Capsule or solid formulation and use thereof

Abstract

A capsule or a solid formulation and use thereof. Provided is a capsule, comprising a substance Z and pharmaceutical excipients. The substance Z is a compound represented by formula I or a pharmaceutically acceptable salt thereof. The content of the compound represented by formula I accounts for at least 5% of the mass of the capsule. The pharmaceutical excipients comprise a binder, a disintegrant, and a filler. The capsule or the solid formulation 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

Capsule or solid preparation and use thereof

[0001] This application claims priority to Chinese patent application 2024104778523, 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 capsule or solid preparation and use thereof. 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 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 capsule or a solid preparation and use thereof. The capsule or solid preparation provided by the present application has stable product properties; the capsule or solid preparation shows a low effective dose in clinical application of gout and hyperuricemia, and has a more obvious effect of reducing blood uric acid than commercial products.

[0007] The present application provides a capsule 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 content of the compound as shown in formula I is at least 5% of the mass of the capsule; the pharmaceutically acceptable excipient comprises a binder, a disintegrant and a filler;

[0008] In an embodiment, the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch, sucrose and pregelatinized starch.

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

[0010] In an embodiment, the binder is selected from one or more of povidone, hydroxypropyl cellulose, hypromellose and sodium carboxymethyl cellulose, for example hypromellose.

[0011] In an embodiment, the hypromellose is hypromellose E5.

[0012] In an embodiment, the content of the binder is 1-5% of the mass of the capsule, preferably 2-4.5%, for example 3%.

[0013] In an embodiment, the filler is selected from one or more 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.

[0014] In an embodiment, the starch is corn starch.

[0015] In an embodiment, the microcrystalline cellulose is microcrystalline cellulose PH101.

[0016] In an embodiment, the lactose is lactose 200 mesh.

[0017] In one aspect, the filler can be present in an amount of 40-90% by weight of the capsule, preferably 60.5-87%, for example 68.5%, 70.5% or 73.8%.

[0018] In one aspect, the disintegrant can be selected from one or more of crospovidone, crosscarmellose sodium, low-substituted hydroxypropylcellulose and sodium carboxymethyl starch; for example crospovidone or sodium carboxymethyl starch.

[0019] In one aspect, the crospovidone can be crospovidone XL.

[0020] In one aspect, the disintegrant can be present in an amount of 2-10% by weight of the capsule, preferably 2-8%, for example 3%, 5% or 7%.

[0021] In one aspect, the glidant can be selected from one or both of silicon dioxide and talc, for example colloidal silicon dioxide.

[0022] In one aspect, the glidant can be present in an amount of 0-1% by weight of the capsule, for example 0.5%, 0.3% or 0.1%.

[0023] In one aspect, the lubricant can be selected from one or more of magnesium stearate, sodium stearyl fumarate, calcium stearate and sodium lauryl sulfate, for example magnesium stearate.

[0024] In one aspect, the lubricant can be present in an amount of 0-1% by weight of the capsule, for example 0.1%, 0.5% or 1%.

[0025] In one aspect, the granules of the capsule can have a particle size D50 of 1-45 μm, preferably 9.55-44.30 μm or 1.29-25.58 μm, more preferably 2-30 μm, further preferably 5-30 μm, yet further preferably 9.55-25.58 μm, for example 10-25 μm.

[0026] In one aspect, the composition comprises 2.5-40 mg of the substance Z, for example 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg or 40 mg of the substance Z.

[0027] In one aspect, the capsule comprises 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, hypromellose, hypromellose acetate succinate, 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 crospovidone, croscarmellose sodium, low-substituted hypromellose, and sodium carboxymethyl starch; the glidant is selected from one or more of silicon dioxide and talc; and the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, calcium stearate, and sodium lauryl sulfate.

[0028] In one aspect, the capsule comprises by weight:

[0029] 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 crospovidone or sodium carboxymethyl starch; the glidant is colloidal silicon dioxide; and the lubricant is magnesium stearate.

[0030] In one aspect, the capsule comprises any combination of by weight:

[0031] 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;

[0032] 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% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;

[0033] Combination 3, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 73.83 microcrystalline cellulose PH101, 3% hypromellose E5, 5% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;

[0034] 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;

[0035] 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 crospovidone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0036] 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 crospovidone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0037] 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 crospovidone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0038] 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 crospovidone XL, 0.5% of colloidal silicon dioxide and 0.5% of magnesium stearate;

[0039] 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 crospovidone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate;

[0040] 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 crospovidone XL, 0.3% of colloidal silicon dioxide and 0.5% of magnesium stearate;

[0041] 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 crospovidone XL, 0.1% of colloidal silicon dioxide and 0.1% of magnesium stearate.

[0042] In the present application, the pharmaceutical excipient consists of the binder, the disintegrant, the filler and the glidant, or the pharmaceutical excipient consists of the binder, the disintegrant, the filler and the lubricant, or the pharmaceutical excipient consists of the binder, the disintegrant, the filler, the glidant and the lubricant.

[0043] In the present application, the content of each excipient in the capsule or the content of each excipient is the mass of the capsule, and the content of "capsule" in the capsule mass does not include the shell of the capsule.

[0044] In a certain aspect, the capsule is prepared by the following method:

[0045] (1) mixing the substance Z, which is a compound of formula I or a pharmaceutically acceptable salt thereof, the filler and 40-60 (e.g. 50%) of the disintegrant;

[0046] (2) spraying the binder solution (5% aqueous solution) into the mixture in step 1, controlling the atomization pressure to be greater than 1 bar to uniformly atomize the solution;

[0047] (3) drying the material in step 2 (40-50°C), controlling the final moisture content to be less than 3%; the dried granules are sieved (24 mesh screen);

[0048] (4) mixing the dried granules in step 3, the glidant, the glidant and the remaining disintegrant for 10 minutes;

[0049] (5) filling the mixture in step 4 into capsules.

[0050] The present application provides a solid preparation comprising a substance Z and a pharmaceutical excipient; the substance Z is a compound of formula I or a pharmaceutically acceptable salt thereof; the pharmaceutical excipient comprises a binder, a disintegrant and a filler; the content of the compound of formula I accounts for at least 5% of the mass of the solid preparation; the raw material particle size D50 of the solid preparation is 5-30 μm;

[0051] In a certain aspect, the content and definition of each component of the solid preparation are as described above for the capsule.

[0052] In a certain aspect, the solid preparation can be a tablet or a capsule.

[0053] In a certain aspect, the solid preparation is prepared by the following method: the preparation method is method A or method B;

[0054] The method A comprises the following steps:

[0055] (1) mixing the substance Z, the binder, the disintegrant and the filler as described above, obtaining granules by wet granulation (after granulation, wet granulation is performed through a 24-mesh screen); drying (40-50°C) to obtain dry granules (through a 24-mesh screen);

[0056] (2) mixing the aforementioned glidant and lubricant with the dry granules;

[0057] (3) tabletting;

[0058] The method B comprises the following steps:

[0059] Mixing, sieving and tabletting the components of the solid preparation as described above.

[0060] The present application also provides a use of a substance W in the preparation of a URAT1 inhibitor, the substance W being the aforementioned capsule or solid preparation.

[0061] The present application also provides a use of a substance W in the preparation of a medicament, the substance W being the aforementioned capsule or solid preparation; the medicament being used for the treatment and / or prevention of hyperuricemia or gout.

[0062] The present application also provides a method for the treatment and / or prevention of hyperuricemia or gout, the method comprising administering to a subject an effective amount of a substance W; the substance W being the aforementioned capsule or solid preparation; the medicament being used for the treatment and / or prevention of hyperuricemia or gout.

[0063] The present application also provides a substance W for the treatment and / or prevention of hyperuricemia or gout, the substance W being the aforementioned capsule or solid preparation.

[0064] The present application also provides a method for preparing a capsule, the method comprising the following steps:

[0065] (1) mixing the substance Z being a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, the filler and 40%-60 (e.g. 50%) of the disintegrant;

[0066] (2) spraying the binder solution into the mixture in step 1, controlling the atomization pressure to be greater than 1 bar to uniformly atomize the solution;

[0067] (3) drying (40-50°C) the material in step 2, controlling the final moisture content to be less than 3%; the dried granules are sieved (24-mesh screen);

[0068] (4) mixing the dry granules in step 3, the glidant, the glidant and the remaining disintegrant for 10 min;

[0069] (5) filling the mixture in step 4 into capsules.

[0070] The above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present application without departing from the common knowledge in the art.

[0071] The reagents and raw materials used in the present application are commercially available.

[0072] The positive progress effect of the present application is that the present application provides a URAT1-containing capsule or solid preparation, a preparation method and application thereof. The preparation contains a URAT1 inhibitor and a pharmaceutically acceptable excipient. By controlling the particle size of the URAT1 inhibitor raw material, the amount of specific raw materials and the addition process of the binder, the stability of the pharmaceutical properties of the preparation is ensured. Compared with commercially available products, the composition provided by the present application shows low onset dose, safety and efficiency in the clinical application of gout and hyperuricemia. BRIEF DESCRIPTION OF DRAWINGS

[0073] Figure 1 is the results of the clinical study of safety and effectiveness of Example 9. DETAILED DESCRIPTION

[0074] 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 without specific conditions are selected according to conventional methods and conditions, or according to the instructions of the commodity.

[0075] The structure of the URAT1 inhibitor used in the examples is

[0076] The impurity or related substance detection method in the present application is as follows:

[0077] The detection and analysis method is as follows:

[0078] Related substances were determined by high performance liquid chromatography (general rule 0512).

[0079] Solvent Acetonitrile-water (50:50).

[0080] Test sample solution Randomly take 10 samples, accurately weigh, and finely grind with a marbled mortar. Accurately weigh the fine powder, place it in a volumetric flask, dilute to the mark with a 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 revolutions per minute for 10 minutes. Take the supernatant;

[0081] Control solution Take an appropriate amount of control, accurately weigh, dissolve and dilute to prepare a solution of a specific concentration.

[0082] 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 performed according to the following table; the detection wavelength was 250 nm; the column temperature was 40°C; the injection volume was 10 μl.

[0083] Determination method: accurately measure the test sample solution and the control sample solution, inject into the liquid chromatograph respectively, and record the chromatogram. Limit: calculate the content of each impurity and the total impurities by peak area according to the external standard method.

[0084] Example 1

[0085] According to the effective dose and toxicological safety dose of the API in multiple animal models, the specification of the product is designed to be in the range of 2.5 mg to 40 mg, and the dosage form is preliminarily designed to be 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 of the present application is illustrated by taking the 25 mg specification preparation as an example.

[0086] Preparation method of composition A:

[0087] a. premix the API and excipients;

[0088] b. wet granulate the mixed material;

[0089] c. after the granulation is completed, pass the wet granules through a 24 mesh sieve for wet sizing;

[0090] d. dry the wet granules at 40°C to 50°C, and size the dried granules through a 24 mesh sieve;

[0091] e. mix colloidal silicon dioxide, magnesium stearate and the dry granules;

[0092] f. tablet compression;

[0093] Preparation method of composition B, composition C, composition D and composition E:

[0094] a. premix the API and excipients;

[0095] b. pass the mixed material through a 24 mesh sieve;

[0096] c. tablet compression;

[0097] In this example, the prescription of composition A adopts wet granulation, and the compressibility is good, the tablet weight is stable, and there is no sticking and collision, etc.

[0098] Example 2

[0099] Raw material particle size investigation: 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 embodiment, 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 results detected by the Malvern laser particle size analyzer are as follows:

[0100] The formulations of Composition I, Composition J, Composition K and Composition L are consistent with the preparation method, and the prescription amounts are shown in the table below.

[0101] Preparation method:

[0102] a. Pre-mixing of raw materials and excipients;

[0103] b. Wet granulation of the mixed materials;

[0104] c. Wet granulation after granulation;

[0105] d. Drying and granulating the wet granules;

[0106] e. Mixing colloidal silicon dioxide, magnesium stearate and dry granules;

[0107] f. Tabletting;

[0108] The compositions in this embodiment were determined by dissolution and release determination method (Chinese Pharmacopoeia General 0931 Second Method). The dissolution conditions were as follows: 900 ml of phosphate buffer solution (pH 6.8) (dissolve 8.96 g of sodium hydroxide and 68.05 g of potassium dihydrogen phosphate in 10 L of pure water, mix well, and adjust the pH to 6.8 with phosphoric acid or sodium hydroxide) was used as the dissolution medium, the rotation speed was 50 revolutions per minute, and the samples were taken at 5, 10, 15, 20, 30, 45, 60 and 90 minutes, respectively. The dissolution results are shown in the table below.

[0109] The results show that due to the good water solubility of the raw materials, there is no significant difference in the dissolution of the raw material particle size D50 in the range of 1.29 μm to 44.30 μm, and the dissolution at 15 min is greater than 85%. For in vitro dissolution, the particle size does not need to be strictly controlled;

[0110] Stability: the compositions were placed at 60°C / 75% RH for 7 days under open conditions, and the related substance conditions are shown in the table below.

[0111] The stability data show that when the raw material particle size D50 in Composition L is 1.29 μm, the impurity RRT 0.84 increases significantly. Based on the control of impurities, the raw material particle size D50 should be controlled in the range of 9.55 μm to 44.30 μm.

[0112] Bioavailability: The compositions were subjected to oral bioavailability studies in dogs (n=6) respectively. Each dog was administered a single intravenous injection of 1 mg / kg, and compositions F, G, H, and I were administered one tablet (2 mg / kg) respectively in turn. The blood concentration was detected 24 hours after administration. The oral bioavailability of compositions with different raw material particle sizes was determined.

[0113] Oral bioavailability = AUC of oral administration 0-last AUC of injection administration 0-last * Injection dose / oral dose * 100%

[0114] The bioavailability results of different raw material particle sizes show that the bioavailability of compositions G, H, and I is equivalent, the raw material particle size D50 is 1.29 μm-25.58 μm, and the bioavailability is 44.0%-48.7%, and the results are equivalent. The raw material D50 of composition I is 44.30 μm, and the bioavailability is significantly reduced to only 34.8%.

[0115] Existing research data shows that when the raw material particle size D50 is 9.55 μm-25.58 μm, the particle size does not affect the in vitro dissolution, in vivo bioavailability, and stability of the product itself.

[0116] Example 3

[0117] API prescription ratio investigation: Using the same batch of API, the prescription ratio was designed to be 2.5%, 5%, and 20% respectively, and compositions M, N, and O were prepared. The preparation method was consistent with that described in Example 3, and the prescription information is shown in the table below.

[0118] The compositions were placed in an open container at 60°C / 75% RH for 7 days, and the related substance conditions are shown in the table below.

[0119] The results show that compared with composition M, the increase in impurity RRT 0.83 / 0.84 is significantly reduced after increasing the proportion of raw materials in compositions N and O. Combined with the effect of raw material particle size on impurities in Example 2, 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 raw material prescription ratio is ≥5%, and 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.

[0120] Example 4:

[0121] Based on the research conclusions of Examples 1-3, it has been confirmed that the process, particle size of raw materials, 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 Examples 1-4, in order 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 contains the prescription ratio 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 hypromellose; (e) 0-1% by weight of magnesium stearate; the prescription ratio range and preferred range of the excipients are shown in the following table.

[0122] The preparation method of this example is as follows:

[0123] 1. Mix the URAT1 inhibitor, microcrystalline cellulose, lactose, and crospovidone.

[0124] 2. Spray the hypromellose solution into the mixture in step 1.

[0125] 3. Dry and granulate the material in step 2.

[0126] 4. Mix the dry granules in step 3, colloidal silicon dioxide, magnesium stearate, and additional crospovidone.

[0127] 5. Press the mixture in step 4 into tablets of appropriate hardness.

[0128] 6. Coat the tablets in step 5 with coating material of the desired color.

[0129] 7. Optionally, fill the mixture in step 4 into a capsule shell.

[0130] Example 5:

[0131] The composition containing the URAT1 inhibitor described in this example contains the prescription ratio 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 hypromellose; (e) 0-1% by weight of magnesium stearate; the specific prescription ratio is shown in the following table.

[0132] The preparation method of this example is as follows:

[0133] 1. Mix the URAT1 inhibitor, microcrystalline cellulose, lactose, and part of the crospovidone for 20 min.

[0134] 2. Hydroxypropyl methylcellulose is prepared into a solution and then sprayed into the mixture in step 1, with the atomization pressure controlled to be greater than 1 bar;

[0135] 3. The material in step 2 is dried at 40-50°C, with the final moisture controlled to be less than 3%; the dried granules are sized using a 24-mesh screen;

[0136] 4. The dried granules in step 3, colloidal silicon dioxide, magnesium stearate, and the remaining crospovidone are mixed for 10 min;

[0137] 5. The mixture in step 4 is compressed into tablets, with the tablet hardness controlled to be in the range of 30-120 N;

[0138] 6. The tablets in step 5 are coated using a coating material of the desired color, with the coating weight gain controlled to be in the range of 2%-5%.

[0139] Example 6:

[0140] The compositions P, Q, R, and S of Example 5 are measured according to the dissolution and release determination method (Chinese Pharmacopoeia General 0931, second method).

[0141] Dissolution conditions: 900 ml of phosphate buffer solution (pH 6.8) (take sodium hydroxide 8.96 g and potassium dihydrogen phosphate 68.05 g in 10 L of pure water, dissolve completely, mix uniformly, adjust the pH to 6.8 with phosphoric acid or sodium hydroxide, and obtain) is used as the dissolution medium, the rotation speed is 50 revolutions per minute, and samples are taken at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, respectively. The dissolution results are shown in the table below. Within the specific prescription ratio range, the compositions are all fast-dissolving, with more than 85% dissolved at 15 min.

[0142] Example 7:

[0143] Investigation of excipients

[0144] After studying the main increased impurity (RRT about 0.84) in Examples 2 and 3, the inventors determined that it is a hydrolysis impurity. Through mechanism analysis, the raw material is more likely to degrade into impurities under the condition of an acidic / alkaline excipient environment. The inventors have fully optimized the prescription amount of the acidic / alkaline materials silicon dioxide and magnesium stearate in the composition prescription, and the impurity increase has been controlled.

[0145] The preparation process of the above composition is as follows:

[0146] 1. The URAT1 inhibitor, microcrystalline cellulose, lactose, and part of the crospovidone are mixed for 20 min;

[0147] 2. Hydroxypropyl methylcellulose is prepared into a solution and then sprayed into the mixture in step 1, with the atomization pressure controlled to be greater than 1 bar to uniformly atomize the solution;

[0148] 3. The material in step 2 is dried at 40-50°C, with the terminal moisture controlled to be less than 3%; the dried granules are sized using a 24-mesh screen;

[0149] 4. The dried granules in step 3, colloidal silicon dioxide, magnesium stearate, and the remaining crospovidone are mixed for 10 min;

[0150] 5. The mixture in step 4 is compressed into tablets, with the tablet hardness controlled to be in the range of 30-120 N;

[0151] 6. The tablets in step 5 are coated using a coating material of the desired color, with the coating weight gain controlled to be in the range of 2-5%.

[0152] The long-term test is performed 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 results of the present stage of research show that the amount of silicon dioxide and magnesium stearate is small, and the growth rate is slow; the impurities of compositions S, T, and U are all lower than the preset limit of 0.5% after 12 months of long-term testing, and the compositions have good stability.

[0153] Example 8:

[0154] Investigation of the dosage form

[0155] The dosage form of the present composition is designed as a conventional solid dosage form, and in combination with the production conditions and the needs of clinical medication, the present composition can be designed as tablets or capsules. On the basis of the preparation process of composition V in Example 7, a capsule dosage form is prepared. The specific preparation process is as follows:

[0156] 1. The URAT1 inhibitor, microcrystalline cellulose, lactose, and 50% crospovidone are mixed for 20 min;

[0157] 2. Hydroxypropyl methylcellulose is prepared into a 5% aqueous solution and then sprayed into the mixture in step 1, with the atomization pressure controlled to be greater than 1 bar to uniformly atomize the solution;

[0158] 3. The material in step 2 is dried at 40-50°C, with the terminal moisture controlled to be less than 3%; the dried granules are sized using a 24-mesh screen;

[0159] 4. The dried granules in step 3, colloidal silicon dioxide, magnesium stearate, and the remaining crospovidone are mixed for 10 min;

[0160] 5. The mixture in step 4 is filled into capsules, with the capsule fill weight difference controlled to be less than 7.5%.

[0161] The impurity growth of the comparative composition V tablets and capsules in different dosage forms is all lower than the preset limit of 0.5%; according to the impurity levels of the tablets and capsules in the long-term 12-month period, it is inferred that both dosage forms can meet the stability requirements in 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.

[0162] Example 9:

[0163] A clinical study for evaluating the safety and effectiveness of the composition P of Example 6 in adult patients with hyperuricemia with or without gout was carried out, using a randomized, double-blind, parallel, positive drug / placebo control design. Hyperuricemia (with or without gout) patients were enrolled in the study and administered for 4 consecutive weeks. The results of the study are shown in the following table and Figure 1.

[0164] Safety analysis: In the composition (10 mg BID), benzbromarone group and placebo group, the study found that the highest incidence was mainly increased creatinine and gout, 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.

[0165] Effectiveness analysis: In the treatment of gout / hyperuricemia, external guidelines recommend that for the presence of tophi, chronic gouty arthritis or frequent gouty arthritis attacks, the target of uric acid reduction is <5 mg / dl until the tophi are completely dissolved and the symptoms of frequent arthritis attacks are improved. The study found that in subjects with baseline serum uric acid ≥9 mg / dL, the compliance rate of serum uric acid of 6 mg / dl was about 25% for benzbromarone at 4 weeks, and the compliance rate of the composition was 53.3%, which was much higher than that of the benzbromarone group; the compliance rate of 4 / 5 mg / dl showed a significant advantage of the composition over the benzbromarone group. The compliance rate of 4 / 5 mg / dl represents a deeper remission, which has great clinical significance and advantage for the treatment of complex / refractory gout or gout combined with underlying diseases.

[0166] 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 feature disclosed in the present application or any new combination, as well as any new method or process steps or new combination disclosed. Any equivalent replacement or change according to the technical solutions and inventive concepts of the present application within the technical scope disclosed in the present application falls within the protection scope of the present application.

Claims

1. A capsule 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 content of the compound as shown in Formula I is at least 5% of the mass of the capsule; the pharmaceutically acceptable excipient comprises a binder, a disintegrant, and a filler; 2. The capsule of claim 1, wherein The capsule meets one or more of the following conditions: (1) The capsule 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 weight of the capsule; (4) The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch, sucrose, and pregelatinized starch; preferably, 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 weight of the capsule; (7) The capsule has a raw material particle size D50 of 1-45 μm; and (8) The composition comprises 2.5-40 mg of the substance Z.

3. The capsule of claim 2, wherein The capsule meets one or more of the following conditions: (1) The binder is present in an amount of 2-4.5% by weight of the capsule; (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 weight of the capsule; (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 weight of the capsule; (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 weight of the capsule; (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 weight of the capsule; (12) The capsule has a raw material particle size D50 of 9.55-44.30 μm or 1.29-25.58 μm; and (13) The composition comprises 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, or 40 mg of the substance Z.

4. The capsule of claim 3, wherein The capsule meets 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 crospovidone is crospovidone XL; (7) The disintegrant is present in an amount of 3%, 5%, or 7% by weight of the capsule; (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 capsule; (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 capsule; (12) the starch is corn starch; (13) the raw material of the capsule has a particle size D50 of 5-30 μm, preferably 9.55 μm-25.58 μm, for example 10 μm-25 μm; and (14) the pharmaceutical excipient consists of the binder, the disintegrant, the filler and the glidant, or, the pharmaceutical excipient consists of the binder, the disintegrant, the filler and the lubricant, or the pharmaceutical excipient consists of the binder, the disintegrant, the filler, the glidant and the lubricant.

5. The capsule according to any of claims 1 to 4, wherein The capsule comprises, by weight, 1-5% of a binder, 40-90% of a filler, 2-10% of a disintegrant, 0-1% of a glidant and 0-1% of a 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 crospovidone, croscarmellose sodium, 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 capsule comprises, by weight, 2-4.5% of a binder, 60.5-87% of a filler, 2-8% of a disintegrant, 0-1% of a glidant and 0-1% of a 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 crospovidone or sodium carboxymethyl starch; the glidant is colloidal silicon dioxide; the lubricant is magnesium stearate.

6. The capsule of claim 1, wherein The capsule comprises, by weight, any combination of: Combination 1, 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 crospovidone XL, 0.5% of colloidal silicon dioxide and 1% of magnesium stearate; Combination 2, 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% of microcrystalline cellulose PH101, 24.5% of pregelatinized starch, 3% of hypromellose E5, 5% of crospovidone XL, 0.5% of colloidal silicon dioxide and 1% of 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 crospovidone 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 crospovidone 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 crospovidone 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 crospovidone 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 crospovidone 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 crospovidone 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 crospovidone 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 crospovidone XL, 0.1% of colloidal silicon dioxide and 0.1% of magnesium stearate.

7. The capsule of claim 1, wherein The capsule is prepared by the following method: (1) mixing the substance Z which is the compound of Formula I or a pharmaceutically acceptable salt thereof, the filler and 40%-60 (for example 50%) of the deagglomeration agent; (2) spraying the binder solution (5% aqueous solution) into the mixture in step 1, controlling the atomization pressure to be greater than 1 bar to uniformly atomize the solution; (3) drying the material in step 2 (40-50°C), controlling the final moisture to be less than 3%; the dried granules are sieved (24 mesh screen); (4) mixing the dried granules in step 3, the glidant, the glidant and the remaining deagglomeration agent for 10 min; (5) filling the mixture in step 4 into a capsule.

8. A solid preparation 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 is at least 5% by mass of the solid preparation; and the raw material particle size D50 of the solid preparation is 5-30 μm. Preferably, the content and definition of each component of the solid preparation are as described in any one of claims 1-7 for the capsule; and / or, the solid preparation is a tablet or a capsule; More preferably, the solid preparation is prepared by a method A or a method B; The method A comprises the following steps: (1) mixing the substance Z, the binder, the disintegrant and the filler, and obtaining granules by wet granulation (wet granulation is completed by passing through a 24 mesh screen for wet granulation); drying (40-50°C) to obtain dry granules (passing through a 24 mesh screen); (2) mixing the glidant and the lubricant with the dry granules; (3) tabletting; The method B comprises the following steps: mixing, sieving and tabletting each component of the solid preparation.

9. Use of a substance W in the preparation of a medicament, the substance W being the capsule of any one of claims 1-7 or the solid preparation of claim 8; the medicament being used for the treatment and / or prevention of hyperuricemia or gout.

10. Use of a substance W in the preparation of a URAT1 inhibitor, the substance W being the capsule of any one of claims 1-7 or the solid preparation of claim 8.

Images