A composition for reducing uric acid and a method for preparing the same

Abstract

A uric acid-lowering composition includes a pharmaceutically effective ingredient, a pharmaceutically acceptable filler, a flavoring agent, a disintegrant, cross-linked polyvinylpyrrolidone (PVPP), and a lubricant. The pharmaceutically effective ingredient is composed of febuxostat and sodium bicarbonate in a mass ratio of 20-30:1, wherein the sodium bicarbonate is prepared into sodium bicarbonate spray particles by spray granulation after mixing with PVPP. This invention provides a uric acid-lowering pharmaceutical composition that solves the technical problem of low stability and reduced efficacy when sodium bicarbonate and febuxostat are mixed. It is used for the treatment of hyperuricemia, has a rapid onset of action, and can reduce the incidence of adverse digestive system reactions such as acid reflux and gastritis during use. The product disintegrates rapidly, completely within 10 seconds, exhibits good stability, and shows almost no change in product content and related substances during its shelf life, ensuring full efficacy. It is worthy of market promotion and application.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a uric acid-lowering composition and its preparation method. Background Technology

[0002] Hyperuricemia (HUA) is defined as an elevated fasting serum uric acid level (HU) of more than 420 mmol / L for men and more than 360 mmol / L for women on two separate occasions, under normal purine dietary conditions. From 2016 to 2020, the number of people with HU worldwide increased from 740 million to 930 million, and continues to rise. It is projected that the number of people with HU worldwide will exceed 1.4 billion by 2030.

[0003] Gout is a crystal-related arthropathy caused by the deposition of monosodium urate (MSU). It is directly related to hyperuricemia caused by purine metabolism disorders and / or decreased uric acid excretion. It mainly includes acute flare-ups of arthritis, tophaceous chronic arthritis, urate nephropathy, and uric acid urinary tract stones. Severe cases can lead to joint disability and renal insufficiency. Gout is also often accompanied by abdominal obesity, hyperlipidemia, hypertension, type 2 diabetes, and cardiovascular disease. During acute gout attacks, patients experience excruciating pain and severe deformities, causing serious physical and psychological harm. Currently, the number of people with hyperuricemia in my country has reached 170 million, of which more than 80 million suffer from gout, and this number is rapidly increasing at an annual growth rate of 9.7%. The incidence of hyperuricemia rose from 10.10% in 1998 to 17.90% in 2008, while the incidence of gout rose from 0.34% in 1998 to 2.0% in 2008. Gout has now become the second leading metabolic disease in my country after diabetes, and is the "fourth high" after hypertension, hyperlipidemia and hyperglycemia.

[0004] Febuxostat is a xanthine oxidase (XO) inhibitor that selectively binds to XO, thereby inhibiting the production of uric acid by blocking the action of XOR (an enzyme that leads to uric acid formation). It effectively reduces the concentration of urate in the blood and does not interact with other enzymes in the metabolism of purines and pyrimidines (such as purine nucleoside phosphorylase), nor does it affect the metabolism of pyrimidines and purines. It is suitable for the long-term treatment of hyperuricemia with gout symptoms and is a new drug for the treatment of gout. However, this type of drug also has side effects on the human body. Long-term use can damage other organs. It should be noted that febuxostat tablets have the following effects on the gastrointestinal tract: (1) damage to the gastric mucosa, which may cause symptoms such as abdominal pain and nausea; (2) affect gastric absorption and lead to gastric dysfunction; (3) affect intestinal peristalsis and cause intestinal flora imbalance. Common adverse reactions include gastrointestinal discomfort, gastritis, and hyperacidity. In order to solve this problem, sodium bicarbonate is used in combination with febuxostat. The alkaline sodium bicarbonate can alleviate the gastrointestinal side effects of febuxostat. Summary of the Invention

[0005] The purpose of this invention is to provide a uric acid-lowering composition.

[0006] Another objective of this invention is to provide a method for preparing the above-mentioned uric acid-lowering composition, which effectively solves the problem that mixing sodium bicarbonate and febuxostat can produce impurities, reducing product stability and efficacy.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] A uric acid-lowering composition, characterized in that: the uric acid-lowering composition comprises a pharmacologically acceptable filler, a flavoring agent, a disintegrant, cross-linked polyvinylpyrrolidone (PVPP), and a lubricant, wherein the pharmacologically acceptable component is composed of febuxostat and sodium bicarbonate in a mass ratio of 20 to 30:1, wherein the sodium bicarbonate is prepared into sodium bicarbonate spray particles by spray granulation with PVPP.

[0009] Furthermore, the filler may be one or more of mannitol, lactose, sorbitol, glucose, and starch.

[0010] Furthermore, the flavoring agent may be one or more of sorbitol, sucrose, and simple syrup.

[0011] Furthermore, the disintegrant is at least one of low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.

[0012] Furthermore, the lubricant is one of magnesium stearate, talc, and calcium stearate.

[0013] Furthermore, by weight, the present product comprises 40-60 parts febuxostat, 2 parts sodium bicarbonate, 25-40 parts filler, 11-20 parts flavoring agent, 3-7 parts disintegrant, 1-5 parts crosslinked polyvinylpyrrolidone, and 0.8-1.5 parts lubricant.

[0014] More preferably, by weight, the febuxostat comprises 40-60 parts, sodium bicarbonate comprises 2 parts, the filler comprises 15-25 parts of mannitol and 10-15 parts of lactose, the flavoring agent comprises 11-20 parts of sorbitol, the disintegrant comprises 3-7 parts of sodium carboxymethyl starch, 1-5 parts of cross-linked polyvinylpyrrolidone, and the lubricant comprises 0.8-1.5 parts of magnesium stearate.

[0015] More preferably, by weight, the present invention comprises 45-60 parts febuxostat, 2 parts sodium bicarbonate, 20-23 parts mannitol, 10-15 parts lactose, 13-18 parts sorbitol, 4-6 parts sodium carboxymethyl starch, 2-4 parts crosporovinylpyrrolidone, and 0.9-1.3 parts magnesium stearate.

[0016] The method for preparing the above-mentioned uric acid-lowering composition is characterized by: mixing febuxostat, filler, flavoring agent and disintegrant to prepare wet granules, drying and granulating them into dry granules, mixing sodium bicarbonate and cross-linked polyvinylpyrrolidone to prepare sodium bicarbonate spray granules, and then mixing the sodium bicarbonate spray granules and lubricant with the dry granules and compressing them into tablets.

[0017] Furthermore, by weight, the present product comprises 40-60 parts febuxostat, 2 parts sodium bicarbonate, 25-40 parts filler, 11-20 parts flavoring agent, 3-7 parts disintegrant, 1-5 parts crosslinked polyvinylpyrrolidone, and 0.8-1.5 parts lubricant.

[0018] More preferably, by weight, the febuxostat comprises 40-60 parts, sodium bicarbonate comprises 2 parts, the filler comprises 15-25 parts of mannitol and 10-15 parts of lactose, the flavoring agent comprises 11-20 parts of sorbitol, the disintegrant comprises 3-7 parts of sodium carboxymethyl starch, 1-5 parts of cross-linked polyvinylpyrrolidone, and the lubricant comprises 0.8-1.5 parts of magnesium stearate.

[0019] More preferably, by weight, the present invention comprises 45-60 parts febuxostat, 2 parts sodium bicarbonate, 20-23 parts mannitol, 10-15 parts lactose, 13-18 parts sorbitol, 4-6 parts sodium carboxymethyl starch, 2-4 parts crosporovinylpyrrolidone, and 0.9-1.3 parts magnesium stearate.

[0020] Furthermore, the preparation of sodium bicarbonate spray particles involves dissolving sodium bicarbonate in water to prepare a sodium bicarbonate aqueous solution with a mass fraction of 5-10%, then adding cross-linked polyvinylpyrrolidone at 25-35°C with stirring, continuing to heat and stir to form a slurry, and then spray drying to obtain sodium bicarbonate spray particles.

[0021] Furthermore, the mass ratio of sodium bicarbonate to PVPP is 2:1 to 5.

[0022] Furthermore, the preparation of wet granules involves mixing febuxostat, mannitol, sorbitol, lactose, and sodium carboxymethyl starch according to the formula to obtain a premixed powder. Purified water is added to the premixed powder, and after continuous stirring, the powder is discharged and sieved through an 18-mesh sieve to obtain wet granules. The purified water accounts for 15-20% of the mass of the premixed powder.

[0023] Furthermore, the drying and granulation process involves drying the wet granules at an inlet air temperature of 80–90°C and an inlet air frequency of 40–50 Hz until the moisture content is 1.0–3.0%, and then granulating them through an 18-mesh sieve to obtain dry granules.

[0024] The method for preparing the above-mentioned uric acid-lowering composition is characterized by the following steps:

[0025] (1) Processing of excipients: Febuxostat, mannitol, sorbitol, lactose, sodium carboxymethyl starch, crosinol, and magnesium stearate are passed through a 100-mesh sieve and the sieved powder is collected for later use; 2 parts by weight of sodium bicarbonate are dissolved in water to prepare a sodium bicarbonate aqueous solution with a mass fraction of 5-10%; then, under stirring at 25-35℃, 2-4 parts of crosinol are slowly added. After the addition is complete, the mixture is kept warm and stirred for 15-20 minutes to form a slurry, which is then spray-dried to obtain sodium bicarbonate spray particles for later use.

[0026] (2) Premix granulation: According to the weight, 40-60 parts of febuxostat, 20-23 parts of mannitol, 13-18 parts of sorbitol, 10-15 parts of lactose, and 4-6 parts of sodium carboxymethyl starch are mixed to obtain a premix powder. Purified water is added to the premix powder, and after continuous stirring, the material is discharged and wet granules are obtained by screening through an 18-mesh sieve. The purified water accounts for 15-20% of the mass of the premix powder.

[0027] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 80-90℃ and an air inlet frequency of 40-50Hz until the moisture content is 1.0-3.0%, and then granulated through an 18-mesh sieve to obtain dry granules;

[0028] (4) Total mixing and tableting: The dry granules obtained in step (3) are mixed with 0.9 to 1.3 parts of magnesium stearate and sodium bicarbonate spray granules prepared in step (1) for 12 minutes, and then added to the tableting material and tableted. The hardness is 3 to 5 kg.

[0029] Febuxostat is an existing drug for lowering uric acid, but it has many side effects. Because febuxostat contains carboxylic acids, long-term use can damage the gastrointestinal tract, manifesting as bloating, abdominal pain, constipation, dry mouth, and indigestion. Sodium bicarbonate, being alkaline, can be used in combination with febuxostat to neutralize stomach acid and alleviate symptoms such as stomach pain, bloating, and acid reflux caused by increased stomach acid after taking febuxostat.

[0030] However, when febuxostat was mixed with sodium bicarbonate, it was found that a large number of impurities were generated after mixing. As a result, the product stability decreased, and the efficacy of febuxostat also decreased significantly.

[0031] To address this issue, sodium bicarbonate was dissolved in water, and then cross-linked polyvinylpyrrolidone (PVPP) was added. After the addition was complete, the mixture was kept warm and stirred for 15–20 minutes to form a slurry. This slurry was then spray-dried to obtain sodium bicarbonate spray granules. PVPP encapsulation of sodium bicarbonate during spray granulation reduced direct contact between sodium bicarbonate and febuxostat. Furthermore, by first preparing febuxostat and other excipients into granules, and then adding the sodium bicarbonate spray granules and compressing them into tablets, the mixing of sodium bicarbonate and febuxostat was further inhibited. This suppressed the generation of impurities, improved the stability of the finished product, and ensured that both febuxostat and sodium bicarbonate could fully exert their therapeutic effects during administration.

[0032] The present invention has the following technical effects:

[0033] This invention discloses a uric acid-lowering pharmaceutical composition that solves the technical problem of impurities arising from the mixing of sodium bicarbonate and febuxostat, which reduces product stability and efficacy. Sodium bicarbonate exhibits a significant synergistic effect with febuxostat, providing rapid onset of action for the treatment of hyperuricemia. During use, it can also reduce the incidence of adverse digestive system reactions such as acid reflux and gastritis. The product is formulated as an orally disintegrating tablet, preventing sticking and disintegration during compression. It disintegrates rapidly, completely within 10 seconds, exhibits good stability, and shows almost no change in product content or related substances over its shelf life, ensuring full efficacy. This composition is worthy of market promotion and application. Detailed Implementation

[0034] The present invention will be specifically described below through embodiments. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above description.

[0035] Febuxostat, the drug used in the following examples and comparative examples, was purchased from Teijin Pharmaceutical Co., Ltd. of Japan, and sodium bicarbonate tablets were purchased from Yunnan Longfa Pharmaceutical Co., Ltd.

[0036] Example 1

[0037] The above-mentioned uric acid-lowering composition is prepared according to the following steps:

[0038] (1) Processing of excipients: Febuxostat, mannitol, sorbitol, lactose, sodium carboxymethyl starch, crosinol, and magnesium stearate were passed through a 100-mesh sieve and the sieved powder was collected for later use; 2 parts of sodium bicarbonate were dissolved in water to prepare an 8% sodium bicarbonate aqueous solution by weight, and then 3 parts of crosinol were slowly added at 30°C with stirring. After the addition was completed, the mixture was kept warm and stirred for 18 minutes to form a slurry, which was then spray-dried to obtain sodium bicarbonate spray particles for later use.

[0039] (2) Premix granulation: 50 parts febuxostat, 22 parts mannitol, 15 parts sorbitol, 12 parts lactose and 5 parts sodium carboxymethyl starch are mixed according to the weight to obtain a premix powder. Purified water is added to the premix powder, and after continuous stirring, the material is discharged and wet granules are obtained by sieving through an 18-mesh sieve. The purified water accounts for 18% of the mass of the premix powder.

[0040] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 85℃ and an air inlet frequency of 45Hz until the moisture content is 2.0%, and then granulated through an 18-mesh sieve to obtain dry granules;

[0041] (4) Total mixing and tableting: Mix the dry granules prepared in step (3) with 1 part magnesium stearate and sodium bicarbonate spray granules prepared in step (1) for 12 min, then add them to the tablet press and compress them into tablets with a hardness of 3-5 kg.

[0042] Comparative Example 1

[0043] In the preparation process, sodium bicarbonate is not added. Febuxostat is used directly as the active ingredient and mixed with the other components that are the same as in Example 1. The specific steps are as follows:

[0044] (1) Processing of excipients: Febuxostat, mannitol, sorbitol, lactose, sodium carboxymethyl starch and magnesium stearate are passed through a 100-mesh sieve, and the sieved powder is collected for later use.

[0045] (2) Premix granulation: 50 parts febuxostat, 22 parts mannitol, 15 parts sorbitol, 12 parts lactose and 5 parts sodium carboxymethyl starch are mixed according to the weight to obtain a premix powder. Purified water is added to the premix powder, and after continuous stirring, the material is discharged and wet granules are obtained by sieving through an 18-mesh sieve. The purified water accounts for 18% of the mass of the premix powder.

[0046] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 85℃ and an air inlet frequency of 45Hz until the moisture content is 2.0%, and then granulated through an 18-mesh sieve to obtain dry granules;

[0047] (4) Total mixing and tableting: Mix the dry granules prepared in step (3) with 1 part magnesium stearate and 3 parts cross-linked polyvinylpyrrolidone for 12 min, then add them to the tablet and compress them into tablets with a hardness of 3-5 kg.

[0048] Comparative Example 2:

[0049] Compared to Example 1, the difference lies in the use of hydroxypropyl methylcellulose instead of PVPP when preparing sodium bicarbonate into spray particles. The specific preparation steps are as follows:

[0050] (1) Processing of excipients: Febuxostat, mannitol, sorbitol, lactose, sodium carboxymethyl starch and magnesium stearate were passed through a 100-mesh sieve and the sieved powder was collected for later use; 2 parts by weight of sodium bicarbonate were dissolved in water to prepare an 8% sodium bicarbonate aqueous solution. Then, 3 parts of hydroxypropyl methylcellulose were slowly added at 30°C with stirring. After the addition was completed, the mixture was kept warm and stirred for 18 minutes to form a slurry. The slurry was then spray-dried to obtain sodium bicarbonate spray granules for later use.

[0051] (2) Premix granulation: 50 parts febuxostat, 22 parts mannitol, 15 parts sorbitol, 12 parts lactose and 5 parts sodium carboxymethyl starch are mixed according to the weight to obtain a premix powder. Purified water is added to the premix powder, and after continuous stirring, the material is discharged and wet granules are obtained by sieving through an 18-mesh sieve. The purified water accounts for 18% of the mass of the premix powder.

[0052] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 85℃ and an air inlet frequency of 45Hz until the moisture content is 2.0%, and then granulated through an 18-mesh sieve to obtain dry granules;

[0053] (4) Total mixing and tableting: Mix the dry granules prepared in step (3) with 1 part magnesium stearate and sodium bicarbonate spray granules prepared in step (1) for 12 min, then add them to the tablet and compress the tablets. The hardness is 3-5 kg.

[0054] Comparative Example 3

[0055] Compared to Example 1, sodium bicarbonate spray particles were added during premixing to prepare wet particles. The remaining steps were the same as in Example 1, and the specific steps are as follows:

[0056] (1) Processing of excipients: Febuxostat, mannitol, sorbitol, lactose, sodium carboxymethyl starch, crosinol, and magnesium stearate were passed through a 100-mesh sieve and the sieved powder was collected for later use; 2 parts of sodium bicarbonate were dissolved in water to prepare an 8% sodium bicarbonate aqueous solution by weight, and then 3 parts of crosinol were slowly added at 30°C with stirring. After the addition was completed, the mixture was kept warm and stirred for 18 minutes to form a slurry, which was then spray-dried to obtain sodium bicarbonate spray particles for later use.

[0057] (2) Premix granulation: According to the weight, 50 parts febuxostat, 22 parts mannitol, 15 parts sorbitol, 12 parts lactose, 5 parts sodium carboxymethyl starch and the sodium bicarbonate spray particles prepared in step (1) are mixed to obtain a premix powder. Purified water is added to the premix powder, and after continuous stirring, the material is discharged and wet granules are obtained by sieving through an 18-mesh sieve. The purified water accounts for 18% of the mass of the premix powder.

[0058] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 85℃ and an air inlet frequency of 45Hz until the moisture content is 2.0%, and then granulated through an 18-mesh sieve to obtain dry granules;

[0059] (4) Total mixing and tableting: Mix the dry granules prepared in step (3) with 1 part magnesium stearate for 12 min, then add it to the tablet and compress it into tablets with a hardness of 3-5 kg.

[0060] Example 2

[0061] The method for preparing the above-mentioned uric acid-lowering composition is characterized by the following steps:

[0062] (1) Processing of excipients: Febuxostat, mannitol, sorbitol, lactose, sodium carboxymethyl starch, crosinol, and magnesium stearate were passed through a 100-mesh sieve and the sieved powder was collected for later use; 2 parts by weight of sodium bicarbonate were dissolved in water to prepare a 5% sodium bicarbonate aqueous solution. Then, 1 part of crosinol was slowly added at 35°C with stirring. After the addition was completed, the mixture was kept warm and stirred for 15 minutes to form a slurry. The slurry was then spray-dried to obtain sodium bicarbonate spray particles for later use.

[0063] (2) Premix granulation: 60 parts febuxostat, 25 parts mannitol, 11 parts sorbitol, 15 parts lactose and 7 parts sodium carboxymethyl starch are mixed according to the weight to obtain a premix powder. Purified water is added to the premix powder, and after continuous stirring, the material is discharged and wet granules are obtained by sieving through an 18-mesh sieve. The purified water accounts for 15% of the mass of the premix powder.

[0064] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 90℃ and an air inlet frequency of 40Hz until the moisture content is 1.0%, and then granulated through an 18-mesh sieve to obtain dry granules;

[0065] (4) Total mixing and tableting: The dry granules obtained in step (3) are mixed with 0.8 parts of calcium stearate and sodium bicarbonate spray granules prepared in step (1) for 10 min, and then added to the tableting material and tableted. The hardness is 3-5 kg.

[0066] Example 3

[0067] The method for preparing the above-mentioned uric acid-lowering composition is characterized by the following steps:

[0068] (1) Processing of excipients: Febuxostat, mannitol, sorbitol, lactose, sodium carboxymethyl starch, crosinol, and magnesium stearate were passed through a 100-mesh sieve and the sieved powder was collected for later use; 2 parts by weight of sodium bicarbonate were dissolved in water to prepare a sodium bicarbonate aqueous solution with a mass fraction of 10%; then, 5 parts of crosinol were slowly added at 25°C with stirring. After the addition was completed, the mixture was kept warm and stirred for 20 minutes to form a slurry, which was then spray-dried to obtain sodium bicarbonate spray particles for later use.

[0069] (2) Premix granulation: 40 parts febuxostat, 15 parts mannitol, 20 parts sorbitol, 10 parts lactose and 3 parts sodium carboxymethyl starch are mixed according to the weight to obtain a premix powder. Purified water is added to the premix powder, and after continuous stirring, the material is discharged and wet granules are obtained by sieving through an 18-mesh sieve. The purified water accounts for 15-20% of the mass of the premix powder.

[0070] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 80℃ and an air inlet frequency of 50Hz until the moisture content is 3.0%, and then granulated through an 18-mesh sieve to obtain dry granules;

[0071] (4) Total mixing and tableting: Mix the dry granules prepared in step (3) with 1.5 parts of magnesium stearate and sodium bicarbonate spray granules prepared in step (1) for 15 min, then add them to the tablet and compress the tablets. The hardness is 3-5 kg.

[0072] Experiment 1: Long-term stability tests were conducted on Examples 1-3 and Comparative Examples 1-3:

[0073] 1. Test method: Stability testing was conducted according to Part II of the 2015 edition of the Chinese Pharmacopoeia.

[0074] 2. Test conditions:

[0075] Long-term test temperature: 25±2℃; Long-term test humidity: RH 60%±10%

[0076] Long-term experimental observation periods: 0, 3, 6, 9, 12, 18, and 24 months.

[0077] 3. Experimental Results:

[0078] The long-term stability records are shown in Table 1.

[0079] Table 1: Results of long-term stability tests on products prepared by each scheme

[0080]

[0081]

[0082] Long-term testing shows that in Examples 1, 2, and 3, there were no significant changes in appearance, disintegration time, identification, content, related substances (impurities produced by the reaction of febuxostat and sodium bicarbonate), and microbial limits over a long period of 24 months. Furthermore, the highest increase in related substances over the long period of 24 months was only 0.12%, which is a small increase. Therefore, the quality stability of this product is excellent after a long-term test of 24 months. The product prepared in Comparative Example 1 showed a slower disintegration time compared to the product in Example 1. The product prepared in Comparative Example 2 had a significantly longer disintegration time, but the increase in related substances was high, reaching 0.75% after 12 months, indicating poor product stability. This suggests that the hydroxypropyl methylcellulose coating on sodium bicarbonate did not provide a good barrier effect in the product, leading to impurities from contact between sodium bicarbonate and febuxostat after long-term storage. The product prepared in Comparative Example 3 showed a significantly longer disintegration time, and the related substances also increased to some extent compared to the other examples of this invention. This indicates that the direct premixing of sodium bicarbonate spray particles further reduced the barrier effect between sodium bicarbonate and febuxostat. Furthermore, the product prepared in Comparative Example 3 did not meet the requirements for orally disintegrating tablets. In summary, the products prepared in this invention (Examples 1, 2, and 3) exhibited stable quality during the stable storage period and a shelf life of up to 24 months.

[0083] Experiment 2: Clinical efficacy observation of the combination of febuxostat and sodium bicarbonate:

[0084] A clinical efficacy observation was conducted on 1000 patients with hyperuricemia, whose uric acid levels were between 400 and 600 μmol / L. They were randomly divided into two groups of 500 patients each. The control group received direct oral febuxostat tablets (20 mg / tablet once daily), while the experimental group received a combination of oral febuxostat tablets and sodium bicarbonate tablets (20 mg / tablet of febuxostat once daily and 0.3 g / tablet of sodium bicarbonate). The patients were observed after one month of treatment.

[0085] The efficacy evaluation criteria for uric acid-lowering drugs are as follows:

[0086] Significant: After one month of use, uric acid levels decreased by more than 20%;

[0087] Effective: After one month of use, uric acid levels decreased by 10-20%;

[0088] Overall effectiveness rate: The proportion of participants in each group whose uric acid levels decreased by more than 10% after one month of treatment. The statistical structure is shown in Table 2.

[0089] Table 2: Statistical Analysis of Clinical Efficacy

[0090] category Significant number of cases Valid cases Overall effectiveness (%) Gastrointestinal bloating Excessive stomach acid Acid reflux control group 338 96 86.8 54 42 21 experimental group 302 79 76.2 8 0 0

[0091] As shown in the table above, the overall effective rate in the control group was 86.8%, with the highest number of cases experiencing gastrointestinal bloating, excessive stomach acid, and acid reflux after taking febuxostat tablets. In contrast, the experimental group showed significant relief from gastrointestinal side effects, with excessive stomach acid and acid reflux disappearing. However, the presence of sodium bicarbonate in the combined use of febuxostat and the resulting reaction produced impurities, reducing the efficacy of febuxostat and leading to a slight decrease in the overall effective rate. These data indicate that the combined use of sodium bicarbonate tablets and febuxostat tablets effectively addresses the high incidence of gastrointestinal adverse reactions to febuxostat, thus improving its effectiveness in lowering uric acid.

[0092] Experiment 3: Clinical efficacy observation of uric acid-lowering drugs in animal experiments:

[0093] Experimental Methods: 180 Kunming mice from the same batch were uniformly intraperitoneally injected with 60 mg / kg uric acid and then randomly divided into 9 groups of 20 mice each. Specifically, there was a blank control group, two experimental groups (administered with febuxostat at a ratio of 2 mg / kg to mouse body weight), and two control groups 1, 2, and 3 (administered with febuxostat at 2 mg / kg body weight). The blank control group was administered 2 ml of physiological saline by gavage. The two experimental groups were given the 0-month product prepared in Example 1 of this invention and the product stored for 12 months, respectively, and were given the same volume of physiological saline by gavage to the blank control group. In each of the control groups 1-3, two groups were administered the 0-month product prepared in Comparative Examples 1-3 of this invention and the product stored for 12 months, respectively, and were given the same volume of physiological saline by gavage to the blank control group. The administration was once daily for 3 consecutive days. The mice were sacrificed 24 hours after administration. Whole blood was centrifuged at 8000 r / min for 3 min, the supernatant serum was separated, and the uric acid level in the blood was measured. The results are shown in Table 3.

[0094] Table 3: Uric Acid Lowering Effects of Different Product Options

[0095]

[0096]

[0097] As shown in the table above, the uric acid level was highest in the blank group (no medication). After taking the composition prepared in Example 1, the uric acid level decreased significantly by adjusting the disintegration efficiency of febuxostat, and the efficacy of the composition remained largely unaffected after 12 months of storage. In contrast, Comparative Example 1, which did not contain sodium bicarbonate, showed similar febuxostat efficacy to the experimental group. Although the final uric acid level decrease was roughly the same, the rate of uric acid level decrease in Comparative Example 1 was slower than that in the experimental group within the same timeframe. This was due to the longer disintegration time of the composition in Comparative Example 1. In Comparative Example 2, hydroxypropyl methylcellulose was used instead of PVPP. Although it had some film-forming properties, the effect was poor, leading to an increase in impurities generated in the composition during long-term storage, resulting in a certain decrease in febuxostat efficacy. In Comparative Example 3, sodium bicarbonate spray particles were added during premixing, resulting in a slightly weaker barrier effect between febuxostat and sodium bicarbonate. Long-term storage also led to a certain degree of decrease in febuxostat efficacy.

Claims

1. A uric acid-lowering composition, characterized in that: The uric acid-lowering composition includes a pharmacologically acceptable filler, flavoring agent, disintegrant, and lubricant, as well as cross-linked polyvinylpyrrolidone (PVPP) for spray granulation to prepare sodium bicarbonate spray particles. The pharmacologically acceptable component is composed of febuxostat and sodium bicarbonate in a mass ratio of 20-30:

1. The process involves mixing febuxostat, filler, flavoring agent, and disintegrant to prepare wet granules, drying and granulating them into dry granules, mixing sodium bicarbonate with PVPP to prepare sodium bicarbonate spray particles, and then mixing the sodium bicarbonate spray particles, lubricant, and dry granules to compress them into tablets. The spray granulation process for preparing sodium bicarbonate spray particles involves dissolving sodium bicarbonate in water to prepare a 5%-10% sodium bicarbonate aqueous solution, then adding PVPP at 25-35°C with stirring, continuing to maintain the temperature and stir to form a slurry, and then spray drying to obtain sodium bicarbonate spray particles.

2. The uric acid-lowering composition according to claim 1, characterized in that: The filler may be one or more of mannitol, lactose, sorbitol, glucose, and starch; the disintegrant may be at least one of low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; and the lubricant may be one of magnesium stearate, talc, and calcium stearate.

3. A uric acid-lowering composition as described in claim 1 or 2, characterized in that: Based on weight, the present ingredient comprises 40-60 parts febuxostat, 2 parts sodium bicarbonate, 25-40 parts filler, 11-20 parts flavoring agent, 3-7 parts disintegrant, 1-5 parts crosslinked polyvinylpyrrolidone, and 0.8-1.5 parts lubricant.

4. A method for preparing a uric acid-lowering composition, characterized in that: Febuxostat, filler, flavoring agent, and disintegrant are mixed to prepare wet granules, which are then dried and granulated into dry granules. Sodium bicarbonate is mixed with cross-linked polyvinylpyrrolidone to prepare sodium bicarbonate spray granules. The sodium bicarbonate spray granules, lubricant, and dry granules are then mixed and compressed into tablets. The mass ratio of febuxostat to sodium bicarbonate is 20-30:

1. The preparation of sodium bicarbonate spray granules by spray granulation involves dissolving sodium bicarbonate in water to prepare a sodium bicarbonate aqueous solution with a mass fraction of 5%-10%. Cross-linked polyvinylpyrrolidone is then added under stirring at 25-35°C, and the mixture is kept warm and stirred to form a slurry. Finally, the slurry is spray-dried to obtain sodium bicarbonate spray granules.

5. The method for preparing a uric acid-lowering composition as described in claim 4, characterized in that: Based on weight, the present invention comprises 40-60 parts febuxostat, 2 parts sodium bicarbonate, 15-25 parts mannitol and 10-15 parts lactose as fillers, 11-20 parts sorbitol as flavoring agent, 3-7 parts sodium carboxymethyl starch as disintegrant, 1-5 parts croscarmellose, and 0.8-1.5 parts magnesium stearate as lubricant.

6. The method for preparing a uric acid-lowering composition as described in claim 5, characterized in that: The preparation of wet granules involves mixing febuxostat, mannitol, sorbitol, lactose, and sodium carboxymethyl starch according to the formula to obtain a premixed powder. Purified water is added to the premixed powder, and after continuous stirring, the powder is discharged and passed through an 18-mesh sieve to obtain wet granules. The purified water accounts for 15-20% of the mass of the premixed powder.

7. The method for preparing a uric acid-lowering composition as described in claim 6, characterized in that: The drying and granulation process involves drying the wet granules at an inlet air temperature of 80-90℃ and an inlet air frequency of 40-50Hz until the moisture content is 1.0-3.0%, and then granulating them through an 18-mesh sieve to obtain dry granules.

8. A method for preparing a uric acid-lowering composition, characterized in that, Follow these steps: (1) Processing of excipients: Febuxostat, mannitol, sorbitol, lactose, sodium carboxymethyl starch, crosinol, and magnesium stearate are passed through a 100-mesh sieve and the sieved powder is collected for later use; 2 parts of sodium bicarbonate are dissolved in water according to the weight to prepare a sodium bicarbonate aqueous solution with a mass fraction of 5-10%; then, under the condition of stirring at 25-35℃, 2-4 parts of crosinol are slowly added. After the addition is completed, the mixture is kept warm and stirred for 15-20 minutes to form a slurry. The slurry is then spray-dried to obtain sodium bicarbonate spray particles for later use. (2) Premix granulation: According to the weight, 40-60 parts of febuxostat, 20-23 parts of mannitol, 13-18 parts of sorbitol, 10-15 parts of lactose, and 4-6 parts of sodium carboxymethyl starch are mixed to obtain a premix powder. Purified water is added to the premix powder, and after continuous stirring, the powder is discharged and wet granules are obtained by screening through an 18-mesh sieve. The purified water accounts for 15-20% of the mass of the premix powder. (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 80~90℃ and an air inlet frequency of 40~50Hz until the moisture content is 1.0~3.0%, and then granulated through an 18-mesh sieve to obtain dry granules; (4) Total mixing and tableting: The dry granules obtained in step (3) are mixed with 0.9~1.3 parts of magnesium stearate and sodium bicarbonate spray granules prepared in step (1) for 12 min, and then added to the tableting material and tableted. The hardness is 3~5Kg.

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