Pharmaceutical formulation, coated pharmaceutical formulation, method for preparing same, and use thereof

Abstract

The present invention relates to a pharmaceutical formulation, a coated pharmaceutical formulation, a method for preparing same, and use thereof. The pharmaceutical formulation comprises a compound of formula I, or a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof, a filler, a disintegrant, and a lubricant. On the basis of the total mass of the pharmaceutical formulation, the mass percentage of the compound of formula I is 1% to 50%, the mass percentage of the filler is 60% to 90%, the mass percentage of the disintegrant is 1% to 10%, and the mass percentage of the lubricant is 1% to 10%. The formulation is used for preparing a medicament for treating and / or preventing GLP-1R-related diseases. The present invention achieves a better administration form by mixing the active ingredient with excipients and formulating, and provides the formulation with excellent in vivo absorption.

Description

Pharmaceutical preparations, coated pharmaceutical preparations, preparation methods and applications

[0001] This application claims priority to Chinese patent application 2024119174579, filed on 2024 / 12 / 24. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference.

[0002] This application claims priority to Chinese patent application 202511851372X, filed on 2025 / 12 / 9. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0003] This invention relates to a pharmaceutical preparation, a coated pharmaceutical preparation, a preparation method thereon, and its application. Background Technology

[0004] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxacyclobut-2-aminomethyl)-1H-benzis[d]imidazole-6-carboxylic acid is a GLP-1R agonist used to treat metabolic-related diseases such as diabetes, obesity, non-alcoholic fatty liver disease, and hypertension.

[0005] Glucagon-like peptide-1 (GLP-1) is an endogenous incretin that stimulates insulin release. It binds to and activates the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor (GPCR) class B family, to exert its regulatory function. GLP-1 receptor agonists (GLP-1RAs) are synthetic drugs designed to mimic the physiological functions of GLP-1. After binding to GLP-1R in pancreatic cells, they glucose-dependently stimulate insulin synthesis and secretion; reduce glucagon release; act on GLP-1R in the central nervous system, thereby reducing food intake; increase energy expenditure by promoting thermogenesis in brown adipose tissue and catabolism in white adipose tissue; and delay gastric emptying. GLP-1RAs are clinically indicated for adult patients with type 2 diabetes mellitus (T2DM), exhibiting significant hypoglycemic effects while also reducing weight, systolic blood pressure, and improving dyslipidemia. GLP-1RAs can be used alone or in combination with other hypoglycemic agents. Multiple clinical studies have shown that adding GLP-1RAs is effective after treatment with an oral hypoglycemic agent (metformin, sulfonylureas) has failed.

[0006] Example 3 of patent application CN114591308 A discloses the preparation of compound (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, the structure of which is as follows:

[0007] Patent application CN118812522A discloses a monohydrate of compound II, the structure of which is as follows:

[0008] Among them, the compound of formula II has been confirmed to be effective and safe in the treatment of diabetes and obesity through preclinical and clinical trials. Summary of the Invention

[0009] This invention addresses the technical problems existing in the prior art by providing a pharmaceutical formulation, a coated pharmaceutical formulation, a preparation method, and its application. This invention achieves a better form of drug delivery by mixing the active ingredient with excipients and then processing the formulation.

[0010] To achieve the above objectives, the present invention adopts the following technical solution:

[0011] In a first aspect, the present invention provides a pharmaceutical formulation comprising a compound of formula I or a solvate thereof or a pharmaceutically acceptable salt thereof or a solvate thereof, a filler, a disintegrant, and a lubricant;

[0012] Based on the total mass of the pharmaceutical preparation, the mass percentage of the compound of Formula I is 1%-50%, the mass percentage of the filler is 60%-90%, the mass percentage of the disintegrant is 1%-10%, and the mass percentage of the lubricant is 1%-10%.

[0013] In this invention, the pharmaceutically acceptable salt of the compound of formula I can be the compound of formula II ((S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazol-6-carboxylic acid tromethamine salt);

[0014] In this invention, the solvate of a pharmaceutically acceptable salt of a compound of formula I can be a monohydrate of a compound of formula II;

[0015] Preferably, the compound of formula II exists in the form of crystal form A.

[0016] Preferably, the crystal form A has diffraction peaks at 4.1±0.2°, 8.2±0.2°, 10.7±0.2°, 12.3±0.2° and 20.7±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed at an angle of 2θ.

[0017] Preferably, the X-ray powder diffraction pattern of the crystal form A using Cu-Kα radiation, expressed in 2θ angle, also has diffraction peaks at one or more of the following locations: 14.1±0.2°, 14.9±0.2°, 20.5±0.2°, and 21.8±0.2°.

[0018] Preferably, the crystal form A has diffraction peaks at 4.1±0.2°, 8.2±0.2°, 10.7±0.2°, 12.3±0.2°, 14.1±0.2°, 14.9±0.2°, 20.5±0.2° and 21.8±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed at 2θ angle.

[0019] Preferably, the crystal form A has diffraction peaks at 4.1±0.2°, 8.2±0.2°, 10.7±0.2°, 12.3±0.2°, 14.1±0.2°, 14.9±0.2°, 20.5±0.2°, 20.7±0.2° and 21.8±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed at 2θ angle.

[0020] Furthermore, the X-ray powder diffraction pattern of crystal form A using Cu-Kα radiation, expressed at a 2θ angle, exhibits the diffraction peaks shown in Table 1 below:

[0021] Table 1

[0022] For example, the X-ray powder diffraction pattern of crystal form A using Cu-Kα radiation can be basically as shown in Figure 1.

[0023] Preferably, the differential scanning calorimetry curve of crystal form A has endothermic peaks at 129.98±3℃ and 196.25±3℃.

[0024] For example, the differential scanning calorimetry curve of crystal form A is shown in Figure 2.

[0025] Preferably, the thermogravimetric analysis curve of crystal form A shows a weight loss of 2.468% in the temperature range of 30℃±3℃ to 135℃±3℃.

[0026] For example, the thermogravimetric analysis curve of crystal form A is shown in Figure 3.

[0027] In this invention, the mass percentage of the compound of formula I can be 2%-40%, preferably 3%-30%, more preferably 10%-30%, and even more preferably 10%-25%, for example 5%, 5.26%, 10%, 12.5%, 12.53%, 16.67%, 20% or 25%.

[0028] In this invention, the filler may be selected from one or more of the following: microcrystalline cellulose, lactose, lactose monohydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, dextrin, and inorganic salts such as calcium carbonate, calcium silicate, calcium phosphate, and calcium hydrogen phosphate dihydrate, for example, two of them.

[0029] Preferably, the filler is lactose monohydrate and / or mannitol. When the filler is lactose monohydrate and mannitol, the mass ratio of lactose monohydrate to mannitol can be (0.3-1):1, for example, 0.3:1 or 0.7:1.

[0030] Preferably, the filler is mannitol and microcrystalline cellulose. The mass ratio of mannitol to microcrystalline cellulose can be (1.5-3):1, for example, 1.83:1, 2.04:1, 2.49:1 or 2.58:1.

[0031] Preferably, the filler is mannitol and calcium carbonate. The mass ratio of mannitol to calcium carbonate can be (2-3):1, for example, 2.47:1.

[0032] In this invention, the filler preferably has a mass percentage of 65%-85%.

[0033] In some specific embodiments of the present invention, the mass percentage of the filler is 67%, 67.17%, 67.5%, 74.38%, 75%, 75.88%, 76.13%, 76.38%, 76.5%, 77.38%, 83.5%, 84.75%, or 89.21%.

[0034] In this invention, the disintegrant may be selected from one or more of the following, for example, two: dry starch, croscarmellose sodium, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl methylcellulose, croscarmellose, pregelatinized starch, carboxymethyl cellulose, sodium alginate and sodium starch hydroxyacetate.

[0035] Preferably, the disintegrant is croscarmellose sodium.

[0036] Preferably, the disintegrant is croscarmellose sodium and hydroxypropyl cellulose. The mass ratio of croscarmellose sodium to hydroxypropyl cellulose can be (0.6-1):1.

[0037] In this invention, the mass percentage of the disintegrant is preferably 2%-5%, for example 2%, 3% or 5%.

[0038] In this invention, the lubricant may be selected from one or more of metal stearate, stearic acid, hydrogenated vegetable oil and glyceryl betaine.

[0039] Preferably, the lubricant is a metal stearate salt.

[0040] The stearate metal salt may be magnesium stearate, sodium stearate fumarate, or calcium stearate.

[0041] In this invention, the mass percentage of the lubricant is preferably 1%-5%, for example 1%, 1.5%, 2%, 3% or 5%.

[0042] In this invention, the pharmaceutical formulation may further include a binder. The binder may be hydroxypropyl cellulose. Based on the total mass of the pharmaceutical formulation, the mass percentage of the binder may be 2.5%-5%.

[0043] In this invention, the pharmaceutical formulation may further include a flow aid. The flow aid may be colloidal silica. Based on the total mass of the pharmaceutical formulation, the mass percentage of the flow aid may be 1%.

[0044] In this invention, the pharmaceutical preparation may further include a surfactant. The surfactant may be one or more of higher fatty acid salts, oleic acid, lauric acid, sulfates, sulfonic acid compounds, quaternary ammonium compounds, lecithin, Span, and poloxamer. The higher fatty acid salt may be sodium dodecyl sulfate. Based on the total mass of the pharmaceutical preparation, the mass percentage of the surfactant may be 1%.

[0045] Preferably, the surfactant is a higher fatty acid salt.

[0046] In this invention, the pharmaceutical formulation may further include a modifier. The modifier may be calcium carbonate or meglumine. Based on the total mass of the pharmaceutical formulation, the mass percentage of the modifier may be 0.5%.

[0047] Preferably, the regulator is meglumine.

[0048] In this invention, the dosage form of the pharmaceutical preparation may be a solid oral dosage form, such as tablets, capsules, capsule-type tablets, powders, or granules.

[0049] In this invention, the dosage form of the pharmaceutical preparation may be an immediate-release solid dosage form.

[0050] In this invention, the pharmaceutical preparation may be a pharmaceutical preparation for activating GLP-1R.

[0051] In this invention, the pharmaceutical preparation may be a pharmaceutical preparation for the treatment and / or prevention of diabetes, obesity, non-alcoholic fatty liver disease, or hypertension.

[0052] In this invention, the pharmaceutical preparation may be a pharmaceutical preparation for treating and / or preventing diseases related to GLP-1R, preferably diabetes, obesity, non-alcoholic fatty liver disease, or hypertension.

[0053] In this invention, the pharmaceutical preparation may contain a compound of formula I in an amount equivalent to about 5 mg to about 300 mg, for example, an amount equivalent to about 5 mg to about 300 mg of compound I, about 10 mg to about 200 mg of compound I, about 10 mg to about 160 mg of compound I, about 20 mg to about 80 mg of compound I, or about 20 mg to about 40 mg of compound I.

[0054] In this invention, the pharmaceutical preparation may contain a compound of formula I equivalent to about 10 mg to about 300 mg, for example, an amount equivalent to about 5 mg to about 20 mg of compound I, about 20 mg to about 40 mg of compound I, about 40 mg to about 80 mg of compound I, about 40 mg to about 120 mg of compound I, about 120 mg to about 160 mg of compound I, about 160 mg to about 200 mg of compound I, about 200 mg to about 240 mg of compound I, and 240 mg to 300 mg of compound I.

[0055] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, mannitol, microcrystalline cellulose, croscarmellose sodium cellulose, and sodium stearate fumarate.

[0056] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 6.25% of compound II monohydrate, 54.75% of mannitol, 30% of microcrystalline cellulose, 3% of croscarmellose sodium cellulose, and 1% of sodium stearate fumarate.

[0057] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 6.58% of compound II monohydrate, 57.63% of mannitol, 31.58% of microcrystalline cellulose, 3.16% of croscarmellose sodium, and 1.05% of sodium stearate fumarate (Formula 1).

[0058] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 12.5% ​​of compound II monohydrate, 56% of mannitol, 27.5% of microcrystalline cellulose, 3% of croscarmellose sodium, and 1% of sodium stearate fumarate (Formula II).

[0059] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium cellulose, hydroxypropyl cellulose, colloidal silica, magnesium stearate, and sodium dodecyl sulfate.

[0060] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 12.5% ​​of compound II monohydrate, 26.5% of lactose monohydrate, 50% of microcrystalline cellulose, 3% of croscarmellose sodium cellulose, 5% of hydroxypropyl cellulose, 1% of colloidal silica, 1% of magnesium stearate, and 1% of sodium dodecyl sulfate (Formula 3).

[0061] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, mannitol, microcrystalline cellulose, croscarmellose sodium cellulose, hydroxypropyl cellulose, magnesium stearate, and sodium dodecyl sulfate.

[0062] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 12.5% ​​of compound II monohydrate, 53.5% of mannitol, 21.5% of microcrystalline cellulose, 5% of croscarmellose sodium cellulose, 5% of hydroxypropyl cellulose, 1.5% of magnesium stearate, and 1% of sodium dodecyl sulfate (Formula 4).

[0063] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, microcrystalline cellulose, mannitol, sodium dodecyl sulfate, croscarmellose sodium cellulose, hydroxypropyl cellulose, and sodium stearate fumarate.

[0064] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 20.83% of compound II monohydrate, 18.77% of microcrystalline cellulose, 48.4% of mannitol, 2.5% of sodium dodecyl sulfate, 5% of croscarmellose sodium cellulose, 2.5% of hydroxypropyl cellulose, and 2% of sodium stearate fumarate (Formula 5).

[0065] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, mannitol, lactose monohydrate, croscarmellose sodium, and sodium stearate fumarate.

[0066] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 52.75% of mannitol, 21.63% of lactose monohydrate, 5% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula 6).

[0067] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, mannitol, lactose monohydrate, croscarmellose sodium, and sodium stearate fumarate.

[0068] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 54.25% of mannitol, 21.88% of lactose monohydrate, 3% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula 7).

[0069] In certain embodiments of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.66% of compound II monohydrate, 54.39% of mannitol, 21.93% of lactose monohydrate, 3.01% of croscarmellose sodium, and 5.01% of sodium stearate fumarate (Formula 7). In another specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 54.38% of mannitol, 22% of lactose monohydrate, 3% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula 8).

[0070] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 55.38% of mannitol, 22% of lactose monohydrate, 2% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula 9).

[0071] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, mannitol, lactose monohydrate, precrossyl starch, and sodium stearate fumarate.

[0072] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 54.38% of mannitol, 22% of lactose monohydrate, 3% of pregelatinized starch, and 5% of sodium stearate fumarate (Formula X).

[0073] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, mannitol, calcium carbonate, croscarmellose sodium cellulose and sodium stearate fumarate.

[0074] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 54.38% of mannitol, 22% of calcium carbonate, 3% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula 11).

[0075] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, mannitol, lactose monohydrate, meglumine, croscarmellose sodium, and sodium stearate fumarate.

[0076] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 54.13% of mannitol, 21.75% of lactose monohydrate, 0.5% of meglumine, 3% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula XII).

[0077] In some specific embodiments of the present invention, the pharmaceutical preparation comprises compound II monohydrate, mannitol, lactose monohydrate, croscarmellose sodium, and sodium stearate fumarate.

[0078] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 25% of compound II monohydrate, 48% of mannitol, 19% of lactose monohydrate, 3% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula XIII).

[0079] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 25% of compound II monohydrate, 47.6% of mannitol, 19.4% of lactose monohydrate, 3% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula XIV).

[0080] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 25% of compound II monohydrate, 39.4% of mannitol, 27.6% of lactose monohydrate, 3% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula XV).

[0081] In a specific embodiment of the present invention, based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 25% of compound II monohydrate, 39.9% of mannitol, 27.1% of lactose monohydrate, 3% of croscarmellose sodium, and 5% of sodium stearate fumarate (Formula XVI, Formula XVII).

[0082] Secondly, the present invention provides a method for preparing a pharmaceutical preparation as described above, wherein when the pharmaceutical preparation is a tablet, the method includes the following steps: compressing a mixture into a tablet; wherein the mixture includes the raw materials of the pharmaceutical preparation after sieving;

[0083] When the pharmaceutical preparation is in granule form, it includes the following steps: granulating the mixture; the mixture includes the raw materials of the pharmaceutical preparation after sieving;

[0084] Alternatively, it may include the following steps:

[0085] S1. Granulate the first mixture; the first mixture includes raw materials for a portion of the pharmaceutical preparation after sieving;

[0086] S2. Compress the second mixture into tablets; the second mixture includes the product from step S1 and the raw materials for the remaining pharmaceutical preparation after sieving;

[0087] When the pharmaceutical preparation is a capsule, it includes the following steps: filling the mixture into capsules; the mixture includes the raw materials of the pharmaceutical preparation after sieving.

[0088] In this invention, the compound of formula I or its solvate or its pharmaceutically acceptable salt or a solvate of its pharmaceutically acceptable salt, and the filler may be ground first and then sieved. The grinding speed may be 2-20 rpm, preferably 10-15 rpm. The sieving may be performed using a 20-60 mesh sieve.

[0089] In this invention, the raw materials for the pharmaceutical preparation, except for the compound of Formula I or its solvates or pharmaceutically acceptable salts or solvates of pharmaceutically acceptable salts, and the filler, can be sieved using a sieve of 10-100 mesh, preferably 30-60 mesh.

[0090] In this invention, the speed of the tablet press turntable can be 20-60 rpm, for example 30 rpm.

[0091] In this invention, the feed machine speed for tableting can be 10-40 rpm, for example 15 rpm.

[0092] In this invention, the pressure of the tablet can be 2.5-20.0kN, for example 11.0kN.

[0093] In this invention, the average hardness range of the pressed tablet is 5-200N, for example 40-100N, 60-120N or 120-180N.

[0094] In this invention, the pressure of the granulation roller can be 2.0-10 kN / cm, for example 5.0 kN / cm.

[0095] In this invention, the gap between the granulation rollers can be 1.0-3.0 mm, for example, 1.8 mm.

[0096] In this invention, the speed of the granulation roller can be 3.0-30.0 rpm, for example 4.0 rpm.

[0097] In this invention, the filling / feeding rate ratio of the granulation process can be 120%-180%, for example, 165%.

[0098] In this invention, the granulation speed can be (30-150) rpm / (30-150) rpm, for example, 60 rpm / 60 rpm.

[0099] In this invention, the granulation angle can be (150°-1800°) / (150°-1800°), for example 250° / 280°.

[0100] Thirdly, the present invention provides a coated pharmaceutical preparation comprising the pharmaceutical preparation as described above, wherein the dosage form of the pharmaceutical preparation is a tablet or granule, and the coated pharmaceutical preparation further comprises a coating outside the pharmaceutical preparation, wherein the mass of the coating is 1%-3% of the total mass of the pharmaceutical preparation.

[0101] Fourthly, the present invention provides a method for preparing a coated pharmaceutical preparation as described above, comprising the following steps: coating the pharmaceutical preparation.

[0102] In this invention, the GLP-1R agonist formulation is in the form of tablets or granules, and the GLP-1R agonist formulation further includes coating. The rotation speed of the coating drum can be 3.0 rpm. The rotation time of the coating drum can be 5 seconds. The stopping time of the coating drum can be 60 seconds. The distance between the coating nozzle and the tablet bed can be 10-30 cm, for example, 20 cm. The inlet air temperature of the coating can be 50-70℃, for example, 60.0℃. The inlet air volume of the coating can be 2000-4800 m³ / h. 3 / h, for example 3500m 3 / h.

[0103] Fifthly, the present invention provides the use of the pharmaceutical formulation or coated pharmaceutical formulation as described above in the preparation of a medicament for treating and / or preventing diseases related to GLP-1R.

[0104] In this invention, the diseases associated with GLP-1R are preferably diabetes or obesity.

[0105] In this invention, the pharmaceutical preparation can be used as an agonist of GLP-1R.

[0106] In this invention, the pharmaceutical preparation can be used to treat and / or prevent diabetes, obesity, non-alcoholic fatty liver disease, or hypertension.

[0107] In this invention, the pharmaceutical preparation can be used to treat and / or prevent diseases associated with GLP-1R.

[0108] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0109] As described above, the terms "pharmaceutical-acceptable salt" and "solvent" in the term "pharmaceutical-acceptable salt solvate" refer to substances formed by combining the compounds of the present invention with 1, substances prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, or substances formed with a stoichiometric or non-stoichiometric solvent.

[0110] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0111] The reagents and raw materials used in this invention are all commercially available.

[0112] The positive and progressive effects of this invention are as follows: This invention provides a GLP-1R agonist formulation that has excellent in vivo absorption. Attached Figure Description

[0113] Figure 1 shows the XRD pattern of crystal form A of the active ingredient II compound monohydrate;

[0114] Figure 2 shows the differential scanning calorimetry curve of crystal form A of the active ingredient II compound monohydrate.

[0115] Figure 3 shows the thermogravimetric analysis curve of crystal form A of the active ingredient II compound monohydrate;

[0116] Figure 4 shows the dissolution curve of the formulation in Example 2. Detailed Implementation

[0117] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0118] The main raw materials used in the following examples and comparative examples are as follows:

[0119] Active ingredient: Crystal form A of the monohydrate of compound II, which is a crystalline compound, and its representative characterization is shown in Figures 1 to 3.

[0120] Lactose monohydrate: Manufacturer: DFE pjarma China Co., Ltd., Batch No.: 109SJCS, Model: Pharmatose@200M.

[0121] Mannitol: Manufacturer: Roquette Freres, Lot No. 753725, Model: 200SD.

[0122] Microcrystalline cellulose, manufacturer: DuPont, batch number: 2173851227.

[0123] Crosslinked sodium carboxymethyl cellulose, manufacturer: International Flavors & Fragrances Inc; model: SD711.

[0124] Hydroxypropyl cellulose E5, Manufacturer: DOW; Batch No.: D011J4JL02.

[0125] Colloidal silica, manufacturer: Evonik; batch number: 150081114.

[0126] Tween 80, Manufacturer: CRODA, Batch No.: 0001775925.

[0127] Methylcellulose A4M, manufacturer: Aslan Corporation.

[0128] Pre-exfoliated starch, manufacturer: Shanghai Calcare Coating Technology Co., Ltd., model: STARCH Batch number: N546607.

[0129] Coating powder, manufacturer: Shanghai Carrefour Coating Technology Co., Ltd., model: Film-coated premixed powder (gastric-soluble type) 88A180021-CN White, Batch No.: SH684494.

[0130] Sodium dodecyl sulfate, manufacturer: BASF, batch number: 0022607077.

[0131] Sodium stearate: JRS PHARMA GMBH & CO.KG, batch number: 3207, 3477.

[0132] Polysorbate, manufacturer: Croda; batch number: 0001775925.

[0133] The actual reagents and methods used in the embodiments of this invention are all conventional reagents and methods in the art. Those skilled in the art should understand that, unless otherwise specified, temperature is expressed in degrees Celsius (°C) hereinafter. Operations are conducted at room temperature, which is 10-30°C.

[0134] Instruments and methods:

[0135] The obtained reaction samples were analyzed using a variety of detection and analysis methods, among which...

[0136] (1) The X-ray diffraction pattern was acquired by a Bruker D2 Phaser instrument. The instrument parameters are shown in Table 2 below:

[0137] Table 2

[0138] (2) DSC

[0139] The DSC curve was acquired using a TA instrument with a DSC 250 sensor. The sample was accurately weighed into a sample pan, and the weight was recorded. The sample was then tested after puncturing an aluminum crucible. The temperature was increased from 25°C to a final temperature of 300°C at a rate of 10°C / min.

[0140] (3) TGA

[0141] The TGA curves were acquired using a TGA 550 instrument from TA. Samples were weighed into a sample pan and tested open-top, with the temperature increased from 40°C to 300°C at a rate of 10°C / min.

[0142] Example 1: Tablets

[0143] In this embodiment, the dosage form is a tablet, specifically an immediate-release (IR) tablet, comprising the following formulation, as detailed below:

[0144] Prescription 1 (containing 5mg of active ingredient compound I), as shown in Table 3 below.

[0145] Table 3

[0146] Prescription 2 (containing 10mg of active ingredient compound I), as shown in Table 4 below.

[0147] Table 4

[0148] Prescription 3 (containing 10mg of active ingredient compound I), as shown in Table 5 below.

[0149] Prescription 4 (containing 40mg of active ingredient compound I), as shown in Table 6 below.

[0150] Table 6

[0151] Prescription 5 (containing 50mg of active ingredient compound I), as shown in Table 7 below.

[0152] Table 7

[0153] Prescription 6 (containing 50mg of active ingredient compound I), as shown in Table 8 below.

[0154] Table 8

[0155] Prescription 7 (containing 50mg of active ingredient compound I), as shown in Table 9 below.

[0156] Table 9

[0157] Prescription 8 (containing 10mg of active ingredient compound I), as shown in Table 10 below.

[0158] Table 10

[0159] Prescription 9 (containing 10mg of active ingredient compound I), as shown in Table 11 below.

[0160] Table 11

[0161] Prescription 10 (containing 10mg of active ingredient compound I), as shown in Table 12 below.

[0162] Table 12

[0163] Prescription 11 (containing 10mg of active ingredient compound I), as shown in Table 13 below.

[0164] Table 13

[0165] Prescription 12 (containing 10mg of active ingredient compound I), as shown in Table 14 below.

[0166] Table 14

[0167] Prescription 13 (containing 10mg of active ingredient compound I), as shown in Table 15 below.

[0168] Table 15

[0169] Prescription 14 (containing 50mg of active ingredient compound I), as shown in Table 16 below.

[0170] Table 16

[0171] Prescription 15 (containing 20mg of active ingredient compound I), as shown in Table 17 below.

[0172] Table 17

[0173] Prescription 16 (containing 40mg of active ingredient compound I), as shown in Table 18 below.

[0174] Table 18

[0175] Prescription 17 (containing 80mg of active ingredient compound I), as shown in Table 19 below.

[0176] Table 19

[0177] The tablets are prepared using a dry direct compression process, without distinguishing between external and internal additives. The specific steps are as follows:

[0178] Step 1: Weighing

[0179] According to the prescription quantities in the table above, weigh out the compound monohydrate of Formula II, filler, lubricant, disintegrant, binder, glidant and surfactant in sequence (if certain excipients are not present in a prescription, do not weigh them), and place all raw materials and excipients separately in double-layer LDPE bags for later use.

[0180] Step 2: Mix and sieve

[0181] Add half of the filler and half of the Formula II compound monohydrate to the mixing tank and mix for 3-7 minutes. Then, add the mixture to a grinding mill for grinding and sieving through a 20-60 mesh sieve. After 3-15 minutes, add the other half of the filler and the other half of the Formula II compound monohydrate, and add the mixture to the grinding mill again for grinding and sieving through a 20-60 mesh sieve to ensure better and more uniform dispersion of the material. Add the sieved material to the mixing tank and mix at a speed of 15 rpm for 15 minutes. During both grinding processes, the grinding mill speed should be 10-15 rpm.

[0182] Add the lubricant, disintegrant, binder, gliding agent, and surfactant to the mixing tank after passing them through a 30-60 mesh sieve. Continue mixing until the mixture is homogeneous. Transfer the mixed material to double-layer LDPE bags and seal the bags tightly.

[0183] Step 3: Tableting

[0184] Different dies are selected for tableting according to different specifications. The tableting parameters and indicators are as follows:

[0185] Turntable speed: 30 rpm; feeder speed: 15 rpm; main pressure: 11.0 kN; single tablet / average weight difference controlled within (1 ± 7.5%) × target tablet weight, average hardness range: 5-200 N. For example, 20 mg formulation: average hardness range: 40-100 N; 40 mg formulation: average hardness range: 60-120 N; 80 mg formulation: average hardness range: 120-180 N.

[0186] Step 4: Coating

[0187] Apply the prescribed amount of coating solution, setting appropriate parameters, until the coating weight gain reaches the target weight (if a prescription does not involve coating, then no coating operation is performed). The coating parameters are as follows:

[0188] Drum rotation mode: Drum speed 3.0 rpm; Drum rotation time 5 s; Drum stop time 60 s; Distance between gun and disc bed 20 cm; Inlet air temperature 60.0℃; Inlet air volume 3500 m³ / h3 / h.

[0189] Example 2: Granules

[0190] In this embodiment, the dosage form is granules, the formulation is the same as in Example 1, and a dry granulation process is used. The specific steps are as follows:

[0191] Step 1: Weighing

[0192] According to the prescription quantities in the table above, weigh out the compound monohydrate of Formula II, filler, lubricant, disintegrant, binder, glidant and surfactant in sequence (if certain excipients are not present in a prescription, do not weigh them), and place all raw materials and excipients in double-layer LDPE bags for later use.

[0193] Step 2: Mix and sieve

[0194] Add half of the filler and half of the Formula II compound monohydrate to the mixing tank and mix for 3-7 minutes. Then, add the mixture to a grinding mill for grinding and sieving through a 20-60 mesh sieve. After 3-15 minutes, add the other half of the filler and the other half of the Formula II compound monohydrate, and add the mixture to the grinding mill again for grinding and sieving through a 20-60 mesh sieve to ensure better and more uniform dispersion of the material. Add the sieved material to the mixing tank and mix at a speed of 15 rpm for 15 minutes. During both grinding processes, the grinding mill speed should be 10-15 rpm.

[0195] Add the internally added lubricant, disintegrant, binder, gliding agent, and surfactant (if a formulation does not involve internal or external additives, this refers to all of the above excipients) through a 30-60 mesh sieve and add them to the mixing tank. Continue mixing until homogeneous. Transfer the mixed material to double-layer LDPE bags and seal the bags tightly.

[0196] Step 3: Dry granulation

[0197] The premixed powder is added to a dry granulator for granulation. Appropriate parameters are set for dry granulation. The dry granulation parameters are as follows: roller pressure 5.0 kN / cm; roller gap 1.8 mm; roller speed 4.0 rpm; filling / feed speed ratio 165%; granulator speed (clockwise / counterclockwise): 60 rpm / 60 rpm; granulator angle (clockwise / counterclockwise): 250° / 280°.

[0198] Step 4: Total Mixing

[0199] The added lubricants, disintegrants, binders, gliding agents and surfactants are manually sieved and converted according to the actual weight of the dry particles. They are then added to the mixing tank and stirred (this step is not performed if a formulation does not involve internal or external additives).

[0200] Step 5: Tableting

[0201] Different dies are selected for tableting according to different specifications. The tableting parameters and indicators are as follows:

[0202] Turntable speed: 30 rpm; feeder speed: 15 rpm; main pressure: 11.0 kN; single tablet / average weight difference controlled within (1 ± 7.5%) × target tablet weight, average hardness range: 5-200 N. For example, 20 mg formulation: average hardness range: 40-100 N; 40 mg formulation: average hardness range: 60-120 N; 80 mg formulation: average hardness range: 120-180 N.

[0203] Step 6: Coating

[0204] Apply the prescribed amount of coating solution, setting appropriate parameters, until the coating weight gain reaches the target weight (if a prescription does not involve coating, then no coating operation is performed). The coating parameters are as follows:

[0205] Drum rotation mode: Drum speed 3.0 rpm; Drum rotation time 5 s; Drum stop time 60 s; Distance between gun and disc bed 20 cm; Inlet air temperature 60.0℃; Inlet air volume 3500 m³ / h 3 / h.

[0206] Example 3: Capsules

[0207] In this embodiment, the dosage form is capsules, and the prescription is the same as in Example 1. There is no distinction between external and internal addition. Only for prescriptions that do not involve coating, the capsule filling process is adopted. The specific steps are as follows:

[0208] Step 1: Weighing

[0209] According to the prescription quantities in the table above, weigh out the compound monohydrate of Formula II, filler, lubricant, disintegrant, binder, glidant and surfactant in sequence (if certain excipients are not present in a prescription, do not weigh them), and place all raw materials and excipients in double-layer LDPE bags for later use.

[0210] Step 2: Mix and sieve

[0211] Add half of the filler and half of the Formula II compound monohydrate to the mixing tank and mix for 3-7 minutes. Then, add the mixture to a grinding mill for grinding and sieving through a 20-60 mesh sieve. After 3-15 minutes, add the other half of the filler and the other half of the Formula II compound monohydrate, and add the mixture to the grinding mill again for grinding and sieving through a 20-60 mesh sieve to ensure better and more uniform dispersion of the material. Add the sieved material to the mixing tank and mix at a speed of 15 rpm for 15 minutes. During both grinding processes, the grinding mill speed should be 10-15 rpm.

[0212] After passing the lubricant, disintegrant, binder, gliding agent, and surfactant through a 30-60 mesh sieve, add them to the mixing tank and continue mixing until homogeneous. Transfer the mixed material to double-layer LDPE bags and seal the bags tightly.

[0213] Step 3: Capsule filling

[0214] Select the appropriate capsules based on the formulation specifications.

[0215] Example 1: Stability Study of the Formulation

[0216] 1. Test subjects: Prescriptions 2, 3, 7 to 12 and 14 in Example 1.

[0217] 2. Testing Method:

[0218] (1) Experimental storage conditions are shown in Table 20 below.

[0219] Table 20

[0220] (2) The liquid phase conditions for the related substances method are shown in Table 21 below.

[0221] Table 21

[0222] 3. Test Results:

[0223] (1) Test 1, as shown in Table 22 below.

[0224] Table 22

[0225] Under high-temperature conditions, both formulations 2 and 3 showed some increase in impurities, while under high-humidity conditions, formulation 3 showed a slight increase in impurities. In comparison, formulation 2 exhibited better stability.

[0226] (2) Test 2, as shown in Table 23 below.

[0227] Table 23

[0228] The formulations of prescriptions eight to twelve are mainly composed of mannitol and lactose monohydrate as excipients, and are relatively stable under conditions of 40℃ / 75%RH.

[0229] (3) Test 3, as shown in Table 24 below.

[0230] Table 24

[0231] Compared with the formulations of formulations 7 and 14, the formulations of formulation 7 are more stable under conditions of 40℃ / 75%RH, with mannitol and lactose monohydrate as the main excipients; under conditions of 60℃ / 75%RH, the formulation of formulation 14, which has a higher drug loading, is more stable.

[0232] Example 2: Dissolution test of the formulation

[0233] 1. Test subjects: the preparations of prescriptions seven and fourteen in Example 1.

[0234] 2. Testing Method:

[0235] (1) Dissolution test method: The paddle method was used with a rotation speed of 75 rpm. The dissolution medium was pH 5.0 phosphate buffer + 0.1% cetyltrimethylamine bromide (CTAB) solution with a volume of 900 ml. The details are shown in Table 25 below.

[0236] Table 25

[0237] (2) Dissolution detection conditions: See Table 26 below for details.

[0238] Table 26

[0239] 3. Test results: See Table 27 and Figure 2 below.

[0240] Table 27

[0241] The dissolution test results above show that the formulation can be completely released in vitro, meeting the requirements for rapid disintegration and release.

[0242] Example 3: Dissolution test of the formulation

[0243] 1. Test subjects: the preparations of prescriptions seven and fourteen in Example 1.

[0244] 2. Testing Method:

[0245] (1) Laboratory animals: Species & strains: Crab-eating macaques;

[0246] Age at administration: approximately 2-4 years old;

[0247] Number of animals and sex: 11, males.

[0248] Administration method: Tablets, administered orally.

[0249] Animals were fasted for at least 12 hours before administration of medication and resumed eating 4 hours after administration. Drinking water was provided from their living water bottles. Except for special requirements (such as fasting or water restriction), animals had free access to water, which was changed daily. During the experiment, the cynomolgus monkeys were closely observed, and any abnormalities were recorded.

[0250] (2) Sample collection: 1-2 mL of blood was collected via the forelimb vein, anticoagulated with EDTA-K2, and gently inverted to mix. Collection time: Blood samples were collected 0 min before administration and 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, and 48 h after administration.

[0251] (3) Sample processing: After blood samples are collected, they are placed in labeled ice bath centrifuge tubes and the plasma is quickly separated by centrifugation. Centrifugation conditions: 4000 rpm, 10 minutes, 4℃. The plasma is stored at -40℃ or below for testing.

[0252] (4) Sample analysis: Liquid chromatography, with the following specific conditions.

[0253] HPLC: LC-20A, SHIMADZU

[0254] Liquid phase pump: LC-20AD

[0255] Column oven: CTO-20AC

[0256] Automated Sampler: SIL-20AC HT

[0257] Controller: CBM-20A

[0258] Degasser: DGU-20A3R

[0259] Column: ZORBAX Eclipse XDB-C18 2.1×50mm, 3.5μm, Agilent

[0260] Pre-column: Security Guard Cartridges C18 4×2.0mm, Phenomenex

[0261] Mobile phase: A: 0.1wt% formic acid & 5mM ammonium acetate aqueous solution; B: acetonitrile;

[0262] Automatic syringe syringe cleaning solution: 50wt% acetonitrile & 0.5wt% formic acid aqueous solution

[0263] Automated syringe needle washing program: Rinse Mode: Before and after aspiration

[0264] The mobile phase gradient is shown in Table 28 below.

[0265] Table 28

[0266] Flow rate: 0.75 mL / min

[0267] Autosampler temperature: 30℃

[0268] Column temperature: NA

[0269] Injection volume: 1 μL

[0270] Run time: 2.50 min

[0271] Mass spectrometry analysis conditions:

[0272] API 4000 mass spectrometer with ESI source, using positive ion MRM scanning.

[0273] Source parameters are shown in Table 29 below.

[0274] Table 29

[0275] 3. Test results: as shown in Table 30 below.

[0276] Table 30

[0277] Remark:* 1 PF06882961, prepared to a final concentration of 2 mg / mL, was used for oral administration. The solvent was 2 wt% Tween 80 + 98 wt% 0.5% (w / v) methylcellulose A4M aqueous solution. After preparation, the formulation was a homogeneous suspension.

[0278] Under suspension administration conditions, the absorption parameters of the monohydrate of Formula II are significantly better than those of PF06882961. After formulation development, the formulation of the monohydrate of Formula II maintained similar PK properties, indicating that the formulation of this invention exhibits good in vivo absorption in cynomolgus monkeys.

Claims

1. A pharmaceutical preparation, characterized in that, It includes compounds of formula I or solvates thereof or pharmaceutically acceptable salts thereof or solvates thereof, fillers, disintegrants and lubricants; Based on the total mass of the pharmaceutical preparation, the mass percentage of the compound of Formula I is 1%-50%, the mass percentage of the filler is 60%-90%, the mass percentage of the disintegrant is 1%-10%, and the mass percentage of the lubricant is 1%-10%.

2. The pharmaceutical preparation according to claim 1, characterized in that, It satisfies at least one of the following conditions: (1) The pharmaceutically acceptable salt of compound I is compound II; (2) The pharmaceutically acceptable salt solvate of compound I is the monohydrate of compound II; (3) The mass percentage of the compound of Formula I is 2%-40%, preferably 3%-30%, more preferably 10%-30%, and even more preferably 10%-25%, for example 5%, 5.26%, 10%, 12.5%, 12.53%, 16.67%, 20% or 25%; (4) The filler is selected from one or more of microcrystalline cellulose, lactose, lactose monohydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, dextrin, and inorganic salts such as calcium carbonate, calcium silicate, calcium phosphate, and calcium hydrogen phosphate dihydrate, for example, two of them; preferably, the filler is lactose monohydrate and / or mannitol; when the filler is lactose monohydrate and mannitol, the mass ratio of lactose monohydrate to mannitol is preferably (0.3-1):

1. For example, a ratio of 0.3:1 or 0.7:1; preferably, the filler is mannitol and microcrystalline cellulose; the mass ratio of mannitol to microcrystalline cellulose is preferably (1.5-3):1, for example 1.83:1, 2.04:1, 2.49:1 or 2.58:1; preferably, the filler is mannitol and calcium carbonate; the mass ratio of mannitol to calcium carbonate is preferably (2-3):1, for example 2.47:1; (5) The filler has a mass percentage of 65%-85%, for example 67%, 67.17%, 67.5%, 74.38%, 75%, 75.88%, 76.13%, 76.38%, 76.5%, 77.38%, 83.5%, 84.75%, or 89.21%; (6) The disintegrant is selected from one or more of the following: dry starch, croscarmellose sodium, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl methylcellulose, croscarmellose, pregelatinized starch, carboxymethyl cellulose, sodium alginate, and starch-hydroxyacetic acid sodium, for example, two of them; preferably, the disintegrant is croscarmellose sodium; preferably, the disintegrant is croscarmellose sodium and hydroxypropyl cellulose; the mass ratio of croscarmellose sodium to hydroxypropyl cellulose is preferably (0.6-1):1; (7) The mass percentage of the disintegrant is 2%-5%, for example, 2%, 3% or 5%; (8) The lubricant is selected from one or more of metal stearate, stearic acid, hydrogenated vegetable oil and glyceryl betaine; the metal stearate is preferably magnesium stearate, sodium stearate fumarate or calcium stearate; preferably, the lubricant is a metal stearate. (9) The lubricant has a mass percentage of 1%-5%, for example, 1%, 1.5%, 2%, 3% or 5%.

3. The pharmaceutical preparation according to claim 2, characterized in that, The compound of formula II exists in the form of crystal form A, and preferably satisfies at least one of the following conditions: (1) The X-ray powder diffraction pattern of crystal form A, expressed as 2θ angle, shows diffraction peaks at 4.1±0.2°, 8.2±0.2°, 10.7±0.2°, 12.3±0.2° and 20.7±0.2° when using Cu-Kα radiation; for example, the X-ray powder diffraction pattern of crystal form A using Cu-Kα radiation is basically as shown in Figure 1; (2) The differential scanning calorimetry curve of crystal form A has endothermic peaks at 129.98±3℃ and 196.25±3℃; for example, the differential scanning calorimetry curve of crystal form A is basically as shown in Figure 2.

4. The pharmaceutical preparation according to claims 1-3, characterized in that, It satisfies at least one of the following conditions: (1) The pharmaceutical preparation further includes an adhesive; the adhesive is preferably hydroxypropyl cellulose; the mass percentage of the adhesive is preferably 2.5%-5% based on the total mass of the pharmaceutical preparation; (2) The pharmaceutical preparation further includes a flow aid; the flow aid is preferably colloidal silica; the mass percentage of the flow aid is preferably 1% based on the total mass of the pharmaceutical preparation; (3) The pharmaceutical preparation further includes a surfactant; the surfactant is preferably one or more of higher fatty acid salts, oleic acid, lauric acid, sulfates, sulfonic acid compounds, quaternary ammonium compounds, lecithin, Span and poloxamer; preferably, the surfactant is a higher fatty acid salt; the higher fatty acid salt is preferably sodium dodecyl sulfate; based on the total mass of the pharmaceutical preparation, the mass percentage of the surfactant is preferably 1%; (4) The pharmaceutical preparation further includes a modifier; the modifier is preferably calcium carbonate or meglumine; preferably, the modifier is meglumine; the mass percentage of the modifier is preferably 0.5% based on the total mass of the pharmaceutical preparation.

5. The pharmaceutical preparation according to claims 1-4, characterized in that, It satisfies at least one of the following conditions: (1) The dosage form of the pharmaceutical preparation is a solid oral dosage form, such as tablets, capsules, capsule-type tablets, powders or granules; (2) The dosage form of the pharmaceutical preparation is an immediate-release solid dosage form; (3) The pharmaceutical preparation is a pharmaceutical preparation for activating GLP-1R; (4) The pharmaceutical preparation is a pharmaceutical preparation for the treatment and / or prevention of diabetes or obesity; (5) The pharmaceutical preparation is a pharmaceutical preparation for the treatment and / or prevention of diseases related to GLP-1R, wherein the GLP-1R-related diseases are preferably diabetes or obesity.

6. The pharmaceutical preparation according to claims 1-5, characterized in that, It satisfies at least one of the following conditions: (1) The pharmaceutical preparation comprises compound II monohydrate, mannitol, microcrystalline cellulose, croscarmellose sodium cellulose and sodium stearate fumarate; (2) The pharmaceutical preparation comprises compound II monohydrate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium cellulose, hydroxypropyl cellulose, colloidal silica, magnesium stearate and sodium dodecyl sulfate; (3) The pharmaceutical preparation comprises compound II monohydrate, mannitol, microcrystalline cellulose, croscarmellose sodium cellulose, hydroxypropyl cellulose, magnesium stearate and sodium dodecyl sulfate; (4) The pharmaceutical preparation comprises compound II monohydrate, microcrystalline cellulose, mannitol, sodium dodecyl sulfate, croscarmellose sodium cellulose, hydroxypropyl cellulose and sodium stearate fumarate; (5) The pharmaceutical preparation comprises compound II monohydrate, mannitol, lactose monohydrate, croscarmellose sodium and stearate sodium fumarate; (6) The pharmaceutical preparation comprises compound II monohydrate, mannitol, lactose monohydrate, pregelatinized starch and sodium stearate; (7) The pharmaceutical preparation comprises compound II monohydrate, mannitol, calcium carbonate, croscarmellose sodium cellulose and sodium stearate; (8) The pharmaceutical preparation comprises compound II monohydrate, mannitol, lactose monohydrate, meglumine, croscarmellose sodium and stearate sodium fumarate.

7. The pharmaceutical preparation according to claim 6, characterized in that, It satisfies at least one of the following conditions: (1) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 6.25% of compound II monohydrate, 54.75% of mannitol, 30% of microcrystalline cellulose, 3% of croscarmellose sodium cellulose and 1% of sodium stearate fumarate. (2) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 12.5% ​​of compound II monohydrate, 56% of mannitol, 27.5% of microcrystalline cellulose, 3% of croscarmellose sodium cellulose and 1% of sodium stearate fumarate. (3) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 12.5% ​​of compound II monohydrate, 26.5% of lactose monohydrate, 50% of microcrystalline cellulose, 3% of croscarmellose sodium cellulose, 5% of hydroxypropyl cellulose, 1% of colloidal silica, 1% of magnesium stearate and 1% of sodium dodecyl sulfate. (4) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 12.5% ​​of compound II monohydrate, 53.5% of mannitol, 21.5% of microcrystalline cellulose, 5% of croscarmellose sodium cellulose, 5% of hydroxypropyl cellulose, 1.5% of magnesium stearate and 1% of sodium dodecyl sulfate. (5) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 20.83% of compound monohydrate of formula II, 18.77% of microcrystalline cellulose, 48.4% of mannitol, 2.5% of sodium dodecyl sulfate, 5% of croscarmellose sodium cellulose, 2.5% of hydroxypropyl cellulose and 2% of sodium stearate fumarate. (6) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 52.75% of mannitol, 21.63% of lactose monohydrate, 5% of croscarmellose sodium and 5% of stearate fumarate sodium; (7) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 54.25% of mannitol, 21.88% of lactose monohydrate, 3% of croscarmellose sodium and 5% of stearate fumarate sodium. (8) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 54.38% of mannitol, 22% of lactose monohydrate, 3% of croscarmellose sodium and 5% of sodium stearate fumarate. (9) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 55.38% of mannitol, 22% of lactose monohydrate, 2% of croscarmellose sodium cellulose and 5% of sodium stearate fumarate. (10) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 25% of compound II monohydrate, 48% of mannitol, 19% of lactose monohydrate, 3% of croscarmellose sodium and 5% of stearate fumarate sodium. (11) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 25% of compound II monohydrate, 47.6% of mannitol, 19.4% of lactose monohydrate, 3% of croscarmellose sodium and 5% of stearate fumarate sodium; (12) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 25% of compound II monohydrate, 39.9% of mannitol, 27.1% of lactose monohydrate, 3% of croscarmellose sodium and 5% of sodium stearate fumarate. (13) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 25% of compound II monohydrate, 39.4% of mannitol, 27.6% of lactose monohydrate, 3% of croscarmellose sodium and 5% of stearate fumarate sodium; (14) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 54.38% of mannitol, 22% of lactose monohydrate, 3% of pregelatinized starch and 5% of sodium stearate fumarate. (15) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of compound II monohydrate, 54.38% of mannitol, 22% of calcium carbonate, 3% of croscarmellose sodium cellulose and 5% of sodium stearate fumarate. (16) Based on the total mass of the pharmaceutical preparation, the pharmaceutical preparation comprises the following mass percentages: 15.63% of the monohydrate of compound II, 54.13% of mannitol, 21.75% of lactose monohydrate, 0.5% of meglumine, 3% of croscarmellose sodium and 5% of sodium stearate fumarate.

8. A method for preparing a pharmaceutical formulation as described in claims 1-7, characterized in that, When the pharmaceutical preparation is a tablet, it includes the following steps: compressing the mixture into a tablet; the mixture includes the raw materials of the pharmaceutical preparation after sieving; When the pharmaceutical preparation is in granule form, it includes the following steps: granulating the mixture; the mixture includes the raw materials of the pharmaceutical preparation after sieving; Alternatively, it may include the following steps: S1. Granulate the first mixture; the first mixture includes raw materials for a portion of the pharmaceutical preparation after sieving; S2. Compress the second mixture into tablets; the second mixture includes the product from step S1 and the raw materials for the remaining pharmaceutical preparation after sieving; When the pharmaceutical preparation is a capsule, it includes the following steps: filling the mixture into capsules; the mixture includes the raw materials of the pharmaceutical preparation after sieving.

9. The method for preparing a pharmaceutical formulation according to claim 8, characterized in that, It satisfies at least one of the following conditions: (1) The compound of Formula I or its solvate or its pharmaceutically acceptable salt or a solvate of its pharmaceutically acceptable salt and the filler are first ground and then sieved; (2) Except for the raw materials of the compound of Formula I or its solvates or pharmaceutically acceptable salts or pharmaceutically acceptable salts, the raw materials of the filler are sieved using a sieve of 10-100 mesh, preferably 30-60 mesh. (3) The speed of the tablet press turntable is 20-60 rpm, for example 30 rpm; (4) The feed machine speed for tableting is 10-40 rpm, for example 15 rpm; (5) The pressure of the tablet is 2.5-20.0 kN, for example 11.0 kN; (6) The average hardness range of the pressed tablet is 5-200N, for example 40-100N, 60-120N or 120-180N; (7) The pressure of the granulation roller is 2.0-10 kN / cm, for example 5.0 kN / cm; (8) The gap between the granulation rollers is 1.0-3.0 mm, for example, 1.8 mm; (9) The speed of the granulation roller is 3.0-30.0 rpm, for example 4.0 rpm; (10) The filling / feeding rate ratio of the granulation is 120%-180%, for example 165%; (11) The granulation speed is (30-150) rpm / (30-150) rpm, for example, 60 rpm / 60 rpm; (12) The granulation angle is (150°-1800°) / (150°-1800°), for example 250° / 280°.

10. The method for preparing a pharmaceutical formulation according to claim 9, characterized in that, It satisfies at least one of the following conditions: (1) The mixing speed of the grinding is 2-20 rpm, for example 10-15 rpm; (2) The sieving is carried out using a 20-60 mesh screen.

11. A coated pharmaceutical preparation, characterized in that, It includes the pharmaceutical formulations as described in claims 1-7, wherein the dosage form of the pharmaceutical formulation is a tablet or granule, and the coated pharmaceutical formulation further includes a coating outside the pharmaceutical formulation, wherein the mass of the coating is 1%-3% of the total mass of the pharmaceutical formulation.

12. A method for preparing a coated pharmaceutical formulation as described in claim 11, characterized in that, It includes the following steps: The drug formulation is coated.

13. The method for preparing a coated pharmaceutical formulation according to claim 12, characterized in that, It satisfies at least one of the following conditions: (1) The rotational speed of the coating drum is 3.0 rpm; (2) The rotation time of the coating drum is 5 seconds; (3) The drum stop time of the coating is 60s; (4) The distance between the coating gun and the sheet bed is 10-30cm, for example 20cm; (5) The air inlet temperature of the coating is 50-70℃, for example 60℃; (6) The air intake volume of the coating is 2000-4800 m³ / h. 3 / h, for example 3500m 3 / h.

14. Use of a pharmaceutical formulation as described in any one of claims 1-7 or a coated pharmaceutical formulation as described in claim 11 in the preparation of a medicament for treating and / or preventing diseases associated with GLP-1R.

15. The application according to claim 14, characterized in that, The diseases associated with GLP-1R are diabetes, obesity, non-alcoholic fatty liver disease, or hypertension.

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