A pharmaceutical composition, its preparation method and use

Abstract

The application discloses a kind of pharmaceutical composition and its preparation method and purposes, and the present application is with (R) 2 (3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-indole nitrogen-8-yl) oxy) phenyl) 3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbon nitrile as active ingredient, add suitable filler, binder, disintegrating agent and lubricant, and control the proportion of each component, and the pharmaceutical composition is made.The preparation of the present application is prepared by the prescription and preparation method, and the process is stable, the quality is controllable, the disintegration time limit of drug is short, the dissolution is good, the content uniformity is good, and the bioavailability is high.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, and more specifically, relates to a pharmaceutical composition, its preparation method, and its use. Background Technology

[0002] Nonalcoholic fatty liver disease (NAFLD) is a common metabolic liver disease and the most common chronic liver disease in most parts of the world. It is a dynamic disease with a spectrum that includes nonalcoholic simple fatty liver disease (SFL), nonalcoholic steatohepatitis (NASH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). NASH is a severe, progressive form of NAFLD that often progresses to cirrhosis and increases the risk of HCC. NAFLD / NASH affects a large population and seriously impacts people's health.

[0003] Currently, medications for treating non-alcoholic fatty liver disease (NAFLD) mainly include insulin sensitizers, antioxidants, lipid-lowering drugs, GLP-1 receptor agonists, FXR agonists, and traditional Chinese medicine. In addition, some novel drugs, such as FGF21 analogs, are under research and development, and are expected to improve metabolism and hepatic steatosis.

[0004] Thyroid hormone receptor-β (THR-β) is highly expressed in the human liver and participates in regulating hepatic glucose and lipid metabolism and inflammation: 1) It is responsible for regulating the liver-damaged metabolic pathways in NAFLD and NASH, regulating lipid metabolism, reducing LDL cholesterol and triglycerides, improving insulin sensitivity, promoting liver regeneration, and reducing cell apoptosis; 2) It promotes fatty acid breakdown and stimulates mitochondria to reduce lipotoxicity and improve liver function, reducing liver fat; 3) It inhibits the transforming growth factor-β (TGF-β) signaling pathway, exerting anti-inflammatory and anti-fibrotic effects. Thyroid hormone receptor agonists are a class of compounds that can activate thyroid hormone receptors and are mainly used to regulate metabolism and energy balance. They show potential in the treatment of metabolic diseases such as hypothyroidism, obesity, and non-alcoholic fatty liver disease (NAFLD).

[0005] The formulation of pharmaceutical products using thyroid hormone receptor agonists as active ingredients requires comprehensive consideration of multiple aspects, including the physicochemical properties of the active ingredient, formulation design, manufacturing process, quality control, and cost, in order to ensure the quality, efficacy, and safety of the final product.

[0006] In view of this, the present invention is proposed. Summary of the Invention

[0007] The technical problem to be solved by this invention is to overcome at least one of the shortcomings of the prior art and provide a pharmaceutical composition, its preparation method, and its uses. This invention uses (R)-2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate as the active ingredient, employs suitable excipients, and controls the proportions of each component to prepare the pharmaceutical composition. The formulation and preparation method of this invention result in a stable process, controllable quality, short disintegration time, good dissolution, good content uniformity, and high bioavailability.

[0008] To solve the above-mentioned technical problems, the basic concept of the technical solution adopted by the present invention is as follows:

[0009] This invention provides a pharmaceutical composition comprising the following components in weight percentage:

[0010]

[0011] The structural formula of compound I is shown below:

[0012]

[0013] Compound I is (R)-2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate, a pale yellow, grayish-yellow to yellow powder. It is a thyroid hormone receptor β agonist. This compound has high agonistic activity and selectivity for thyroid hormone β receptors and can be used to treat metabolic diseases, especially those related to thyroid hormone receptors.

[0014] In vitro enzyme activity assays of thyroid receptor β (THR-β) revealed that compound I can promote the binding of THR-β to its coactivator peptide and also exhibits potential agonistic activity against THR-β. Cellular activity assays of thyroid receptor β (THR-β) showed that compound I has good agonistic activity against thyroid receptor β (THR-β). Pharmacokinetic evaluation in rats revealed that compound I exhibited low plasma concentrations and relatively high hepatic concentrations, indicating good hepatic targeting.

[0015] The pharmaceutical composition of the present invention uses compound I as the active ingredient, and adds suitable fillers, binders, disintegrants and lubricants, while controlling the proportions of each component, to prepare the pharmaceutical composition. The formulation of this pharmaceutical composition is appropriate and reasonable, and the amount of each functional excipient is appropriate, resulting in good dissolution, good content uniformity, high bioavailability and good stability of the final product.

[0016] In a further embodiment, the filler includes at least one of microcrystalline cellulose, mannitol, lactose, starch, and pregelatinized starch;

[0017] Preferably, the filler comprises mannitol, and the mannitol accounts for 26%-37% by mass in the pharmaceutical composition.

[0018] Preferably, the filler comprises microcrystalline cellulose, wherein the microcrystalline cellulose comprises 33%-59% by mass in the pharmaceutical composition.

[0019] In a further embodiment, the microcrystalline cellulose comprises microcrystalline cellulose PH101 and microcrystalline cellulose PH112, wherein the mass ratio of microcrystalline cellulose PH101 to microcrystalline cellulose PH112 is 1:(3.5-4.5).

[0020] In this invention, two different types of microcrystalline cellulose are used. Microcrystalline cellulose PH101 has a small particle size and poor flowability, and is used as an internal additive in wet granulation; microcrystalline cellulose PH112 has low moisture content and good flowability, and can be used externally. In this way, the overall moisture content of the material can be controlled, ensuring stable product quality.

[0021] In a further embodiment, the adhesive is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, methylcellulose, and ethylcellulose;

[0022] Preferably, the adhesive is hydroxypropyl methylcellulose.

[0023] In a further embodiment, the disintegrant is selected from at least one of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and croscarmellose.

[0024] Preferably, the disintegrant is croscarmellose sodium.

[0025] In a further embodiment, the lubricant is selected from at least one of magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycol, and sodium stearate fumarate.

[0026] Preferably, the lubricant is magnesium stearate.

[0027] In a further embodiment, the pharmaceutical composition of the present invention can be formulated into tablets, granules, or capsules.

[0028] As a preferred embodiment, the pharmaceutical composition of the present invention is a tablet with suitable hardness, short disintegration time, and good dissolution, which can ensure the release and absorption of the drug.

[0029] In a further embodiment, the pharmaceutical composition of the present invention further includes a gastric-soluble film-coating premix, which increases the weight by 3%-5% after coating.

[0030] The pharmaceutical composition is made into tablets, which can be 10mg or 50mg, meaning that each tablet contains 10mg or 50mg of compound I.

[0031] In this invention, a gastrointestinal film-coating premix is ​​used to coat the tablets, which can mask the bitterness of the product, improve patient compliance, and enhance stability.

[0032] In a preferred embodiment, the pharmaceutical composition is a tablet, comprising the following components by weight percentage:

[0033]

[0034] The drug composition using the above-mentioned prescription is a better option, with more reasonable component content, which can shorten the product's disintegration time, improve dissolution, enhance bioavailability, and improve product stability.

[0035] This invention provides a method for preparing the aforementioned pharmaceutical composition, wherein the pharmaceutical composition is a tablet, and the preparation method includes the following steps:

[0036] (1) Sift compound I, part of the filler and part of the disintegrant, and mix them;

[0037] (2) The adhesive is made into an adhesive solution and added to the mixture in (1) by atomization for granulation; then the granules are sized and dried to make dry granules;

[0038] (3) Mix the dry granules, another part of the filler, and the remaining disintegrant, then add the lubricant, mix them together, compress them into tablets, and coat them to obtain the product.

[0039] In a further step, in step (1), compound I, a portion of the filler, and a portion of the disintegrant are all passed through a 16-40 mesh sieve.

[0040] In a further embodiment, in step (2), after adding the adhesive solution to the mixture, the granulation time is 90s-120s;

[0041] Preferably, the granulation time is 100s-120s.

[0042] This invention reveals that granulation time affects particle properties, which in turn affects the dissolution of the final product. If the granulation time is too short, large particles will not be broken down and dispersed, slowing down the dissolution of the final product; conversely, if the granulation time is too long, over-granulation will also slow down the dissolution of the final product. This invention controls the granulation time to 90-120 seconds, resulting in a rapid product dissolution rate.

[0043] In a further embodiment, in step (1), the filler is a prescribed amount of mannitol and microcrystalline cellulose PH101; in step (3), the other filler is a prescribed amount of microcrystalline cellulose PH112.

[0044] In a further embodiment, the disintegrant added in step (1) accounts for 45%-55% of the total disintegrant.

[0045] In a further step, the atomization pressure in step (2) is 0.30–0.40 MPa;

[0046] Preferably, in step (2), the solid content of the adhesive solution is 5-7%.

[0047] As one approach, the adhesive solution is prepared as follows: Weigh purified water and pour it into a mixing tank, set the stirring speed to 200-800 rpm, slowly add hydroxypropyl methylcellulose while continuously stirring, and stir thoroughly to dissolve and prepare a solution with a solid content of 6%, which serves as the adhesive solution.

[0048] This invention provides the use of the pharmaceutical composition or the preparation method described herein in the preparation of a medicament for treating metabolic diseases;

[0049] Preferably, the metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic fatty liver disease, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic cholangioma.

[0050] By adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art.

[0051] 1. This invention uses a thyroid hormone receptor agonist, compound I, as the active ingredient, selects suitable excipients, and controls the proportions of each component to prepare a pharmaceutical composition. The formulation of this pharmaceutical composition is appropriate and reasonable, and the dosage of each functional excipient is suitable, resulting in good dissolution, good content uniformity, and high bioavailability of the final product.

[0052] The pharmaceutical composition of the present invention can be formulated into tablets with suitable hardness and short disintegration time, ensuring drug release and absorption.

[0053] 2. The preparation process of the pharmaceutical composition of the present invention controls the addition of some excipients internally and some externally, and uses two different types of microcrystalline cellulose for internal and external addition respectively, which helps to improve the compressibility and flowability of the materials, improve the stability of the process, and ensure that the prepared product meets the standard requirements. In addition, in the preparation process of the present invention, controlling the granulation time within a certain range can ensure a fast dissolution rate of the final product.

[0054] 3. The formulation and preparation method of this invention produce a stable process with controllable quality. The product content is 100.4% (10mg specification) and 96.9% (50mg specification); the total impurities of related substances are less than 0.05% (10mg specification) and less than 0.05% (50mg specification); the dissolution rate and content uniformity both meet the standard requirements.

[0055] The specific embodiments of the present invention will now be described in further detail with reference to the accompanying drawings. Attached Figure Description

[0056] The accompanying drawings, as part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention, but do not constitute an undue limitation of the invention. Obviously, the drawings described below are merely some embodiments, and those skilled in the art can obtain other drawings based on these drawings without creative effort. In the drawings:

[0057] Figure 1 This is a schematic diagram showing the in vitro dissolution results of the pharmaceutical compositions prepared in Examples 1 and 2 of this invention.

[0058] It should be noted that these accompanying drawings and textual descriptions are not intended to limit the scope of the invention in any way, but rather to illustrate the concept of the invention to those skilled in the art by referring to specific embodiments. Detailed Implementation

[0059] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments will be clearly and completely described below with reference to the accompanying drawings. The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0060] Unless otherwise specified, the detection methods used in the following examples, test cases and comparative examples can all be conventional methods.

[0061] In this invention, the preparation method of compound I ((R)-2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate) is as follows:

[0062]

[0063] Step 1: Compound 1 (5.0 g, 24.75 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) under nitrogen protection. Diisopropylaminolithium (27.23 mL, 54.45 mmol) was added dropwise at -78 °C. After reacting at -50 °C for 40 minutes, (S)-(-)-epoxypropylene (6.587 g) was added. After reacting at -50 °C for 30 minutes, the mixture was allowed to rise to room temperature and reacted for 16 hours. The reaction was quenched with 3 mL of saturated ammonium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 2.

[0064] Step 2: Dissolve compound 2 (2.38 g) in toluene (25.0 mL), add 2,6-dimethylpyridine (2 g), then add trifluoromethanesulfonic anhydride (2.5 g), react for 1 hour, add potassium carbonate (3.2 g), react at 75 °C for 2 hours, add 100 mL of water, extract with ethyl acetate (100 mL x 3), wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain compound 3.

[0065] Step 3: Compound 3 (1.18 g) was dissolved in tetrahydrofuran (24.0 mL), and n-butyllithium (5 mL, 1.5 M) was added dropwise at -60 °C. The mixture was stirred for 30 minutes, and borate ester (2.63 g) was added. The mixture was allowed to heat naturally for 5 hours. The reaction solution was poured into an ammonium chloride aqueous solution, extracted with ethyl acetate, dried, and concentrated. The concentrate was dissolved in a mixed solvent of 30 mL tetrahydrofuran and 4.0 mL water, and 30% hydrogen peroxide (4.0 mL) was added. The mixture was reacted at 25 °C for 16 hours, quenched with sodium sulfite aqueous solution, and then ethyl acetate (30 mL) was added. The mixture was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 5.

[0066] Step 4: Dissolve compound 5 (92.5 mg) in 2.0 mL of N,N-dimethylformamide, add 1,3-dichloro-2-fluoro-5-nitrobenzene (117.6 mg) and potassium carbonate (232.2 mg), react at 25 °C for 2 hours, concentrate under reduced pressure to remove solvent, and purify by column chromatography to obtain compound 6.

[0067] Step 5: Dissolve compound 6 (10g) in 200mL of dichloromethane, add palladium on carbon (0.5g), react in a hydrogen atmosphere for 6 hours, filter, and concentrate the filtrate to obtain compound 7.

[0068] Step 6: Dissolve compound 7 (150 mg) in a mixed solvent consisting of 3.2 mL acetic acid, 0.8 mL water and 0.4 mL concentrated hydrochloric acid. Add sodium nitrite (33.3 mg) at 0 °C. After reacting for 10 minutes, add sodium acetate (113.2 mg) and react for another 10 minutes. Then add N-cyanoaceturane (143.6 mg) and react at room temperature for 72 hours. Add 5 mL of water, filter, and dry to obtain compound 8.

[0069] Step 7: Dissolve compound 8 (180 mg) in 3.0 mL of N,N-dimethylacetamide, add potassium acetate (108.9 mg), react at 120 °C for 2 hours, concentrate under reduced pressure to remove the solvent, and purify to obtain compound I.

[0070] Example 1

[0071] (R)-2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate tablets (10mg / tablet)

[0072] Prescription ingredients:

[0073] Table 1

[0074]

[0075] Preparation method:

[0076] (1) Weighing and sieving of raw materials and excipients: Weigh each excipient and raw material. Pass all added materials through a 24-mesh sieve.

[0077] (2) Premixing, wet granulation, wet granulation

[0078] Preparation of adhesive solution: Add hydroxypropyl methylcellulose to purified water, stir to dissolve, and prepare an adhesive solution with a solid content of 6%.

[0079] Premix: Add the sieved internal mixture to the wet granulation pot, turn on the stirring and shearing, and mix for 10 minutes.

[0080] Wet granulation: Turn on the stirring and shearing functions, and add the binder solution to the wet granulation pot at a uniform rate via atomization (atomization pressure: 0.30~0.40MPa). After the slurry is added, continue granulation for 110 seconds.

[0081] Wet granulation: Granulating wet granules.

[0082] (3) Drying: Dry the wet granules until the moisture content is ≤2.0%.

[0083] (4) Dry granulation: granulating the dried granules.

[0084] (5) Initial mixing, total mixing

[0085] Initial mixing: Mix the dry granules, microcrystalline cellulose PH112 and croscarmellose sodium (added) together for 10 min.

[0086] Total mixing: Add magnesium stearate and continue mixing for 5 minutes.

[0087] (6) Pressing: Circular shallow concave die ∮6mm, hardness 40~80N.

[0088] (7) Coating

[0089] Preparation of coating solution: Prepare a coating solution with a solid content of approximately 12%.

[0090] Coating: Peristaltic pump speed 2.0~12.0rpm, inlet air temperature 50.0℃~60.0℃, coating weight gain 4.0%.

[0091] Example 2

[0092] (R)-2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate tablets (50mg / tablet)

[0093] Prescription ingredients:

[0094] Table 2

[0095]

[0096]

[0097] Preparation method:

[0098] (1) Weighing and sieving of raw materials and excipients: Weigh each excipient and raw material. Pass all added materials through a 24-mesh sieve.

[0099] (2) Premixing, wet granulation, wet granulation

[0100] Preparation of adhesive solution: Add hydroxypropyl methylcellulose to purified water, stir to dissolve, and prepare an adhesive solution with a solid content of 6%.

[0101] Premix: Add the sieved mixture to the wet granulation pot, turn on the stirring and shearing, and mix for 10 minutes.

[0102] Wet granulation: Turn on the stirring and shearing functions, and add the binder solution to the wet granulation pot at a uniform rate via atomization (atomization pressure: 0.30~0.40MPa). After the slurry is added, continue granulation for 110 seconds.

[0103] Wet granulation: Granulating wet granules.

[0104] (3) Drying: Dry the wet granules until the moisture content is ≤2.0%.

[0105] (4) Dry granulation: granulating the dried granules.

[0106] (5) Initial mixing, total mixing

[0107] Initial mixing: Mix the dry granules, microcrystalline cellulose PH112 and croscarmellose sodium (added) together for 10 min.

[0108] Total mixing: Add magnesium stearate and continue mixing for 5 minutes.

[0109] (6) Tableting: 15.6×7.6mm irregular die, hardness 100~150N.

[0110] (7) Coating

[0111] Preparation of coating solution: Prepare a coating solution with a solid content of approximately 12%.

[0112] Coating: Peristaltic pump speed 2.0~12.0rpm, inlet air temperature 50.0℃~60.0℃, coating weight gain 4.0%.

[0113] Examples 3-7

[0114] (R)-2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate tablets (50mg / tablet)

[0115] Prescription ingredients:

[0116] Compound I is (R)-2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate.

[0117] Table 3

[0118]

[0119]

[0120] Preparation method:

[0121] Refer to Example 2.

[0122] Comparative Example 1 - Comparative Example 2

[0123] The prescription components of Comparative Example 1 and Comparative Example 2 are shown below:

[0124] Table 4

[0125]

[0126]

[0127] The preparation method is the same as in Example 2.

[0128] Comparative Example 3

[0129] Comparison of key conditions changes in the preparation process

[0130] Prescription ingredients: Same as in Example 2.

[0131] Preparation method: During the preparation process, after wet granulation and slurry addition, granulation continues for 60 seconds. The remaining preparation steps are carried out according to the preparation method in Example 2.

[0132] Comparative Example 4

[0133] Prescription ingredients: Same as in Example 2.

[0134] Preparation method: During the preparation process, after wet granulation and slurry addition, granulation continues for 150 seconds. The remaining preparation steps are carried out according to the preparation method in Example 2.

[0135] Experimental Example 1

[0136] Content analysis method: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). Octadecylsilane-bonded silica gel was used as the stationary phase; 0.1% trifluoroacetic acid (adjusted to pH 2.5 with triethylamine)-acetonitrile (55:45) was used as the mobile phase; the detection wavelength was 254 nm; the content was calculated by peak area using the external standard method.

[0137] Related substances analysis method: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). Octadecylsilane-bonded silica gel was used as the stationary phase; 0.1% trifluoroacetic acid was used as mobile phase A; acetonitrile was used as mobile phase B, and linear gradient elution was performed; the detection wavelength was 254 nm; the test solution and control solution were accurately measured and injected separately into the liquid chromatograph, and the chromatograms were recorded. If impurity peaks are present in the chromatogram of the test solution, the peak area of ​​impurity 1 (RRT approximately 0.75) shall not exceed 0.2 times (0.2%) the area of ​​the main peak of the control solution, the area of ​​any other single impurity peak shall not exceed 0.5 times (0.5%) the area of ​​the main peak of the control solution, and the sum of the areas of all impurity peaks shall not exceed twice (2.0%) the area of ​​the main peak of the control solution.

[0138] The 10mg sample prepared in Example 1 was tested for various indicators, and the results are shown in the table below.

[0139] Table 5

[0140]

[0141]

[0142] Experimental Example 2

[0143] The methods for content analysis and related substance analysis are the same as those in Experimental Example 1.

[0144] The 50mg sample prepared in Example 2 was tested for various indicators, and the results are shown in the table below.

[0145] Table 6

[0146]

[0147]

[0148] Example 3: In vitro dissolution test. The dissolution method was: Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II for Determination of Dissolution and Release. The detection method was: Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512, High Performance Liquid Chromatography.

[0149] Detection medium: pH 1.0 + 0.1% SDS (SDS is sodium dodecyl sulfate).

[0150] The test results are shown in the table below:

[0151] Table 7

[0152]

[0153] Results analysis:

[0154] Figure 1This is a schematic diagram showing the in vitro dissolution results of the pharmaceutical compositions prepared in Examples 1 and 2 of this invention. From... Figure 1 As can be seen from the results in Table 7, the tablets of compound I prepared in Examples 1-7 of this invention have a fast dissolution rate and good dissolution degree.

[0155] Compared to Example 2, the amount of microcrystalline cellulose used in Comparative Example 1 was increased, while the amount of mannitol was decreased. The sample dissolution was slower. This indicates that increasing the amount of water-soluble excipients helps with the dissolution of this product.

[0156] Compared to Example 2, the amount of the disintegrant croscarmellose sodium in Comparative Example 2 was reduced. The sample dissolution was slower, indicating that the amount of disintegrant affects the dissolution of this product.

[0157] Compared with Example 2, in Comparative Example 3, the granulation time was too short, resulting in large particles not being broken down and dispersed, which slowed down the dissolution of the product.

[0158] Compared with Example 2, the granulation time in Comparative Example 4 was too long, resulting in over-granulation of the particles and slower dissolution of the product.

[0159] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, According to the mass percentage, it includes the following components: The structural formula of compound I is shown below:

2. The pharmaceutical composition according to claim 1, characterized in that, The filler includes at least one of microcrystalline cellulose, mannitol, lactose, starch, and pregelatinized starch; Preferably, the filler comprises mannitol, and the mannitol has a mass percentage of 26%-37% in the pharmaceutical composition; Preferably, the filler comprises microcrystalline cellulose, wherein the microcrystalline cellulose comprises 33%-59% by mass in the pharmaceutical composition; Preferably, the microcrystalline cellulose includes microcrystalline cellulose PH101 and microcrystalline cellulose PH112, and the mass ratio of microcrystalline cellulose PH101 to microcrystalline cellulose PH112 is 1:(3.5-4.5).

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The adhesive is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, methylcellulose, and ethyl cellulose; Preferably, the adhesive is hydroxypropyl methylcellulose.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The disintegrant is selected from at least one of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and croscarmellose. Preferably, the disintegrant is croscarmellose sodium.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The lubricant is selected from at least one of magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycol, and sodium stearate fumarate; Preferably, the lubricant is magnesium stearate.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The pharmaceutical composition also includes a gastrointestinal film-coating premix, which results in a 3-5% weight gain after coating.

7. A method for preparing a pharmaceutical composition according to any one of claims 1-6, characterized in that, The pharmaceutical composition is a tablet, and the preparation method includes the following steps: (1) Sift compound I, part of the filler and part of the disintegrant, and mix them; (2) The adhesive is made into an adhesive solution and added to the mixture in (1) by atomization for granulation; then the granules are sized and dried to make dry granules; (3) Mix the dry granules, another part of the filler, and the remaining disintegrant, then add the lubricant, mix them together, compress them into tablets, and coat them to obtain the product.

8. The preparation method according to claim 7, characterized in that, In step (2), after the adhesive is added to the mixture, the granulation time is 90s-120s; Preferably, the granulation time is 100s-120s.

9. The preparation method according to claim 7, characterized in that, In step (1), the filler is a prescribed amount of mannitol and microcrystalline cellulose PH101; in step (3), the other filler is a prescribed amount of microcrystalline cellulose PH112. Preferably, the partial disintegrant added in step (1) accounts for 45%-55% of the total disintegrant.

10. Use of a pharmaceutical composition according to any one of claims 1-6 or a preparation method according to any one of claims 7-9 in the preparation of a medicament for treating metabolic diseases; Preferably, the metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic fatty liver disease, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic cholangioma.

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