ratio, alpha 1-microglobulin; urine cystatin C, urine trace albumin; urine transferrin, urine immunoglobulin G.

[0017] The improvement of the markers of kidney injury is positively correlated with the increase of the morning urine pH value to 6.2-6.9.

[0018] For the patients with poor uric acid excretion (defined as 24h uric acid excretion UUE ≤ 600 mg / 1.73 m 2 2, and uric acid excretion fraction FEUA < 5.5%), alkalinization of urine is a key adjuvant treatment. The solubility of uric acid in urine is highly dependent on pH value: when the pH value increases from 5.0 to 7.0, the solubility of uric acid increases from 60 mg / L to more than 200 mg / L. The ideal urine pH range is 6.2-6.9, which can maximize the solubility of uric acid and avoid the formation of calcium phosphate stones. Alkalinization of urine can reduce the risk of uric acid stone formation by 80%, and at the same time, improve the efficacy of the drug for promoting excretion. The traditional alkalinization agent is mainly sodium bicarbonate (baking soda), and its mechanism of action is to neutralize stomach acid after oral administration, and the generated HCO3- is directly excreted by the kidney to directly increase the pH value of urine. In clinical application, the first dose is usually 4 g, and then 1-2 g every 4 hours is maintained, and the target urine pH is > 6.24. However, long-term and large-dose use has multiple risks: metabolic alkalosis and secondary hypokalemia, water and sodium retention, aggravation of hypertension and heart failure, combined use with calcium agents to induce milk-alkali syndrome (hypercalcemia and kidney injury), and CO2 generated in the stomach to cause abdominal distension, belching and other digestive tract discomfort.

[0019] The uric acid of gout patients is generally higher, and the pH value of urine is lower than that of normal people, when the pH value is 5.0, 80-120 mg of uric acid can be dissolved in each liter of urine; when the pH value is 6.0, about 220 mg of uric acid can be dissolved; when the pH value is 6.2-6.8, the solubility is the highest, up to 100%, which can prevent the deposition of urate in the body to form stones.

[0020] Sodium bicarbonate is a systemic alkalinizing agent, which can increase the concentration of bicarbonate ions in blood plasma, buffer the concentration of excess hydrogen ions, and increase the pH value of blood, and is clinically used for reversing acidosis. It is also a urinary alkalinizer, which increases the excretion of free bicarbonate ions in urine, thereby effectively increasing the pH value of urine. By maintaining alkaline urine, the purpose of dissolving uric acid stones is achieved. In addition, as an antacid, sodium bicarbonate can neutralize or buffer the existing amount of gastric acid through chemical reaction, but has no direct effect on the amount of gastric acid secretion.

[0021] The main active ingredient of LXH-2301 is sodium bicarbonate, which is a salt, and its pharmacological properties are derived from its basic physiological role as an HCO 3- / CO2 buffer system component, which can increase the pH level of the human body. The active ingredients of sodium and bicarbonate ions are physiological components of animal and human blood plasma, and play a very important role in acid-base homeostasis. The pharmacodynamic effect of bicarbonate ions in drugs is basically the same as the normal physiological effect. LXH-2301 is also a urinary alkalinizer, which increases the excretion of free bicarbonate ions in urine, thereby effectively increasing the pH value of urine, in order to avoid and reduce damage to the kidneys, when the pH value of urine is less than 6.0, the alkaline drug is taken at the same time as the gout treatment drug, so that the pH value of urine is maintained between 6.2-6.8, which is beneficial to the excretion of uric acid and the prevention of stone formation, and protects the kidneys. According to the metabolic conditions, after the reaction of bicarbonate ions with hydrogen ions, carbon dioxide and water are formed in the blood plasma under the control of carbonic anhydrase. The carbon dioxide formed in the reaction process is eliminated through the lungs. Since there are some clinical problems such as gastric distension with sodium bicarbonate tablets (gastric soluble type), this product can be well improved, so this product has obvious advantages in clinical demand compared with sodium bicarbonate tablets (gastric soluble type).

[0022] Compared with the prior art, the present application has the beneficial effects that:

[0023] (1) The LXH-2301 pharmaceutical composition of the present application significantly reduces the adverse reactions of the digestive tract. The enteric coating design releases sodium bicarbonate away from the gastric acid environment, avoiding the generation of CO2 to cause gastric distension, belching, and gastric discomfort in clinical trials. Precise improvement of urine pH, the compliance rate (6.2-6.9) of morning urine pH of subjects in the LXH-2301 group at the end of the study / early withdrawal visit (V5) was 26.7%, which was significantly better than the compliance rate of 18.8% of subjects in the positive control group at the end of the study / early withdrawal visit (V5).

[0024] (2) The combination of the composition of the present application breaks through the treatment bottleneck of poor uric acid excretion. The combination of non-busitai tablets inhibits uric acid synthesis, and simultaneously alkalinizes urine to promote excretion. For patients with UUE≤600mg / d and FEUA<5.5%, the percentage decrease in serum uric acid from baseline in the LXH-2301 group at the end of the study / early withdrawal visit (V5) was 25.87%. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The figure is a schematic diagram of the combined administration of the LXH-2301 pharmaceutical composition of the present application. DETAILED DESCRIPTION

[0026] The present application will be further described below in conjunction with specific examples.

[0027] I. The sources of the drugs used below are shown in Table 1.

[0028] Table 1 Sources of drugs

[0029]

[0030]

[0031] II. Patient criteria

[0032] 1. Gout patients aged 18-75 years (including 18 years and 75 years) (diagnosed as gout according to the 2015 ACR / EULAR gout classification standard), of any gender, and meeting the following conditions;

[0033] (1) Gout patients who did not alkalinize urine within 1 month before screening, and did not receive uric acid-lowering drug treatment before screening; or gout patients who were receiving uric acid-lowering treatment at the time of screening, and were assessed by the investigator to be transferred to non-busitai tablets 20mg for continued treatment;

[0034] (2) In the normal purine diet state, the fasting blood uric acid (SUA) of the non-same-day, 2 times at the screening period was ≥420μmol / L (7mg / dL) (determined according to the detection results of the research center);

[0035] (3) Screening period belongs to uric acid excretion type: UUE≤600mg·d -1 • (1.73m 2 ) -1 and FEUA <5.5%;

[0036] (2) Screening period morning urine pH <6.0.

[0037] (3) 2, male body weight≥50.0kg, female body weight≥45.0kg; and body mass index (BMI): 18.0~32.0kg / m 2 (including 18.0 and 32.0);

[0038] 3, physical examination, vital signs, laboratory tests (excluding urine uric acid and urine pH), 12-lead electrocardiogram (ECG) normal or abnormal without clinical significance (determined by the investigator).

[0039] III. Experimental design

[0040] Multi-center, randomized, double-blind double-dummy, parallel, positive drug / placebo control, planned to enroll 48 patients with uric acid excretion type gout with hyperuricemia, divided into 3 test sequence groups, 16 cases in each group.

[0041] IV. Administration method

[0042] Combination therapy: During the entire test period D2~D14 (day 2 to day 14), Qd (once a day) administration, balanced diet period alone, the first administration of each day during the administration test period was given non-bushe tablet (20mg) as combination therapy, continuous administration for 16 days.

[0043] Test drug group (LXH-2301 group): 2 tablets of LXH-2301 (1.0g in total) and 2 tablets of positive control drug simulation agent each time.

[0044] Positive drug group (sodium bicarbonate tablet group): 2 tablets of sodium bicarbonate tablet (stomach soluble ordinary tablet, 1.0g in total) and 2 tablets of LXH-2301 simulation agent each time;

[0045] Placebo group: 2 tablets of LXH-2301 simulation agent and 2 tablets of positive control drug simulation agent each time;

[0046] Note: During the entire administration test period (D1~D14), test drugs, positive drugs and placebo are all administered Tid (each administration interval is 6~8h), continuous administration for 14 days, time points are given around 1-2h before meals (meal time is fixed throughout the test), each administration is taken with 240mL warm water. Morning urine is collected before the first administration on D8 and in the morning on D15, subjects are required to fast for at least 8 hours before collecting morning urine.

[0047] V. Evaluation index

[0048] 1. Primary efficacy evaluation index:

[0049] The compliance rate of subjects whose morning urine pH reached 6.2-6.9 after the first week and the second week of administration.

[0050] 2. Secondary efficacy evaluation index:

[0051] The change in 24hUUE and FEUA from baseline after the first week and the second week of administration;

[0052] The change in 24h urine uric acid from baseline after the first week and the second week of administration;

[0053] The change in serum bicarbonate and serum uric acid from baseline in each test group was evaluated to analyze the differences between the test drug, the positive control drug, and the placebo.

[0054] 3. Exploratory index:

[0055] The change in renal function evaluation index from baseline was used to exploratory evaluate the protective effect of LXH-2301 and the combination of the positive drug and non-busilast tablets on kidney damage;

[0056] The correlation between the change in morning urine pH and 24hUUE was evaluated.

[0057] 4. Safety evaluation index:

[0058] It includes adverse events, vital signs, laboratory tests, serum pregnancy, and electrocardiogram tests. Adverse events (focus on the incidence of adverse events such as stomach distension, abdominal pain, vomiting, kidney stones, etc. in each sequence group); vital signs (sitting blood pressure, pulse, and body temperature) and physical examination; laboratory tests include: blood routine, urine routine, blood biochemistry, coagulation function, serum virology screening, glomerular filtration rate (GFR), renal function test, drug abuse screening; serum pregnancy test (only for women of childbearing age); 12-lead electrocardiogram test (collected in the resting state of the subjects, if it conflicts with PD blood collection, PD blood collection should be given priority, and the test should be completed within 30 minutes after blood collection is completed).

[0059] Six, multidimensional data set construction and analysis method:

[0060] The multidimensional data set of the subjects was constructed, including the full analysis set FAS, the safety analysis set SS, and the PD analysis set PDS.

[0061] Effectiveness analysis: the compliance rate of subjects whose morning urine pH reached 6.2-6.9 after 1st week and 2nd week of administration, the changes of 24h UUE and FEUA compared with baseline after 1st week and 2nd week of administration; the changes of 24h urine uric acid compared with baseline after 1st week and 2nd week of administration; the changes of serum bicarbonate and serum uric acid after 1st week and 2nd week of administration. Descriptive statistics were performed for each effectiveness parameter, and the statistics included the number of analysis (N), arithmetic mean (Mean), standard deviation (SD), median (Median), minimum value (Min), maximum value (Max), coefficient of variation (CV%), lower quartile (Q1), upper quartile (Q3). The differences before and after administration of the above effectiveness indicators were detected / measured, and the results were respectively summarized and listed by descriptive statistics according to different sequence groups. According to the sequence groups, the average graph and individual superposition graph of the subject effectiveness index relative to the baseline change value-time curve were drawn. For the effectiveness indicators of the categorical type, the Logistic regression model was used for analysis when the data allowed, and the treatment was used as a fixed effect, and the baseline value was used as a covariate. The last observation carried forward (LOCF) method was used for the missing effectiveness data, and for the subjects who received other uric acid-lowering or gout treatment, the last value after the baseline and before receiving other uric acid-lowering or gout treatment was used for effectiveness analysis.

[0062] Safety analysis: safety observations will be conducted throughout the study. Safety indicators include adverse events (focus on the incidence of adverse events such as stomach distension, abdominal pain, vomiting, kidney stones, etc. in each sequence group), laboratory tests (including kidney function test indicators), vital signs, physical examination, 12-lead electrocardiogram, pregnancy test, etc. Descriptive statistics were performed on the adverse events, laboratory tests, vital signs, physical examination, 12-lead electrocardiogram, pregnancy test, etc. of each treatment group and their changes relative to the baseline. Statistical analysis of safety indicators was performed in the form of cross table. All adverse events were coded using the Chinese version of the Medical Dictionary for Regulatory Activities (MedDRA) according to the System Organ Class (SOC) and Preferred Term (PT). AE will be classified according to the coded SOC and PT, and all adverse events will be summarized according to each treatment group.

[0063] Example 1

[0064] I. Specific administration method:

[0065] There are three sequence groups, each group has 16 cases, a total of 48 cases. Each group is administered with the following combination drug (background treatment drug) non-busilast tablets 1 piece (20mg) at the same time.

[0066] (1) Test drug group:

[0067] LXH-2301 (1.0 g) + positive control drug placebo (1.0 g), three times a day, with an interval of 6-8 h between each administration; all study drugs were administered continuously for 14 days.

[0068] (2) Positive control group:

[0069] Positive control drug (1.0 g) + LXH-2301 placebo (1.0 g), three times a day, with an interval of 6-8 h between each administration; all study drugs were administered continuously for 14 days.

[0070] (3) Placebo group:

[0071] LXH-2301 placebo (1.0 g) + positive control drug placebo (1.0 g), three times a day, with an interval of 6-8 h between each administration; all study drugs were administered continuously for 14 days.

[0072] II. Data collection process

[0073] A multicenter, randomized, double-blind double-dummy, parallel, positive drug / placebo controlled study was planned to enroll 48 subjects. The cycle was divided into six phases, including: screening period V1 (day -16 to -3), diet balance period V2 (day -2 to -1), baseline period V3 (day -1), drug administration trial period V4 (day 1 to 14), study end / early withdrawal visit V5 (day 15 to 16), and safety follow-up period (day 16 to 22).

[0074] (1) Screening period V1 (day -16 to -3): The subjects voluntarily signed the informed consent form, assigned a screening number, and were screened according to the trial inclusion and exclusion criteria. Information such as gender, age, nationality, height, weight, medical history and allergy history, physical examination, vital sign examination, drug or alcohol abuse history, and previous participation in clinical trials was collected. A 12-lead electrocardiogram was performed, and laboratory tests (blood biochemistry, blood routine, coagulation function, urine routine, and renal function) and serum pregnancy test (only for women of childbearing age) were conducted. After completing visit V1, subjects who were eligible to continue the study avoided taking prohibited drugs during the entire study period. Concomitant medications were recorded.

[0075] (2) Diet balance period V2 (day -2 to -1): The subjects who passed the screening period were admitted to the research center and stayed in the hospital until the end of the study or early withdrawal. All subjects were not allowed to eat or drink any food, drink, health products, and drugs other than the light and low purine three meals, fruits, and specified water provided by the research center at the specified time. Non-bursar tablet administration was started, and drug abuse screening, serum pregnancy test (only for women of childbearing age), 24-hour urine collection, random number assignment, and concomitant medication recording were performed.

[0076] (3) Baseline period V3 (day-1): Continue febuxostat administration and collect baseline data. Baseline measurements of PK / PD indicators were performed on the same day: urine pH, morning urine pH, 24-hour urine uric acid, 24-hour urine uric acid concentration and 24-hour urine output. Serum bicarbonate, serum creatinine and serum uric acid were collected for kidney injury-related indicators. At the same time, weight, physical examination, vital signs, laboratory tests (blood biochemistry, complete blood count, coagulation function, urinalysis, renal function test), 12-lead electrocardiogram were performed and concomitant medications were recorded.

[0077] (4) Treatment Phase V4 (Days 1-14): Continue febuxostat and investigational drug administration. During treatment, subjects must complete vital sign monitoring, a 12-lead electrocardiogram, collect and record adverse events (AEs), and collect and record information on concomitant medications. Follow-up on days 7-8 after the first dose (D7-D8): Measure height and weight, collect morning urine, collect 24-hour urine samples, collect a whole blood sample within 1 hour before the first dose on D8, collect and record AEs, and collect information on concomitant medications. Follow-up on day 14 after the first dose (D14): Vital sign monitoring, a 12-lead electrocardiogram, collect and record AEs, and collect and record information on concomitant medications.

[0078] (5) Study End / Early Exit Visit V5 (D15): Subjects complete PK / PD sample (morning urine sample, 24-hour urine sample, whole blood collection) collection and all safety checks (including: vital signs and physical examination, complete blood count, complete urine count, renal function and other laboratory tests, serum pregnancy test, 12-lead electrocardiogram, collection and recording of adverse events, collection and recording of concomitant medication information).

[0079] (6) Safety Follow-up V6 (D16–D22): If the subject still has adverse events (AEs) at the end of the study or upon early withdrawal from follow-up, follow-up will continue for 7 days (including day 7) after the subject completes the trial and leaves the study, until the adverse events (AEs) disappear, improve, stabilize, return to baseline levels, or the subject is lost to follow-up. Collect data on AEs related to the study drug (definitely related, very likely related, possibly related) and their corresponding concomitant / combination treatments. Figure 1 As shown.

[0080] III. Statistical Analysis Methods

[0081] 1. Validity Analysis

[0082] The effectiveness analysis will be based on FAS and PPS.

[0083] (1) Key endpoint indicators

[0084] The percentage of subjects achieving a morning urine pH of 6.2-6.9 after week 1 and week 2 of drug administration is listed below, along with the number of subjects achieving the target, the percentage, and their 95% CI (Clopper-Pearson method). The percentage of subjects achieving a morning urine pH of 6.2-6.9 is calculated as follows: (Total number of subjects in this sequence group with a morning urine pH of 6.2-6.9 / Total number of subjects in this sequence group) × 100%.

[0085] (2) Secondary endpoint indicators

[0086] Changes in 24h UUE and FEUA from baseline after week 1 and week 2 of drug administration; changes in uric acid in morning urine and 24h urine from baseline after week 1 and week 2 of drug administration; evaluation of changes in serum bicarbonate and serum uric acid from baseline in each experimental group, used to analyze the differences between the test drug and the positive control drug and placebo.

[0087] FEUA=(uUA / uCr)×(sCr / sUA)×100%;

[0088] UUE = {uUA × 24h urine volume / [0.0061 × height (cm) + 0.0128 × weight (kg) – 0.1529]} × 1.73 (Unit: mg / d / 1.73m) 2 (uUA is calculated using 24-hour urine uric acid) (Note: uUA: urine uric acid; uCr: urine creatinine; sCr: serum creatinine; sUA: serum uric acid)

[0089] Serum HCO3 was measured using a methodologically validated blood biochemistry analyzer. - The concentration of the drug was determined, and a drug-time curve was plotted after administration. The Cmax parameter of the test drug was then calculated.

[0090] (3) Exploratory indicators: The protective effects of LXH-2301 and the combination of positive control drug and febuxostat on renal injury were explored by comparing the changes of renal injury assessment indicators with baseline; the correlation between changes in morning urine pH and 24h UUE was also evaluated. The renal function assessment indicators are shown in Table 2.

[0091] Table 2. Indicators for evaluating renal function

[0092] Urine albumin / creatinine ratio (UACR) Alpha 1 -microglobulin (A1 M) Serum cysteine protease inhibitor in urine (Cys C) Microalbumin in urine (mALB) Transferrin in urine (TRFU) Immunoglobulin G in urine (IgGU) Retinol binding protein (RBPU) Beta 2-microglobulin (BMG)

[0093] 2. Security Analysis

[0094] Security analysis will be based on SS.

[0095] (1) Adverse events

[0096] The number of cases, the number of times and the percentage of adverse events that occurred in subjects were summarized by group, and the number of subjects, the number of times and the percentage of adverse events were summarized by causality and severity (1-5) of the trial drug. The deaths, SAEs and AEs leading to drug discontinuation were summarized and listed.

[0097] The combined drug coding was performed according to the World Health Organization Drug Dictionary (WHODD, version 20230301 or later) issued by the WHO. The AEs, concomitant diseases / medical history coding was performed according to the Medical Dictionary for Regulatory Activities (MedDRA version 27.0 or later) issued by ICH, and the adverse events were summarized by system organ class (SOC) and preferred term (PT). Each SOC and each PT, each subject will be calculated at most once.

[0098] (2) Clinical laboratory tests: laboratory tests (blood routine, urine routine, blood biochemistry, blood coagulation function, blood pregnancy (only for women of childbearing age), glomerular filtration rate (GFR), changes in renal function tests relative to baseline) were described by visit, group (treatment variable). The change table of laboratory tests was listed, and the abnormal results of all laboratory tests of the subjects were listed.

[0099] (3) Other clinical safety indicators: vital signs, physical examination and 12-lead ECG indicators were described by visit, group. For continuous variables among them, the mean, median, standard deviation, minimum and maximum were also described, and the change amount relative to baseline was described, and the change table of vital signs, physical examination and 12-lead ECG indicators was listed, and the abnormal results of vital signs, physical examination and 12-lead ECG of subjects were listed.

[0100] According to the group and the subjects, all the combined treatments during the trial were listed as shown in Tables 3-5.

[0101] I. Results of primary evaluation indicators

[0102] Table 3: The compliance rate of subjects whose morning urine pH reached 6.2-6.9 after 1 week and 2 weeks of administration (FAS)

[0103]

[0104] The above results show that after 1 week and 2 weeks of administration, the compliance rate of the test group whose morning urine pH reached 6.2-6.9 was slightly higher than that of the positive control group.

[0105] II. Results of secondary evaluation indicators

[0106] Table 4: Changes in secondary evaluation indicators relative to baseline after 1 week and 2 weeks of administration (FAS)

[0107]

[0108]

[0109] After the combination of each group of drugs with febuxostat, the 24h UUE of each group was reduced compared with the baseline after 1 week and 2 weeks of administration; the FEUA of each group was increased compared with the baseline after 1 week and 2 weeks of administration, and the increase in the LXH-2301 group and the positive control group was greater than that in the placebo group; after 1 week of administration, the 24h urine uric acid of each group was reduced compared with the baseline, and the reduction percentage in the LXH-2301 group was less than that in the positive control group and the placebo group; after 1 week and 2 weeks of administration, the serum bicarbonate of each group was increased compared with the baseline, and the increase in the LXH-2301 group and the positive control group was greater than that in the placebo group after 2 weeks of administration; after 1 week and 2 weeks of administration, the serum uric acid of each group was reduced compared with the baseline, and the reduction percentage in the LXH-2301 group was greater than that in the placebo group and the positive control group after 2 weeks of administration.

[0110] III. Exploratory indicators:

[0111] After 1 week and 2 weeks of administration, there was no significant change in the renal function evaluation indicators such as GFR compared with the baseline. After 1 week and 2 weeks of administration, there was no significant correlation between the change in morning urine pH and 24h UUE.

[0112] Table 5 Change in renal function evaluation indicators after administration (FAS)

[0113]

[0114]

[0115] In Table 5 above, α1-microglobulin is a very sensitive and specific indicator for early damage to the proximal tubule, and after 2 weeks of administration, the LXH-2301 group decreased by 18.67%; the positive drug group increased after 1 week of administration and decreased to 15.158(8.4231) after 2 weeks, suggesting that sodium bicarbonate may have improved and benefited the abnormal reabsorption function of the proximal tubule. Urinary microalbumin can reflect glomerular damage, and after 2 weeks of administration, the mean value of the LXH-2301 group decreased by -3.043(8.9867) compared with the baseline, and the positive control drug group and the placebo group were basically flat compared with the baseline, suggesting that LXH-2301 may have a protective effect on the glomerulus. However, due to the short administration time, the improvement in renal function indicators did not reach a significant difference.

[0116] Safety results:

[0117] The safety analysis set included 25 AEs in 49 cases in 47 subjects who participated in the study during the treatment period, with an overall incidence of 53.2% (25 / 47). The incidence of TEAEs in the LXH-230 group (N=15), positive control group (N=16) and placebo group (N=16) was 40.0% (6 / 15), 43.8% (7 / 16) and 75.0% (12 / 16), respectively. All were grade 1-2 TEAEs, of which 12 cases (26 cases) were grade 1 TEAEs and 13 cases (23 cases) were grade 2 TEAEs. No subject died during the study; no serious adverse events (SAEs) occurred; no adverse events leading to drug discontinuation or withdrawal occurred.

[0118] According to SOC, 10 cases (21.3%) of 23 cases had various examinations, 8 cases (17.0%) of 9 cases had metabolic and nutritional diseases, 8 cases (17.0%) of 9 cases had heart organ diseases, 2 cases (4.3%) of 2 cases had infectious and invasive diseases, various muscle, bone and connective tissue diseases, blood and lymphatic system diseases, 1 case (2.1%) of 1 case had liver and gallbladder system diseases, and 1 case (2.1%) of 1 case had mental diseases.

[0119] According to PT terminology, 7 cases (14.9%) of 8 cases had gout, 7 cases (14.9%) of 7 cases had sinus bradycardia, 6 cases (12.8%) of 7 cases had alanine aminotransferase elevation, 5 cases (10.6%) of 6 cases had aspartate aminotransferase elevation, 5 cases (10.6%) of 5 cases had gamma-glutamyl transferase elevation, 2 cases (4.3%) of 2 cases had urinary tract infection, 1 case (2.1%) of 1 case had C-reactive protein elevation, 1 case (2.1%) of 1 case had glomerular filtration rate reduction, 1 case (2.1%) of 1 case had blood bilirubin elevation, 1 case (2.1%) of 1 case had blood potassium elevation, 1 case (2.1%) of 1 case had blood glucose, blood lipid abnormality elevation, 1 case (2.1%) of 1 case had supraventricular extrasystoles, 1 case (2.1%) of 1 case had supraventricular arrhythmia, 1 case (2.1%) of 1 case had sacroiliac arthritis, 1 case (2.1%) of 1 case had joint pain, 1 case (2.1%) of 1 case had high fibrinogenemia, 1 case (2.1%) of 1 case had anemia, 1 case (2.1%) of 1 case had liver dysfunction, and 1 case (2.1%) of 1 case had sleep disorder.

Claims

1. A pharmaceutical composition of LXH-2301, characterized by: Comprise: (a) LXH-2301 tablets, with a specification of 0.5g / tablet; (b) Febuxostat tablets, with a specification of 20mg / tablet; Wherein the LXH-2301 tablets are administered 3 times a day, each 2 tablets, with a single total dose of 1.0g, in combination with the Febuxostat tablets.

2. The LXH-2301 pharmaceutical composition according to claim 1, characterized in that: The LXH-2301 tablets are released in the intestinal tract, avoiding gastric irritation.

3. The LXH-2301 pharmaceutical composition according to claim 1, characterized in that: The patients suitable for the composition must simultaneously meet the following screening criteria: morning urine pH <6.0; 24-hour uric acid excretion rate ≤600mg·d-1; uric acid excretion fraction <5.5%; fasting blood uric acid ≥420μmol / L.

4. Use of the LXH-2301 pharmaceutical composition of any one of claims 1-3 in the manufacture of a medicament for the treatment of gout with hyperuricemia, characterized in that: The drug is administered in combination, with a course of administration of 14 days, Febuxostat tablets administered once a day, and LXH-2301 tablets administered 3 times a day.

5. The use of LXH-2301 pharmaceutical composition according to claim 4 in the preparation of a drug for treating gout with hyperuricemia, characterized in that: The goal is to achieve a morning urine pH value of 6.2-6.9 in the patient.

6. The use of the LXH-2301 pharmaceutical composition according to claim 5 in the preparation of a drug for treating gout with hyperuricemia, characterized in that: The evaluation indexes of the combination administration include: morning urine pH reaching 6.2-6.9 at the 1st week and the 2nd week; the change amount of 24-hour uric acid excretion and uric acid excretion fraction compared to the baseline; the change of serum bicarbonate and serum uric acid levels.

7. The use of the LXH-2301 pharmaceutical composition according to claim 6 in the preparation of a drug for treating gout with hyperuricemia, characterized in that: The combination administration is monitored for markers of kidney injury, including: urine albumin / creatinine ratio, alpha 1-microglobulin; urine cystatin C, urine trace albumin; urine transferrin, urine immunoglobulin G.

8. The use of LXH-2301 pharmaceutical composition according to claim 7 in the preparation of a drug for treating gout with hyperuricemia, characterized in that: There is an improvement in the markers of kidney injury.

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