Pharmaceutical composition and use thereof

Abstract

The present invention relates to a pharmaceutical composition and use thereof. The pharmaceutical composition comprises a substance Z and pharmaceutical excipients. The substance Z is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical excipients comprise a binder, a disintegrant, and a filler. The content of the compound represented by formula I accounts for at least 5% of the mass of the pharmaceutical composition. The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch, sucrose, and pregelatinized starch. The pharmaceutical composition has stable pharmaceutical properties, and exhibits the characteristics of low effective dose, safety, superior efficacy, and the like in clinical applications for gout and hyperuricemia.

Description

A pharmaceutical composition and its use

[0001] This application claims priority to Chinese patent application 2024104778557, filed on April 19, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to a pharmaceutical composition and its use. BACKGROUND

[0003] Uric acid is a catabolite of purine nucleotides in the human body. Purine is oxidatively metabolized by the liver to become uric acid, which is then excreted by the kidney and the intestinal tract. Hyperuricemia is usually caused by disorders of purine metabolism and / or decreased uric acid excretion. Due to the low solubility of uric acid, it can form gout when the concentration in the body is elevated. In recent years, the number of people suffering from hyperuricemia and gout has increased significantly, and it has become the most common chronic non-communicable disease and is showing a trend of becoming younger. Complications such as gouty arthritis, gouty kidney lesions, gouty kidney stones, gouty heart disease, gouty hypertension, etc. caused by hyperuricemia seriously affect people's daily life.

[0004] The drugs currently on the market for the treatment of hyperuricemia are divided into two categories: xanthine oxidase inhibitors and uricosuric agents. Xanthine oxidase inhibitors include allopurinol, febuxostat and topiroxostat, etc., which reduce the production of uric acid by interfering with xanthine oxidase. Uricosuric agents include benzbromarone, probenecid and lesinurad, etc., which increase the excretion of uric acid by reducing its reabsorption. Although the existing marketed drugs can reduce the uric acid content in the body of patients, they also have obvious shortcomings; xanthine oxidase inhibitors are not effective enough, and about half of the patients with hyperuricemia do not get effective treatment; and uricosuric drugs have obvious side effects, such as liver and kidney toxicity, which can easily cause liver and kidney damage in patients, and long-term use can also cause disorders of uric acid synthesis and metabolism in the body.

[0005] In the study of the composition of the present product, it was found that due to the molecular structure characteristics and physicochemical properties of the raw materials, the raw materials were easily degraded in the formulation prescription, and a stable pharmaceutical composition with stable physicochemical properties could not be provided, so that the role of URAT1 (Uric acid anion transporter 1) inhibitor in reducing uric acid could not be played. SUMMARY

[0006] The present application provides a pharmaceutical composition and application thereof. The pharmaceutical composition product provided by the present application is stable in product property; the pharmaceutical composition shows a low onset dose in clinical application of gout and hyperuricemia, and has a more obvious effect of reducing blood uric acid compared with commercial products.

[0007] The present application provides a pharmaceutical composition comprising a substance Z and a pharmaceutically acceptable excipient; the substance Z is a compound as shown in formula I or a pharmaceutically acceptable salt thereof; the pharmaceutically acceptable excipient comprises a binder, a disintegrant and a filler; the content of the compound as shown in formula I accounts for at least 5% of the mass of the pharmaceutical composition; the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch, sucrose and pregelatinized starch.

[0008] In an embodiment, the pharmaceutical composition can be a tablet or a capsule, preferably a capsule.

[0009] In an embodiment, the pharmaceutical composition further comprises a glidant and / or a lubricant.

[0010] In an embodiment, when the pharmaceutical composition is a tablet, the pharmaceutical composition comprises a lubricant.

[0011] In an embodiment, when the pharmaceutical composition is a capsule, the pharmaceutical composition comprises a glidant.

[0012] In an embodiment, the binder can be selected from one or more of povidone, hydroxypropyl cellulose, hypromellose and sodium carboxymethyl cellulose, for example, hypromellose.

[0013] In an embodiment, the hypromellose can be hypromellose E5.

[0014] In an embodiment, the content of the binder can be 1-5% of the mass of the pharmaceutical composition, preferably 2-4.5%, for example, 3%.

[0015] In an embodiment, the filler is selected from one or two of lactose, microcrystalline cellulose, mannitol and pregelatinized starch, for example, microcrystalline cellulose, lactose and microcrystalline cellulose, microcrystalline cellulose and pregelatinized starch lactose, or mannitol and pregelatinized starch.

[0016] In an embodiment, the starch is corn starch.

[0017] In one aspect, the microcrystalline cellulose can be microcrystalline cellulose PH101.

[0018] In one aspect, the lactose can be lactose 200 mesh.

[0019] In one aspect, the filler can be present in an amount of 40-90% by weight of the pharmaceutical composition, preferably 60.5-87%, such as 68.5%, 70.5% or 73.8%.

[0020] In one aspect, the disintegrant can be selected from one or more of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; such as crospovidone or sodium carboxymethyl starch.

[0021] In one aspect, the crospovidone can be crospovidone XL.

[0022] In one aspect, the disintegrant can be present in an amount of 2-10% by weight of the pharmaceutical composition, preferably 2-8%, such as 3%, 5% or 7%.

[0023] In one aspect, the glidant can be selected from one or both of silicon dioxide and talc, such as colloidal silicon dioxide.

[0024] In one aspect, the glidant can be present in an amount of 0-1% by weight of the pharmaceutical composition, such as 0.5%, 0.3% or 0.1%.

[0025] In one aspect, the lubricant can be selected from one or more of magnesium stearate, sodium stearyl fumarate, calcium stearate and sodium lauryl sulfate, such as magnesium stearate.

[0026] In one aspect, the lubricant can be present in an amount of 0-1% by weight of the pharmaceutical composition, such as 0.1%, 0.5% or 1%.

[0027] In one aspect, the raw material of the pharmaceutical composition can have a particle size D50 of 1-45 pm, preferably 9.55-44.30 pm or 1.29-25.58 pm, more preferably 2-30 pm, further preferably 5-30 pm, yet further preferably 9.55-25.58 pm, such as 10-25 pm.

[0028] In one aspect, the composition comprises 2.5-40 mg of the substance Z, such as 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg or 40 mg of the substance Z.

[0029] In one embodiment, the pharmaceutical excipients consist of the binder, the disintegrant, the filler, and the glidant, or the pharmaceutical excipients consist of the binder, the disintegrant, the filler, and the lubricant, or the pharmaceutical excipients consist of the binder, the disintegrant, the filler, the glidant, and the lubricant.

[0030] In one embodiment, the pharmaceutical composition comprises, by weight:

[0031] In one embodiment, the pharmaceutical composition comprises, by weight:

[0032] 2-4.5% binder, 60.5-87% filler, 2-8% disintegrant, 0-1% glidant, and 0-1% lubricant; preferably, the binder is hypromellose; the filler is microcrystalline cellulose, lactose, and microcrystalline cellulose, microcrystalline cellulose and pre-gelatinized starch lactose, or mannitol and pre-gelatinized starch; the disintegrant is crospovidone or sodium starch glycolate; the glidant is colloidal silicon dioxide; and the lubricant is magnesium stearate.

[0033] In one embodiment, the pharmaceutical composition comprises, by weight, any combination of:

[0034] Combination 1, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% microcrystalline cellulose PH101, 24.5% lactose 200 mesh, 3% hypromellose E5, 5% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;

[0035] Combination 2, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% microcrystalline cellulose PH101, 24.5% pre-gelatinized starch, 3% hypromellose E5, 5% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;

[0036] Combination 3, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 73.83 of microcrystalline cellulose PH101, 3% of hypromellose E5, 5% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0037] Combination 4, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% of microcrystalline cellulose PH101, 24.5% of lactose 200 mesh, 3% of hypromellose E5, 5% of sodium starch glycolate, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0038] Combination 5, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% of microcrystalline cellulose PH101, 30% of lactose 200 mesh, 3% of hypromellose E5, 5% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0039] Combination 6, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% of pregelatinized starch, 30% of mannitol, 3% of hypromellose E5, 5% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0040] Combination 7, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 7% of hypromellose E5, 3% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0041] Combination 8, 5% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 56% of microcrystalline cellulose PH101, 30% of lactose 200 mesh, 3% of hypromellose E5, 5% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 0.5% of magnesium stearate;

[0042] Combination 9, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 3% of hypromellose E5, 7% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0043] Combination 10, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 41.2% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 3% of hypromellose E5, 7% of cross-linked polyplasdone XL, 0.3% of colloidal silicon dioxide and 0.5% of magnesium stearate;

[0044] Combination 11, 20% of the compound as shown in formula I or a pharmaceutically acceptable salt thereof, 41.8% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 3% of hydroxypropyl methyl cellulose E5, 7% of cross-linked polyvinylpyrrolidone XL, 0.1% of colloidal silicon dioxide and 0.1% of magnesium stearate.

[0045] The pharmaceutical composition of the present application can also be expressed as no new component is added on the basis of each aspect thereof.

[0046] The present application also provides a preparation method of the pharmaceutical composition as described above, which is method A or method B.

[0047] The method A comprises the following steps:

[0048] (1) mixing the substance Z as described above, a binder, a disintegrant and a filler, wet granulating to obtain granules (wet granulation is performed after granulation is completed, and 24 mesh screen is used for wet granulation); drying (40-50°C) to obtain dry granules (24 mesh screen is used);

[0049] (2) mixing the aforementioned glidant and lubricant with the dry granules;

[0050] (3) tabletting;

[0051] The method B comprises the following steps:

[0052] Mixing, sieving and tabletting of each component of the pharmaceutical composition as described above.

[0053] The present application also provides a pharmaceutical composition prepared by the preparation method of the pharmaceutical composition as described above.

[0054] The present application also provides an application of the substance W in the preparation of a URAT1 inhibitor, wherein the substance W is the pharmaceutical composition as described above or the pharmaceutical composition prepared by the preparation method as described above.

[0055] The present application also provides an application of the substance W in the preparation of a medicine, wherein the substance W is the pharmaceutical composition as described above or the pharmaceutical composition prepared by the preparation method as described above; and the medicine is used for treating and / or preventing hyperuricemia or gout.

[0056] The present application also provides a method for treating and / or preventing hyperuricemia or gout, which comprises applying an effective amount of the substance W to a subject, wherein the substance W is the pharmaceutical composition as described above or the pharmaceutical composition prepared by the preparation method as described above; and the medicine is used for treating and / or preventing hyperuricemia or gout.

[0057] The present application also provides a substance W for treating and / or preventing hyperuricemia or gout, wherein the substance W is the pharmaceutical composition as described above or the pharmaceutical composition prepared by the preparation method as described above.

[0058] The above-mentioned preferred conditions can be combined arbitrarily without departing from the common general knowledge in the art, thereby obtaining preferred embodiments of the present application.

[0059] The reagents and raw materials used in the present application are commercially available.

[0060] The positive progress effect of the present application is that the present application provides a composition containing a URAT1 inhibitor and a preparation method and application thereof. The composition contains a URAT1 inhibitor and a pharmaceutically acceptable excipient, and the stability of the pharmaceutical properties of the composition is ensured by controlling the type and amount of the excipient. And further by controlling the particle size of the composition can further improve the stability of the pharmaceutical properties of the pharmaceutical composition. Compared with the commercially available products, the composition proposed in the present application shows the characteristics of low onset dose, safety and efficiency in the clinical application of gout and hyperuricemia. BRIEF DESCRIPTION OF DRAWINGS

[0061] Figure 1 is the results of the clinical study of safety and effectiveness of Example 10. DETAILED DESCRIPTION

[0062] The present application will be further described by way of examples, but the present application is not limited in the scope of the examples. The experimental methods in the following examples are not specified, and the methods are selected according to the conventional methods and conditions, or according to the instructions of the goods.

[0063] The structure of the URAT1 inhibitor used in the examples is

[0064] The impurity or related substance detection method in the present application is as follows:

[0065] The detection and analysis method is as follows:

[0066] Related substances were determined by high performance liquid chromatography (general rule 0512).

[0067] Solvent Acetonitrile-water (50:50).

[0068] Test sample solution Randomly take 10 samples, accurately weigh, and grind finely with a marble mortar. Accurately weigh the fine powder, place it in a volumetric flask, dilute to the mark with solvent, and place it in an ultrasonic instrument for ultrasonic treatment for 30 minutes. After ultrasonic treatment, transfer an appropriate amount to a centrifuge tube and centrifuge at 8000 rpm per minute for 10 minutes, and take the supernatant;

[0069] Control solution Take an appropriate amount of control, accurately weigh, dissolve and dilute to prepare a solution of a specific concentration.

[0070] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler (Agilent Eclipse Plus C18 column, 4.6 mm x 150 mm, 3.5 μm or a chromatographic column with equivalent performance); 0.1% trifluoroacetic acid aqueous solution as mobile phase A and acetonitrile as mobile phase B, the flow rate was 0.8 ml / min, gradient elution was carried out according to the following table; the detection wavelength was 250 nm; the column temperature was 40°C; the injection volume was 10 μl.

[0071] Determination method: accurately measure the test sample solution and the control sample solution, respectively inject into the liquid chromatograph, and record the chromatogram. Limit: calculate the content of each impurity and the total impurities by peak area according to the external standard method.

[0072] Example 1

[0073] According to the effective dose and toxicological safety dose of the API in multiple animal models, the specification of the product is designed in the range of 2.5 mg to 40 mg, and the dosage form is preliminarily designed as a tablet or a capsule for the convenience of dose exploration test administration. In order to illustrate the characteristics of the present application, the selection of the preparation process is illustrated by taking the 25 mg specification preparation as an example.

[0074] Preparation method of composition A:

[0075] a. Pre-mix the raw material drug and excipients;

[0076] b. Wet granulate the mixed material;

[0077] c. After granulation, pass through a 24-mesh screen for wet granulation;

[0078] d. Dry the wet granules at 40°C to 50°C, and pass through a 24-mesh screen for granulation;

[0079] e. Mix colloidal silicon dioxide, magnesium stearate and dry granules;

[0080] f. Tablet compression;

[0081] Preparation method of composition B, composition C, composition D and composition E:

[0082] a. Pre-mix the raw material drug and excipients;

[0083] b. Pass the mixed material through a 24-mesh screen;

[0084] c. Tablet compression;

[0085] In this example, the prescription of composition A adopts wet granulation, which has good compressibility, stable tablet weight and no sticking or collision.

[0086] Example 2

[0087] Preparation method is the same as Example 1 wet granulation

[0088] Composition F, Composition G, Composition H investigate the effect of different fillers on API degradation, three prescription compressibility is good, the dissolution test and pre-acceleration experiment, and investigate the change of related substances of tablets after seven days under different acceleration conditions.

[0089] The results of related substance detection are as follows.

[0090] The screening of the prescription mainly focuses on the influence of the filler on the related substances of API. By comparing the data of related substances under different conditions, it can be seen that the impurity with RRT 0.85 is the main degradation impurity, and the growth rate of impurity with RRT 0.85 in Composition H is significantly higher than that in Composition F and Composition G. Therefore, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, etc. can be selected as fillers in the prescription, and a large amount of calcium hydrogen phosphate and other salts should be avoided as fillers.

[0091] Example 3

[0092] Investigation of raw material particle size: The particle size of raw materials in oral solid preparations affects the in vitro dissolution, in vivo bioavailability and stability of the product itself. In this example, the same batch of raw materials was pulverized to different particle sizes using a pulverizer to prepare compositions, and the effect of particle size on the properties of the preparation was studied. The particle size detected by Malvern laser particle size analyzer is as follows:

[0093] The prescription and preparation method of Composition I, Composition J, Composition K and Composition L are consistent, and the prescription dosage is shown in the table.

[0094] Preparation method:

[0095] a. Pre-mix the raw materials and excipients;

[0096] b. Wet granulation of the mixed material;

[0097] c. After granulation, wet granulation is carried out;

[0098] d. Dry the wet granules and granulate;

[0099] e. Mix colloidal silicon dioxide, magnesium stearate with dry granules;

[0100] f. Tabletting;

[0101] The composition in this example was tested according to the dissolution and release rate determination method (Chinese Pharmacopoeia General Chapter 0931, Method 2). Dissolution conditions: 900 ml of phosphate buffer solution (pH 6.8) (8.96 g of sodium hydroxide and 68.05 g of potassium dihydrogen phosphate were dissolved completely in 10 L of pure water, mixed uniformly, and the pH was adjusted to 6.8 with phosphoric acid or sodium hydroxide) was used as the dissolution medium, the rotation speed was 50 rpm, and samples were taken at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, respectively. The dissolution results are shown in the table below.

[0102] The results showed that due to the good water solubility of the raw material, there was no significant difference in dissolution between the particle size D50 of 1.29 μm and 44.30 μm, and the dissolution rate was greater than 85% within 15 minutes. Therefore, strict control of the particle size was not necessary for in vitro dissolution.

[0103] Stability: The composition was exposed to the influence factor condition of 60°C / 75%RH for 7 days. The content of relevant substances is shown in the following table.

[0104] Stability data shows that the raw material particle size D50 should be controlled between 9.55μm and 44.30μm, and the impurity content should be less controlled.

[0105] Bioavailability: The compositions were subjected to oral bioavailability studies in dogs (n=6). Each dog received a single intravenous injection of 1 mg / kg. Additionally, one tablet (2 mg / kg) of Composition G, Composition H, and Composition I were administered sequentially. Blood drug concentrations were measured 24 hours after administration. The oral bioavailability of compositions with different particle sizes was determined.

[0106] *Oral bioavailability = AUC of oral administration 0-last / AUC of injection 0-last *Dose for injection / dose for oral administration*100%

[0107] The bioavailability results of different raw material particle sizes showed that the bioavailability of composition G, composition H, and composition I were comparable, the raw material particle size D50 was between 1.29 μm and 25.58 μm, and the bioavailability was between 44.0% and 48.7%, which were comparable results.

[0108] Existing research data show that when the raw material particle size D50 is between 9.55μm and 25.58μm, the particle size does not affect the in vitro dissolution of the drug, the in vivo bioavailability, and the stability of the product itself.

[0109] Example 4

[0110] API prescription ratio investigation: using the same batch of API, design prescription ratios of 2.5%, 5%, and 20% to prepare compositions M, N, and O, respectively, and the preparation method is consistent with that described in Example 3. The prescription information is shown in the following table.

[0111] The compositions were placed in the open air under the influence factor condition of 60℃ / 75%RH for 7 days, and the related substance conditions are shown in the following table.

[0112] The results show that compared with composition M, compositions N and O increase the proportion of raw materials in the prescription, and the increase in impurity RRT 0.83 / 0.84 is significantly reduced. Combined with the influence of raw material particle size on impurities in Example 3, it is preliminarily analyzed that the small API ratio increases the contact with incompatible excipients, thereby causing API degradation. It is preliminarily controlled that the prescription ratio of raw materials is ≥5%, the proportion of each excipient in the prescription is controlled, and the product is stored under reasonable storage conditions, thereby reducing the degradation rate of API.

[0113] Example 5:

[0114] According to the research conclusions of Example 1-Example 4, it has been determined that the process, raw material particle size, and prescription ratio of raw and auxiliary materials have an influence on the in vitro dissolution, bioavailability, and stability of the composition. Within the more preferred range of Example 1-Example 4, to further illustrate the characteristics of the product, the prescription process of the composition is fully described in this example. The composition of the URAT1 inhibitor, the excipients include prescription ratios of (a) 50-87% by weight of lactose or microcrystalline cellulose or a combination of the two; (b) 2-8% by weight of crospovidone; (c) 0-1% by weight of colloidal silicon dioxide, (d) 2-5% by weight of hydroxypropyl methyl cellulose; (e) 0-1% by weight of magnesium stearate; the prescription ratio range and preferred range of excipients are shown in the following table.

[0115] The preparation method of this example is as follows:

[0116] 1. Mix the URAT1 inhibitor, microcrystalline cellulose, lactose, and crospovidone.

[0117] 2. Spray the hydroxypropyl methyl cellulose solution into the mixture in step 1.

[0118] 3. Dry and granulate the material in step 2.

[0119] 4. Mix the dry granules in step 3, colloidal silicon dioxide, magnesium stearate, and additional crospovidone.

[0120] 5. Press the mixture in step 4 into tablets of appropriate hardness

[0121] 6. Coating the tablets from step 5 with a coating material of desired color.

[0122] 7. Optionally, filling the mixture from step 4 into a capsule shell.

[0123] Example 6:

[0124] The composition containing URAT1 inhibitor of this example comprises prescription ratio (a) 50-87% by weight of lactose or microcrystalline cellulose or combination of both; (b) 2-8% by weight of crospovidone; (c) 0-1% by weight of colloidal silicon dioxide, (d) 2-5% by weight of hypromellose; (e) 0-1% by weight of magnesium stearate; specific prescription ratio as follows table.

[0125] The preparation method of this example is as follows:

[0126] 1. Mixing URAT1 inhibitor, microcrystalline cellulose, lactose, part of crospovidone for 20 min;

[0127] 2. Spraying the solution of hypromellose into the mixture of step 1, controlling the atomization pressure greater than 1 bar;

[0128] 3. Drying the material in step 2 at 40-50°C, controlling the final moisture content below 3%; the dried granules are sized with 24 mesh screen;

[0129] 4. Mixing the dried granules in step 3, colloidal silicon dioxide, magnesium stearate and the remaining crospovidone for 10 min;

[0130] 5. Pressing the mixture in step 4 into tablets, controlling the tablet hardness in the range of 30-120 N;

[0131] 6. Coating the tablets from step 5 with a coating material of desired color, controlling the coating weight gain in the range of 2-5%.

[0132] Example 7:

[0133] The composition P, composition Q, composition R, composition S of example 6 are determined according to dissolution and release test method (Chinese Pharmacopoeia General 0931 second method).

[0134] Dissolution condition: 900ml phosphate buffer solution (pH 6.8) (take sodium hydroxide 8.96g and potassium dihydrogen phosphate 68.05g in 10L pure water, dissolve completely, mix evenly, adjust pH to 6.8 with phosphoric acid or sodium hydroxide, and then obtain) as dissolution medium, rotation speed is 50 revolutions per minute, sample at 5, 10, 15, 20, 30, 45, 60, 90 minutes respectively, and the dissolution results are shown in the table below. Within a certain range of prescription ratio, the dissolution of the composition is fast, and the dissolution at 15 min is more than 85%.

[0135] Example 8:

[0136] Investigation of auxiliary materials

[0137] After the inventors studied the main increased impurity (RRT about 0.84) in Examples 2, 3, and 4, it was determined to be a hydrolysis impurity. Through mechanism analysis, it was found that the raw material was more likely to degrade in the environment of auxiliary materials with partial acidity / alkalinity. The inventors fully optimized the prescription amount of silica and magnesium stearate, which are auxiliary materials with partial acidity / alkalinity in the composition prescription, and the increase of impurities was controlled.

[0138] The preparation process of the above composition is as follows:

[0139] 1. Mix the URAT1 inhibitor, microcrystalline cellulose, lactose, and part of the cross-linked polyvinylpyrrolidone for 20 min;

[0140] 2. Spray the solution of hydroxypropyl methylcellulose into the mixture in step 1, and control the atomization pressure to be greater than 1 bar to uniformly atomize the solution;

[0141] 3. Dry the material in step 2 at 40-50°C, and control the final moisture content to be less than 3%; use a 24-mesh screen to size the dried granules;

[0142] 4. Mix the dried granules in step 3, colloidal silicon dioxide, magnesium stearate, and the remaining cross-linked polyvinylpyrrolidone for 10 min;

[0143] 5. Press the mixture in step 4 into tablets, and control the tablet hardness to be in the range of 30-120 N;

[0144] 6. Use a coating material of the desired color to coat the tablets in step 5, and control the coating weight gain to be in the range of 2-5%.

[0145] The long-term test is conducted under conditions close to the actual storage conditions of the drug, and the purpose is to provide a basis for formulating the shelf life of the drug. The current research results show that the amount of silica and magnesium stearate is small, and the growth rate is slow; the impurity levels of compositions S, T, and U are all lower than the preset limit of 0.5% after 12 months of long-term test, and they have good stability.

[0146] Example 9:

[0147] Dosage form investigation

[0148] The dosage form of the present composition is designed as a conventional solid dosage form. In combination with the production conditions and the requirements of clinical medication, the present composition can be designed as a tablet or a capsule. In Example 8, the components of Composition V are prepared into a capsule dosage form. The specific preparation process is as follows:

[0149] 1. Mix the URAT1 inhibitor, microcrystalline cellulose, lactose, and 50% crospovidone for 20 min;

[0150] 2. Prepare a 5% hydroxypropyl methylcellulose aqueous solution and then spray it into the mixture in step 1;

[0151] 3. Dry the material in step 2 at 40-50°C, with the final moisture controlled to be less than 3%; and size the dried granules using a 24-mesh screen;

[0152] 4. Mix the dried granules in step 3, colloidal silicon dioxide, magnesium stearate, and the remaining crospovidone for 10 min;

[0153] 5. Fill the capsules with the mixture in step 4, with the control of the capsule fill weight variation being less than 7.5%.

[0154] The impurity growth of Composition V tablets and capsules in different dosage forms is compared, and the impurity level of each is lower than the preset limit of 0.5%. According to the impurity level of the tablets and capsules for 12 months, it is inferred that both dosage forms can meet the stability requirements within the preset shelf life of 24 months. Moreover, the capsule dosage form has a slower impurity growth rate and a smaller risk during the stability period.

[0155] Example 10:

[0156] A clinical study is carried out to evaluate the safety and effectiveness of the present composition in adult patients with hyperuricemia with or without gout using Composition P of Example 6, using a randomized, double-blind, parallel, positive drug / placebo-controlled design. Hyperuricemia (with or without gout) patients are enrolled in the study and given medication for 4 consecutive weeks. The results of the study are shown in the following table and Figure 1.

[0157] Safety analysis: In the composition (10 mg BID), benzbromarone group, and placebo group, the highest incidence of adverse events was found to be increased creatinine and gout attacks, followed by abnormal urine test and diarrhea. Except for gout, the incidence of other adverse events was similar to that of placebo and benzbromarone. The incidence of gout in the composition was only 6.9%, which was lower than that of placebo and benzbromarone.

[0158] Efficacy analysis: In the treatment of gout / hyperuricemia, the external guidelines recommend that for patients with tophi, chronic gouty arthritis or frequent gouty arthritis, the target of uric acid lowering therapy is < 5 mg / dl, until the tophi are completely dissolved and the symptoms of frequent arthritis are improved. It was found that in subjects with baseline serum uric acid ≥ 9 mg / dL, the compliance rate of benzbromarone 6 mg / dl was about 25% at 4 weeks, and the compliance rate of the composition was 53.3%, which was much higher than that of benzbromarone group; The 4 / 5 mg / dl compliance rate showed a significant advantage of the composition over the benzbromarone group. The 4 / 5 mg / dl compliance rate represents a more in-depth remission, and the in-depth remission has great clinical significance and advantage for the treatment of patients with complex / refractory gout, or gout combined with underlying diseases.

[0159] The above only lists several specific embodiments of the present application, but does not mean that the protection scope of the present application is limited thereto. The present application can be extended to any new features disclosed in the present application or any new combination, as well as any new method or process steps or new combination disclosed. Within the technical scope disclosed in the present application, equivalent replacement or change according to the technical solutions and inventive concepts of the present application by those skilled in the art also falls within the protection scope of the present application.

Claims

1. A pharmaceutical composition comprising a substance Z and a pharmaceutically acceptable excipient; the substance Z is a compound as shown in Formula I or a pharmaceutically acceptable salt thereof; the pharmaceutically acceptable excipient comprises a binder, a disintegrant and a filler; the compound as shown in Formula I is contained in an amount of at least 5% by mass of the pharmaceutical composition; the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch, sucrose and pregelatinized starch; 2. The pharmaceutical composition of claim 1, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) the pharmaceutical composition further comprises a glidant and / or a lubricant; (2) the binder is selected from one or more of povidone, hydroxypropyl cellulose, hypromellose, and sodium carboxymethyl cellulose; (3) the binder is present in an amount of 1-5% by mass of the pharmaceutical composition; (4) the filler is selected from one or two of lactose, microcrystalline cellulose, mannitol, and pregelatinized starch; (5) the binder is hypromellose; (6) the filler is present in an amount of 40-90% by mass of the pharmaceutical composition; (7) the raw material of the pharmaceutical composition has a particle size D50 of 1 μm to 45 μm; (8) the composition contains 2.5-40 mg of the substance Z; and (9) the pharmaceutical composition is a tablet or a capsule.

3. The pharmaceutical composition of claim 2, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) the binder is present in an amount of 2-4.5% by mass of the pharmaceutical composition; (2) the disintegrant is selected from one or more of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch; (3) the disintegrant is present in an amount of 2-10% by mass of the pharmaceutical composition; (4) the filler is microcrystalline cellulose, lactose, and microcrystalline cellulose, microcrystalline cellulose and pregelatinized starch lactose, or mannitol and pregelatinized starch; (5) the filler is present in an amount of 60.5-87%; (6) the disintegrant is crospovidone or sodium carboxymethyl starch; (7) the disintegrant is present in an amount of 2-8% by mass of the pharmaceutical composition; (8) the glidant is selected from one or both of silicon dioxide and talc; (9) the glidant is present in an amount of 0-1% by mass of the pharmaceutical composition; (10) the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, calcium stearate, and sodium lauryl sulfate; (11) the lubricant is present in an amount of 0-1% by mass of the pharmaceutical composition; (12) the raw material of the pharmaceutical composition has a particle size D50 of 9.55 μm to 44.30 μm or 1.29 μm to 25.58 μm; (13) the composition contains 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, or 40 mg of the substance Z; (14) the pharmaceutical composition is a capsule; and (15) the pharmaceutical excipients consist of the binder, the disintegrant, the filler, and the glidant, or the pharmaceutical excipients consist of the binder, the disintegrant, the filler, and the lubricant, or the pharmaceutical excipients consist of the binder, the disintegrant, the filler, the glidant, and the lubricant.

4. The pharmaceutical composition according to claim 3, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) the hypromellose is hypromellose E5; (2) the binder is present in an amount of 3%; (3) the microcrystalline cellulose is microcrystalline cellulose PH101; (4) the lactose is lactose 200 mesh; (5) the filler is present in an amount of 68.5%, 70.5%, or 73.8%; (6) the cross-linked povidone is cross-linked povidone XL; (7) the disintegrant is present in an amount of 3%, 5% or 7% by weight of the pharmaceutical composition; (8) the glidant is colloidal silicon dioxide; (9) the glidant is present in an amount of, for example, 0.1%, 0.5% or 1% by weight of the pharmaceutical composition; (10) the lubricant is magnesium stearate; (11) the lubricant is present in an amount of 0.1%, 0.5% or 1% by weight of the pharmaceutical composition; (12) the starch is corn starch; (13) the raw material of the pharmaceutical composition has a particle size D50 of 5-30 μm, preferably 9.55 μm to 25.58 μm, for example 10 μm to 25 μm; (14) when the pharmaceutical composition is a tablet, the pharmaceutical composition comprises a lubricant; and (15) when the pharmaceutical composition is a capsule, the pharmaceutical composition comprises a glidant.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The pharmaceutical composition is any combination comprising, by weight: 1-5% binder, 40-90% filler, 2-10% disintegrant, 0-1% glidant and 0-1% lubricant; preferably, the binder is selected from one or more of povidone, hydroxypropyl cellulose, hypromellose and sodium carboxymethyl cellulose; the filler is selected from one or two of lactose, microcrystalline cellulose, mannitol and pregelatinized starch; the disintegrant is selected from one or more of cross-linked povidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; the glidant is selected from one or more of silicon dioxide and talc; the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, calcium stearate and sodium lauryl sulfate; preferably, the pharmaceutical composition is any combination comprising, by weight: 2-4.5% binder, 60.5-87% filler, 2-8% disintegrant, 0-1% glidant and 0-1% lubricant; preferably, the binder is hypromellose; the filler is microcrystalline cellulose, lactose and microcrystalline cellulose, microcrystalline cellulose and pregelatinized starch lactose or mannitol and pregelatinized starch; the disintegrant is cross-linked povidone or sodium carboxymethyl starch; the glidant is colloidal silicon dioxide; the lubricant is magnesium stearate.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is any combination comprising, by weight: Combination 1, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% microcrystalline cellulose PH101, 24.5% lactose 200 mesh, 3% hypromellose E5, 5% cross-linked povidone XL, 0.5% colloidal silicon dioxide and 1% magnesium stearate; Combination 2, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% microcrystalline cellulose PH101, 24.5% pregelatinized starch, 3% hypromellose E5, 5% cross-linked povidone XL, 0.5% colloidal silicon dioxide and 1% magnesium stearate; ​ Combination 3, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 73.83 of microcrystalline cellulose PH101, 3% of hypromellose E5, 5% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate; Combination 4, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% of microcrystalline cellulose PH101, 24.5% of lactose 200 mesh, 3% of hypromellose E5, 5% of sodium starch glycolate, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate; Combination 5, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% of microcrystalline cellulose PH101, 30% of lactose 200 mesh, 3% of hypromellose E5, 5% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate; Combination 6, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% of pregelatinized starch, 30% of mannitol, 3% of hypromellose E5, 5% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate; Combination 7, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 7% of hypromellose E5, 3% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate; Combination 8, 5% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 56% of microcrystalline cellulose PH101, 30% of lactose 200 mesh, 3% of hypromellose E5, 5% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 0.5% of magnesium stearate; Combination 9, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 3% of hypromellose E5, 7% of cross-linked polyplasdone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate; Combination 10, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 41.2% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 3% of hypromellose E5, 7% of cross-linked polyplasdone XL, 0.3% of colloidal silicon dioxide and 0.5% of magnesium stearate; Combination 11, 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 41.8% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 3% of hypromellose E5, 7% of cross-linked polyplasdone XL, 0.1% of colloidal silicon dioxide and 0.1% of magnesium stearate.

7. A process for the preparation of a pharmaceutical composition according to any one of claims 1-6, said process being process A or process B; said process A comprising the following steps: (1) mixing the substance Z, the binder, the disintegrant and the filler as claimed in any one of claims 1 to 6, wet granulation to obtain granules (wet granulation after completion of granulation, 24 mesh screen is used for wet sizing), drying (40-50°C) to obtain dry granules (24 mesh screen is used) ; (2) mixing the glidant and the lubricant as claimed in any one of claims 2 to 6 with the dry granules; (3) tabletting; the method B comprises the following steps: mixing, sieving and tabletting of the components of the pharmaceutical composition as claimed in any one of claims 1 to 6.

8. A pharmaceutical composition prepared by the method of claim 7.

9. Use of a substance W in the preparation of a URAT1 inhibitor, the substance W being a pharmaceutical composition as claimed in any one of claims 1 to 6 or a pharmaceutical composition prepared by the method of claim 8.

10. Use of a substance W in the preparation of a medicament, the substance W being a pharmaceutical composition as claimed in any one of claims 1 to 6 or a pharmaceutical composition prepared by the method of claim 8; the medicament being for the treatment and / or prevention of hyperuricemia or gout.

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