Pharmaceutical composition of cycloalkene compound and preparation method therefor

Abstract

The present invention relates to a pharmaceutical composition of a cycloalkene compound and a preparation method therefor. The pharmaceutical composition has the advantages of good stability, good sustained-release effect, etc., and is suitable for large-scale industrial production.

Description

A pharmaceutical composition of a cycloene compound and its preparation method Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a pharmaceutical composition of cycloene compounds and its preparation method. Background Technology

[0002] Diabetes mellitus is a common endocrine and metabolic disease caused by metabolic disorders resulting from various factors, leading to damage to multiple systems and organs. It has a high incidence rate, with approximately 425 million people living with diabetes worldwide. In China, the incidence rate is about 10%, with type 2 diabetes accounting for 90% of cases. Moreover, the prevalence is increasing, and the age of onset is becoming increasingly younger.

[0003] Currently, there are many types of drugs available for the treatment of type 2 diabetes, including insulin, biguanides, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase (DPP-IV) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and α-glucosidase inhibitors, among which GLP-1 receptor agonists have attracted the most attention.

[0004] GLP-1 is a peptide hormone secreted by L cells in the human intestine. Its receptors are distributed in pancreatic islet cells, various gastrointestinal cells, neurons in the central nervous system, and peripheral nervous system. Activation of GLP-1 receptors promotes insulin secretion, inhibits glucagon secretion, suppresses appetite, and delays gastric emptying. Clinical evidence shows that compared to other hypoglycemic drugs, GLP-1 receptor agonists have better hypoglycemic effects and are less likely to cause side effects such as hypoglycemia. Furthermore, they offer additional cardiovascular benefits and can reduce food intake and delay gastric emptying, which is beneficial for weight control.

[0005] Currently available GLP-1 receptor agonists are all peptide drugs, most of which require subcutaneous administration, leading to poor patient compliance. Furthermore, the bioavailability of orally administered peptides is very low. Therefore, there is a significant clinical need to develop oral small-molecule GLP-1 receptor agonists.

[0006] There is a significant clinical need for GLP-1 receptor agonists. Lower-cost, better-compliant oral small-molecule GLP-1 receptor agonists have the potential to treat a variety of metabolic diseases and possess a broad market prospect.

[0007] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxobutylcyclo-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid is a small molecule GLP-1 receptor agonist that can effectively reduce blood sugar and weight. Its structure is shown in Formula I below, hereinafter referred to as Compound I: Summary of the Invention

[0008] The present invention provides a pharmaceutical composition comprising cycloene compounds.

[0009] The pharmaceutical composition provided by this invention can improve the stability of GLP-1 receptor agonists, reduce impurities in the active pharmaceutical ingredient, and enhance the sustained-release effect of the drug.

[0010] The present invention provides a pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable excipient, wherein the active ingredient is a GLP-1 receptor agonist, preferably 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxadicyclo-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid, its isomer, solvate, hydrate, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0011] In some embodiments, the active ingredient comprises the aminobutanetriol salt of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxobutyron-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid.

[0012] In some embodiments, the unit dose of the active ingredient is 1-200 mg, preferably 1-50 mg, more preferably 2-20 mg, and even more preferably 5 mg, 7.5 mg, or 10 mg.

[0013] In some embodiments, the pharmaceutical composition comprises a tablet core and one or more layers of coating, the tablet core containing the active ingredient.

[0014] In some embodiments, the content of active ingredients in the core is 0.5-35 wt%, preferably 1-20 wt%, more preferably 5-15 wt%, more preferably 5-10% or 10-15%, more preferably 5-7%, 7-9%, 9-11%, 11-13% or 13-15%, more preferably 7-9%, 9-11%, more preferably 8.6% or 10%, based on the weight percentage of the core.

[0015] In some embodiments, the tablet core comprises at least one pharmaceutically acceptable tablet core excipient, the tablet core excipient comprising one or more adhesives.

[0016] In some embodiments, the adhesive is selected from one or more of sucrose, starch, povidone, sodium carboxymethyl cellulose, sodium alginate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, pharmaceutical ethanol, and water, preferably hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and sodium alginate, and more preferably hydroxypropyl methylcellulose.

[0017] In some embodiments, the adhesive is selected from hydroxypropyl methylcellulose, and the hydroxypropyl methylcellulose is selected from one or more of E5 Premium LV, E15 Premium LV, E50 Premium LV, E4M Premium, E10M Premium, K3 Premium LV, K100 Premium LV, K100 Premium LVCR, K1500 PH PRM, K4M Premium, K4M Premium CR, K4M Premium DC, K15M Premium, K15M Premium CR, K100M Premium, K100M Premium CR, K100M Premium DC, E4M, E10M, K100LV, K250, K750, K1500, K4M, K15M, K35M, K100M, and K200M; preferably, the hydroxypropyl methylcellulose is selected from one or more of E5 Premium LV, E15 Premium LV, E50 Premium LV, K100LV, K100 Premium LV, and K100 Premium One or more of LVCR, K1500, K1500 PH PRM, K4M, K4M Premium, and K4M Premium CR; more preferably one or more of K100LV, K4M, K100 Premium LVCR, and K4M Premium CR.

[0018] In some embodiments, the adhesive is selected from hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is K100 Premium LVCR.

[0019] In some embodiments, the adhesive is selected from hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is K4M Premium CR.

[0020] In some embodiments, the adhesive is selected from hydroxypropyl methylcellulose, which is a combination of K100 Premium LVCR and E5 Premium LV.

[0021] In some embodiments, the adhesive is selected from hydroxypropyl methylcellulose, specifically K100 Premium LVCR and K1500 PH PRM.

[0022] In some embodiments, the adhesive is selected from hydroxypropyl methylcellulose, which is a combination of K4M Premium CR and K1500 PH PRM, a combination of K4M Premium CR and E50 Premium LV, or a combination of K4M Premium CR and E15 Premium LV.

[0023] In some embodiments, the adhesive comprises hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0024] In some embodiments, the adhesive is added internally and / or externally.

[0025] In some embodiments, the adhesive content is 10-80 wt%, preferably 15-35 wt%, more preferably 20-30 wt%, and even more preferably 25-30 wt%.

[0026] In some embodiments, the adhesive content is 40-80 wt%, preferably 50-75 wt%, more preferably 60-70 wt%, and even more preferably 65-69 wt%.

[0027] In some embodiments, the tablet core comprises at least one pharmaceutically acceptable tablet core excipient, the tablet core excipient comprising one or more fillers.

[0028] In some embodiments, the filler includes one or more of microcrystalline cellulose, starch, lactose, sucrose, dextrin, mannitol, sorbitol, dicalcium phosphate, calcium carbonate, or calcium sulfate, preferably microcrystalline cellulose, lactose, or mannitol, and more preferably microcrystalline cellulose.

[0029] In some embodiments, the filler content is 1-80 wt%, preferably 40-70 wt%, more preferably 50-60 wt%, and even more preferably 52-56 wt%.

[0030] In some embodiments, the filler content is 1-30 wt%, preferably 5-20 wt%, more preferably 10-15 wt%, and even more preferably 11-13 wt%.

[0031] In some embodiments, the tablet core contains at least one pharmaceutically acceptable tablet core excipient, which includes one or more antioxidants and / or pH adjusters.

[0032] In some embodiments, the antioxidant and / or pH adjuster is selected from one or more of magnesium oxide, sodium bicarbonate, sodium carbonate, fumaric acid, sodium bisulfite, sodium sulfite, sodium thiosulfate, sodium bisulfite, cysteine, butylated hydroxytoluene, tartaric acid, disodium edetate, and calcium sodium edetate, preferably from one or more of magnesium oxide, sodium bicarbonate, sodium carbonate, fumaric acid, and sodium bisulfite, more preferably from one or more of magnesium oxide and sodium bicarbonate, and even more preferably from magnesium oxide. By adding antioxidants and / or pH adjusters, the increase of related impurities can be slowed down, further improving the stability of the formulation.

[0033] In some embodiments, the content of the antioxidant and / or pH adjuster is 1-30 wt%, more preferably 5-15 wt%, more preferably 6-10 wt% or 8-12 wt%, more preferably 7-9 wt% or 9-11 wt%.

[0034] In some embodiments, the tablet core comprises at least one pharmaceutically acceptable tablet core excipient, the tablet core excipient comprising one or more lubricants.

[0035] In some embodiments, the lubricant is selected from one or more of talc, stearic acid, sodium stearate fumarate, glyceryl behenate, magnesium stearate, or micronized silica gel, preferably magnesium stearate.

[0036] In some embodiments, the lubricant content is 0.1-10 wt%, preferably 0.5-3 wt%, more preferably 0.75-1.5 wt%, even more preferably 0.9-1.1 wt% or 1.15-1.35 wt%.

[0037] In some embodiments, the lubricant is added internally and / or externally.

[0038] In some embodiments, the chip core comprises the following components:

[0039] In some embodiments, the chip core comprises the following components:

[0040] In some embodiments, the chip core comprises the following components:

[0041] In some embodiments, the chip core comprises the following components:

[0042] In some embodiments, the chip core comprises the following components:

[0043] In some embodiments, the chip core comprises the following components:

[0044] In some embodiments, the chip core comprises the following components:

[0045] In some embodiments, the chip core comprises the following components:

[0046] In some embodiments, the chip core comprises the following components:

[0047] In some embodiments, the chip core comprises the following components:

[0048] In some embodiments, the chip core comprises the following components:

[0049] In some embodiments, the chip core comprises the following components:

[0050] In some embodiments, the chip core comprises the following components:

[0051] In some embodiments, the chip core comprises the following components:

[0052] In some embodiments, the chip core comprises the following components:

[0053] In some embodiments, the chip core comprises the following components:

[0054] In some embodiments, the chip core comprises the following components:

[0055] In some embodiments, the chip core comprises the following components:

[0056] In some embodiments, the chip core comprises the following components:

[0057] In some embodiments, the chip core comprises the following components:

[0058] In some embodiments, the chip core comprises the following components:

[0059] In some embodiments, the chip core comprises the following components:

[0060] In some embodiments, the chip core comprises the following components:

[0061] In some embodiments, the chip core comprises the following components:

[0062] In some embodiments, the chip core comprises the following components:

[0063] In some embodiments, the chip core comprises the following components:

[0064] In some embodiments, the chip core comprises the following components:

[0065] In some embodiments, the chip core comprises the following components:

[0066] In some embodiments, the chip core comprises the following components:

[0067] In some embodiments, the chip core comprises the following components:

[0068] In some embodiments, the chip core comprises the following components:

[0069] In some embodiments, the chip core comprises the following components:

[0070] In some embodiments, the pharmaceutical composition includes a first coating comprising at least one pharmaceutically acceptable first coating excipient, including hydroxypropyl methylcellulose.

[0071] In some embodiments, the hydroxypropyl methylcellulose content in the first coating layer is 1-20 wt%, more preferably 2-10 wt%, more preferably 3-9%, and more preferably 4.25-8.5% by weight percentage.

[0072] In some embodiments, the pharmaceutical composition includes a first coating comprising at least one pharmaceutically acceptable first coating excipient, the first coating excipient comprising polyethylene glycol, preferably polyethylene glycol 400.

[0073] In some embodiments, the content of polyethylene glycol in the first coating layer is 0.1-5 wt%, more preferably 0.2-2.5 wt%, more preferably 0.5-2%, and more preferably 0.75-1.5% by weight percentage.

[0074] In some embodiments, the first coating material further includes ethanol and / or water.

[0075] In some embodiments, the pharmaceutical composition includes a second coating comprising at least one pharmaceutically acceptable second coating excipient, the second coating excipient including a film coating premix.

[0076] In some embodiments, the content of the film coating premix in the second coating is 1-20 wt%, more preferably 4-16 wt%, more preferably 6-14%, and more preferably 8-12%, based on the weight percentage of the second coating.

[0077] In some embodiments, the pharmaceutical composition is an oral formulation, preferably a tablet or capsule, more preferably a coated tablet, and even more preferably a sustained-release tablet.

[0078] In some embodiments, the coating agent of the sustained-release tablet is an enteric-coated film-coating premix.

[0079] The present invention also provides a method for preparing a pharmaceutical composition, comprising the following steps:

[0080] 1) First mixing: Add fillers, active ingredients, binders, antioxidants, pH adjusters, etc. to the hopper mixer for mixing;

[0081] 2) Granulation: After the first mixing, granulation is performed using a fixed vacuum granulator;

[0082] 3) General mixing: Add the granulated material, the prescribed amount of lubricant, to the hopper mixer for general mixing;

[0083] 4) Optionally, compress the tablets;

[0084] 5) Choose any location, coat;

[0085] 6) Packaging is optional.

[0086] The present invention also provides a method for preparing a pharmaceutical composition, comprising the following steps:

[0087] 1) Premixing: The filler, active ingredient, binder, antioxidant, and pH adjuster are added to the wet formulation machine for premixing.

[0088] 2) Granulation: Add an appropriate amount of anhydrous ethanol for speed I granulation and speed II granulation.

[0089] 3) Drying: Transfer the wet granules to a fluidized bed granulator for drying.

[0090] 4) Granulation: The dried granules are granulated.

[0091] 5) Blending: Add the granulated material, the prescribed amount of filler, and the prescribed amount of binder to the hopper mixer for blending I, and add the prescribed amount of lubricant to the hopper mixer for blending II;

[0092] 6) Optionally, tableting.

[0093] 7) Optional, wrapping

[0094] 8) Packaging (optional)

[0095] The present invention also provides a method for preparing a pharmaceutical composition, comprising the following steps:

[0096] 1) First premixing: Add fillers, active ingredients, binders, and antioxidants to a hopper mixer for mixing;

[0097] 2) Second premixing: Add the internal lubricant to the hopper mixer for mixing;

[0098] 3) Granulation: After the second premixing, granulation is performed using a fixed vacuum granulator;

[0099] 4) Third premixing: The granulated material is added to the hopper mixer for mixing;

[0100] 5) Dry granulation: The premixed material is granulated using a dry granulation process;

[0101] 6) General mixing: Add the prescribed amount of lubricant to the hopper mixer and perform general mixing;

[0102] 7) Optionally, compress into tablets;

[0103] 8) Choose any location, coat;

[0104] 9) Packaging, optional.

[0105] The present invention also provides a method for preparing a pharmaceutical composition, comprising the following steps:

[0106] 1) First premixing: Add all additives except lubricant to the hopper mixer for mixing;

[0107] 2) Second premixing: Add the internal lubricant to the hopper mixer for mixing;

[0108] 3) Granulation: After the second premixing, granulation is performed using a fixed vacuum granulator;

[0109] 4) Third premixing: The granulated material is added to the hopper mixer for mixing;

[0110] 5) Dry granulation: The premixed material is granulated using a dry granulation process;

[0111] 6) General mixing: Add the prescribed amount of lubricant to the hopper mixer and perform general mixing;

[0112] 7) Optionally, compress into tablets;

[0113] 8) Choose any location, coat;

[0114] 9) Packaging, optional.

[0115] In some embodiments, the above preparation method further includes a coating step, which includes the following steps:

[0116] 1) First time wrapping clothes:

[0117] a. Preparation of coating solution: Weigh the prescribed amount of purified water, add the prescribed amount of ethanol, and while stirring, add the prescribed amount of hydroxypropyl methylcellulose and polyethylene glycol 400. After all the ingredients have been added, stir until completely dissolved. Sieve the prepared coating solution for later use.

[0118] b. Coating: Add the uncoated slices to the coating pan, and adjust the height of the coating spray gun according to the thickness of the slice bed to perform coating;

[0119] 9) Second wrapping:

[0120] a. Preparation of coating solution: Weigh the prescribed amount of purified water, add the prescribed amount of enteric film coating premix while stirring, and stir until completely dissolved. The prepared coating solution is then sieved for later use.

[0121] b. Coating and Aging: Add the flakes obtained from the first coating to the coating pan. Adjust the height of the coating spray gun according to the flake bed thickness and perform coating. After coating, complete the aging process in the coating pan.

[0122] The pharmaceutical composition prepared by this invention has good stability. Attached Figure Description

[0123] Figure 1 shows the release curves of dissolution tests for formulations 4 and 6;

[0124] Figure 2 shows the release curves under different skeleton materials;

[0125] Figure 3 shows the release curves at different amounts of hydroxypropyl methylcellulose / K100 Premium LVCR as the backbone material;

[0126] Figure 4 shows the release curves at different amounts of hydroxypropyl methylcellulose / K4M Premium CR as the backbone material;

[0127] Figure 5 shows the release curve when the skeleton material is applied externally;

[0128] Figures 6 and 7 show the release curves of the skeleton material with different types of adhesive combinations;

[0129] Figures 8 and 9 show the sustained-release effect under different types and amounts of fillers. Detailed Implementation

[0130] Example 1

[0131] A pharmaceutical composition comprising 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxobutylcyclo-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid, comprising a core, coating 1, and coating 2. The core comprises 6.029 mg of the active ingredient (calculated as tromethamine salt of compound I), 40 mg of hydroxypropyl methylcellulose (K100 Premium LVCR), 7.221 mg of microcrystalline cellulose (PH-113), 6 mg of magnesium oxide (light magnesium oxide powder), 0.45 mg of internally added magnesium stearate (MF-2-V-MB), and 0.3 mg of externally added magnesium stearate (MF-2-V-MB). Coating 1 contains 2.55–5.10 mg of hydroxypropyl methylcellulose (E5 Premium LV), 0.45–0.90 mg of polyethylene glycol 400, 26.53–53.06 mg of ethanol (95%), and 15.47–30.94 mg of purified water. Coating 2 contains 5.04–7.92 mg of film coating premix (enteric-coated, 93O18508-CN) and 20.16–31.68 mg of purified water.

[0132] The prescription is as follows:

[0133] Table 1 Examples of 5mg Specifications

[0134] Sustained-release tablets containing the above components are prepared using the following method:

[0135] 1) Premixed I

[0136] Microcrystalline cellulose, compound I tromethamine salt, hydroxypropyl methylcellulose, and magnesium oxide are added to a hopper mixer for mixing.

[0137] 2) Premixed II

[0138] Magnesium stearate (added internally) is added to the hopper mixer for mixing.

[0139] 3) Whole grains

[0140] After premixing II is completed, a fixed vacuum granulator is used for granulation.

[0141] 4) Premixed III

[0142] After granulation, the material is added to the hopper mixer for mixing;

[0143] 5) Dry granulation

[0144] The premixed material is then dry granulated.

[0145] 6) Total Mix

[0146] Add the prescribed amount of magnesium stearate (added externally) to the hopper mixer for total mixing.

[0147] 7) Tableting

[0148] Add the material to the hopper, set the relevant parameters according to the process requirements, and compress the tablets.

[0149] 8) Coating 1

[0150] (1) Preparation of coating solution:

[0151] Weigh out the prescribed amount of purified water, add the prescribed amount of ethanol, and while stirring, add the prescribed amounts of hydroxypropyl methylcellulose (LV) and polyethylene glycol 400. After all the ingredients have been added, stir until completely dissolved. Sieve the prepared coating solution for later use.

[0152] (2) Coating:

[0153] Add the uncoated film to the coating pan, and adjust the height of the coating spray gun according to the thickness of the film bed to perform coating.

[0154] 9) Coating 2

[0155] (1) Preparation of coating solution:

[0156] Weigh out the prescribed amount of purified water, and while stirring, add the prescribed amount of film coating premix (enteric-coated type). After it is completely added, stir until it is completely dissolved. Sieve the prepared coating solution for later use.

[0157] (2) Coating and aging:

[0158] Add the flakes obtained from coating step 1 into the coating pan. Adjust the height of the coating spray gun according to the thickness of the flake bed and perform coating. After coating, age the flakes in the coating pan.

[0159] Example 2

[0160] A pharmaceutical composition comprising 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxobutylcyclo-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid, comprising a core, coating 1, and coating 2. The core comprises 9.0435 mg of the active ingredient (calculated as tromethamine salt of compound I), 60 mg of hydroxypropyl methylcellulose (K100 Premium LVCR), 10.8315 mg of microcrystalline cellulose (PH-113), 9 mg of magnesium oxide (light magnesium oxide powder), 0.675 mg of internally added magnesium stearate (MF-2-V-MB), and 0.45 mg of externally added magnesium stearate (MF-2-V-MB). Coating 1 contains 3.825–7.65 mg of hydroxypropyl methylcellulose (E5 Premium LV), 0.675–1.35 mg of polyethylene glycol 400, 39.795–79.59 mg of ethanol (95%), and 23.205–46.41 mg of purified water. Coating 2 contains 7.56–11.88 mg of film coating premix (enteric-coated, 93O18508-CN) and 30.24–47.52 mg of purified water.

[0161] The prescription is as follows:

[0162] Table 2 Examples of 7.5mg Specification

[0163] The sustained-release tablets containing the above components are prepared according to Example 1.

[0164] Example 3

[0165] A pharmaceutical composition comprising 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxobutylcyclo-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid, comprising a core, coating 1, and coating 2. The core comprises 12.058 mg of the active ingredient (calculated as tromethamine salt of compound I), 80 mg of hydroxypropyl methylcellulose (K100 Premium LVCR), 14.442 mg of microcrystalline cellulose (PH-113), 12 mg of magnesium oxide (light magnesium oxide powder), 0.9 mg of internally added magnesium stearate (MF-2-V-MB), and 0.6 mg of externally added magnesium stearate (MF-2-V-MB). Coating 1 contains 5.1–10.2 mg of hydroxypropyl methylcellulose (E5 Premium LV), 0.9–1.8 mg of polyethylene glycol 400, 53.06–106.12 mg of ethanol (95%), and 30.94–61.88 mg of purified water. Coating 2 contains 10.08–15.84 mg of film coating premix (enteric-coated, 93O18508-CN) and 40.32–63.36 mg of purified water.

[0166] The prescription is as follows:

[0167] Table 3 Examples of 10mg Specification

[0168] The sustained-release tablets containing the above components are prepared according to Example 1.

[0169] Example 4

[0170] A pharmaceutical composition comprising 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxadiazon-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid, comprising a tablet core, coating 1, and coating 2. The formulation is as follows:

[0171] Table 4 Examples of 5mg Specification

[0172] Sustained-release tablets containing the above components are prepared using the following method:

[0173] 1) Premixing: Add the internal excipients into a wet formulation machine for mixing.

[0174] 2) Granulation: Add an appropriate amount of anhydrous ethanol for speed I granulation and speed II granulation.

[0175] 3) Drying: Transfer the wet granules to a fluidized bed granulator for drying.

[0176] 4) Granulation: The dried granules are granulated.

[0177] 5) Blending: Add the granulated particles and auxiliary materials other than lubricant into the hopper, set the mixing time and speed according to the process requirements, and perform blending I; after blending I is completed, add lubricant and perform blending II.

[0178] 6) Tableting: Set the relevant parameters of the tablet press and perform tableting.

[0179] 7) Coating 1

[0180] (1) Preparation of coating solution:

[0181] Weigh out the prescribed amount of purified water, add the prescribed amount of ethanol, and while stirring, add the prescribed amounts of hydroxypropyl methylcellulose (LV) and polyethylene glycol 400. After all the ingredients have been added, stir until completely dissolved. Sieve the prepared coating solution for later use.

[0182] (2) Coating:

[0183] Add the uncoated film to the coating pan, and adjust the height of the coating spray gun according to the thickness of the film bed to perform coating.

[0184] 8) Coating 2

[0185] (1) Preparation of coating solution:

[0186] Weigh out the prescribed amount of purified water, and while stirring, add the prescribed amount of film coating premix (enteric-coated type). After it is completely added, stir until it is completely dissolved. Sieve the prepared coating solution for later use.

[0187] (2) Coating and aging:

[0188] Add the flakes obtained from coating step 1 into the coating pan. Adjust the height of the coating spray gun according to the thickness of the flake bed and perform coating. After coating, age the flakes in the coating pan.

[0189] Example 5

[0190] A pharmaceutical composition comprising 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxadiazon-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid, comprising a tablet core, coating 1, and coating 2. The formulation is as follows:

[0191] Table 5 Examples of 7.5mg Specification

[0192] The sustained-release tablets containing the above components are prepared according to Example 4.

[0193] Example 6

[0194] A pharmaceutical composition comprising 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxadiazon-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid, comprising a tablet core, coating 1, and coating 2. The formulation is as follows:

[0195] Table 6 Examples of 10mg Specification

[0196] The sustained-release tablets containing the above components are prepared according to Example 4.

[0197] Example 7 Dissolution Detection

[0198] Dissolution testing was performed according to the second method (paddle method) of the Chinese Pharmacopoeia 0931. The medium was prepared using sodium dihydrogen phosphate, sodium hydroxide, and SDS at pH 6.8. The dissolution test was conducted at 37°C and 75 rpm, with samples taken at appropriate intervals for analysis. HPLC was used to detect compounds of formula I to determine the release amount, which was calculated as a percentage of the tablet's labeled content.

[0199] As shown in the table and Figure 1 below, Formulation 4 (5 mg) and Formulation 6 (10 mg) exhibit good sustained-release effects under this dissolution method.

[0200] Table 7 Cumulative Release Rates of Formulas 4 and 6

[0201] Example 8: Examination of the type and model of skeleton material (adhesive)

[0202] This embodiment examines the effect of different types and models of adhesives on the sustained-release effect.

[0203] The prescription composition used in this embodiment is shown in Tables 8-9.

[0204] Table 8. Examination of Skeleton Materials (Adhesives) 1

[0205] Preparation method:

[0206] (1) Mixing: Mix the active ingredients and internal excipients through a 60-mesh sieve until homogeneous.

[0207] (2) Dry granulation: Dry granulation is performed using the tableting method.

[0208] (3) Mixing: Add lubricant and mix through sieving.

[0209] (4) Tableting: Control the appropriate hardness and perform tableting.

[0210] Table 9. Examination of Skeleton Materials 2

[0211] Process:

[0212] (1) Wet granulation: Mix API and internal additives evenly through a 60-mesh sieve, add an appropriate amount of anhydrous ethanol, manually make soft material, and make wet granules through a 30-mesh sieve.

[0213] (2) Drying and granulation: Drying is carried out using an oven, and the drying process is completed when the moisture content is controlled to be ≤5%. After drying, the granules are granulated using a 24-mesh sieve.

[0214] (3) General mixing: Add the auxiliary materials other than the lubricant and mix through a 24-mesh sieve. After the mixing is completed, add the lubricant and mix through a 24-mesh sieve.

[0215] (4) Tableting: Control the appropriate hardness and perform tableting.

[0216] The dissolution assays for formulations 7-1, 7-3, 7-4, and 7-5 were performed using the methods described in Example 7. The cumulative release rates at each time point are shown in the table below and Figure 2.

[0217] Table 10 Cumulative Release Rate of Different Skeleton Materials

[0218] The results showed that formulation 7-1 was completely released within 24 hours, formulation 7-3 was completely released within 4-6 hours, and formulation 7-4 reached a plateau within 2-3 hours. Hydroxypropyl methylcellulose, sodium alginate, and sodium carboxymethyl cellulose exhibited different sustained-release effects when used as binders, with hydroxypropyl methylcellulose showing the best sustained-release effect.

[0219] Example 9: Investigation of the Dosage of Skeleton Material (Adhesive)

[0220] This embodiment examines the sustained-release effect under different amounts of adhesive.

[0221] The prescription composition used in this embodiment is shown in Tables 11-12.

[0222] Table 11 Investigation of Skeleton Material Usage 1

[0223] The preparation method of sustained-release tablets containing the above components is as described in Formula 7-1.

[0224] Table 12 Investigation of Skeleton Material Usage 2

[0225] The preparation method for sustained-release tablets containing the above components is as described in Formula 7-5.

[0226] Table 13 Investigation of Skeleton Material Usage 3

[0227] The sustained-release tablets containing the above components are prepared according to formulations 7-5. Dissolution studies are conducted according to Example 7.

[0228] As shown in Table 14 and Figure 3, formulations 8-1 and 8-2 exhibit good sustained-release effects when the matrix material is hydroxypropyl methylcellulose / K100 Premium LVCR at a dosage of 60%–70%. As shown in Table 15 and Figure 4, formulations 8-3 and 8-4 also exhibit good sustained-release effects when the matrix material is hydroxypropyl methylcellulose / K4M Premium CR at a dosage of 20%–30%. As shown in Table 16 and Figure 5, formulations 8-5 and 8-6 demonstrate that the addition of a matrix material can also achieve good sustained-release effects.

[0229] Table 14 Cumulative Release Rates of Formula 8-1 and Formula 8-2

[0230] Table 15 Cumulative Release Rates of Formulas 8-3 and 8-4

[0231] Table 16 Cumulative Release Rates of Formulas 8-5 and 8-6

[0232] Example 10: Investigation of the combination of skeleton materials (adhesives)

[0233] This embodiment examines the sustained-release effect under different combinations of adhesive types.

[0234] The prescription composition used in this embodiment is shown in Tables 17-20.

[0235] Table 17 Material Analysis of Composite Skeleton 1

[0236] The preparation method for sustained-release tablets containing the above components is as described in prescription 7-5.

[0237] Table 18 Material Analysis of Composite Skeleton 2

[0238] The preparation method for sustained-release tablets containing the above components is as described in Formula 7-5.

[0239] Table 19. Material Analysis of Composite Skeleton 3

[0240] The preparation method for sustained-release tablets containing the above components is as described in Formula 7-5.

[0241] Table 20 Material Analysis of Composite Skeleton 4

[0242] The preparation method for sustained-release tablets containing the above components is as described in Formula 7-5.

[0243] The dissolution test method is described in Example 7.

[0244] The results showed that formulations 9-1 to 9-7, which consisted of a combination of hydroxypropyl methylcellulose / K100 Premium LVCR and hydroxypropyl methylcellulose / K4MPremium CR as the matrix material, also exhibited a certain sustained-release effect when the total dosage was between 35% and 60%. Formulations 9-8 to 9-10 also exhibited a certain sustained-release effect when combined with other different types of hydroxypropyl methylcellulose as the matrix material.

[0245] Table 21 Cumulative Release Rate of Formula 9-3

[0246] Table 22 Cumulative Release Rate of Formulas 9-10

[0247] Table 23 Material Analysis of Composite Skeleton 5

[0248] The preparation method for sustained-release tablets containing the above components is as described in Formula 7-5.

[0249] Example 11 Investigation of different types and amounts of fillers

[0250] This embodiment examines the sustained-release effect under different types and amounts of fillers. The formulation composition used in this embodiment is shown in Tables 24 and 25.

[0251] Table 24. Filler Investigation 1

[0252] The preparation method of sustained-release tablets containing the above components is as described in Formula 7-1.

[0253] Table 25 Filler Investigation 2

[0254] The sustained-release tablets containing the above components are prepared according to Formulation 7-5. Dissolution testing methods are described in Example 7.

[0255] As shown in Tables 26-27 and Figures 8 and 9, Prescriptions 7-1, 10-1 to 10-4 demonstrate the ability of filler types and amounts to finely adjust the sustained-release effect.

[0256] Table 26 Cumulative Release Rates of Formula 10-1 and Formula 10-2

[0257] Table 27 Cumulative Release Rates of Formulas 10-3 and 10-4

[0258] Example 11 Pharmacokinetics in dogs

[0259] Methodology for canine PK research:

[0260] Animals were fasted overnight before administration of the drug, and fed 4 hours later. Before the experiment, dogs underwent gastric acid stimulation treatment: 30 minutes before administration, atropine sulfate solution (10 μg / 0.1 mL / kg) was administered intravenously, followed by pentagastrin solution (10 μg / 0.1 mL / kg) intramuscularly. A small amount of gastric juice was collected to measure the pH before administration. If the pH was 1–2, the oral administration of the drug continued; if the pH was >2, a different dog was used for the experiment. 60 minutes after administration, a small amount of gastric juice was collected to measure the pH. 45 minutes after the intravenous injection of atropine sulfate solution, a second intramuscular injection of pentagastrin solution (10 μg / 0.1 mL / kg) was administered. A third intramuscular injection of pentagastrin solution (10 μg / 0.1 mL / kg) was administered 45 minutes later.

[0261] All prescriptions were administered orally, with samples collected at predetermined time points. Blood samples were placed on ice immediately after collection and then centrifuged to separate the plasma (2-8℃). LC-MS / MS was used to analyze the samples, and pharmacokinetic parameters were calculated using blood drug concentration data at different time points.

[0262] Table 28. Canine Pharmacokinetic Data

[0263] The results showed that formulations 1 and 4 achieved good exposure in animals, and the exposure levels were comparable at a 5 mg dose; formulations 3, 6, and 9-11 also achieved good exposure in animals, and at a 10 mg dose, the exposure levels of formulations 3 and 6 were lower than those of formulation 9-11, achieving a good sustained-release effect.

Claims

1. A pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable excipient, said active ingredient being a GLP-1 receptor agonist, preferably 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxadicyclo-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid, its isomers, solvates, hydrates, or pharmaceutically acceptable salts thereof, or combinations thereof.

2. The pharmaceutical composition according to claim 1, wherein the active ingredient comprises the tromethamine salt of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxobutylcyclo-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The unit dose of the active ingredient is 1-200 mg, preferably 1-50 mg, more preferably 2-20 mg, and even more preferably 5 mg, 7.5 mg or 10 mg.

4. The pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition comprises a tablet core and one or more layers of coating, wherein the tablet core contains the active ingredient; preferably, the content of the active ingredient in the tablet core is 0.5-35 wt% by weight, more preferably 1-20 wt%, more preferably 5-15 wt%, and even more preferably 8.6% or 10%.

5. The pharmaceutical composition according to claim 4, characterized in that, The tablet core contains at least one pharmaceutically acceptable tablet core excipient, which includes one or more binders; preferably, the binder is selected from one or more of sucrose, starch, povidone, sodium carboxymethyl cellulose, sodium alginate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, pharmaceutical ethanol, and water, preferably hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and sodium alginate, and more preferably hydroxypropyl methylcellulose.

6. The pharmaceutical composition according to claim 5, characterized in that, The adhesive content is 10-80 wt%, preferably 15-35 wt%, more preferably 20-30 wt%; Alternatively, the adhesive content is 40-80 wt%, preferably 50-75 wt%, more preferably 60-70 wt%.

7. The pharmaceutical composition according to claim 4, characterized in that, The tablet core contains at least one pharmaceutically acceptable tablet core excipient, which includes one or more fillers; preferably, the filler includes one or more of microcrystalline cellulose, starch, lactose, sucrose, dextrin, mannitol, sorbitol, dicalcium phosphate, calcium carbonate or calcium sulfate, more preferably microcrystalline cellulose, lactose, mannitol, and more preferably microcrystalline cellulose.

8. The pharmaceutical composition according to claim 7, characterized in that, The content of the filler is 1-80 wt%, preferably 40-70 wt%, more preferably 50-60 wt%; Alternatively, the filler content is 1-30 wt%, preferably 5-20 wt%, more preferably 10-15 wt%.

9. The pharmaceutical composition according to claim 4, characterized in that, The tablet core contains at least one pharmaceutically acceptable tablet core excipient, which includes one or more antioxidants and / or pH adjusters; the antioxidants and / or pH adjusters are selected from one or more of magnesium oxide, sodium bicarbonate, sodium carbonate, fumaric acid, sodium bisulfite, sodium sulfite, sodium thiosulfate, sodium bisulfite, cysteine, butylated hydroxytoluene, tartaric acid, disodium edetate, and calcium sodium edetate, preferably selected from one or more of magnesium oxide, sodium bicarbonate, sodium carbonate, fumaric acid, and sodium bisulfite, more preferably selected from one or more of magnesium oxide and sodium bicarbonate, and more preferably magnesium oxide; The content of the antioxidant and / or pH adjuster is 1-30 wt%, more preferably 5-15 wt%, even more preferably 6-10 wt% or 8-12 wt%.

10. The pharmaceutical composition according to claim 9, characterized in that, The tablet core contains at least one pharmaceutically acceptable tablet core excipient, which includes one or more lubricants; The lubricant is selected from one or more of talc, stearic acid, sodium stearate fumarate, glyceryl behenate, magnesium stearate or micronized silica gel, preferably magnesium stearate; The lubricant content is 0.1-10 wt%, preferably 0.5-3 wt%, more preferably 0.75-1.5 wt%; Lubricant is added internally and / or externally.

11. The pharmaceutical composition according to claim 4, characterized in that, The chip core comprises the following components: Preferably, the chip core comprises the following components: More preferably, the core comprises the following components:

12. The pharmaceutical composition according to claim 4, characterized in that, The chip core comprises the following components: Preferably, the chip core comprises the following components: More preferably, the core comprises the following components:

13. The pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition is an oral preparation, preferably a tablet or capsule, more preferably a coated tablet, and even more preferably a sustained-release tablet.

14. A method for preparing the pharmaceutical composition according to any one of claims 1 to 13, characterized in that, Includes the following steps: 1) First premixing: Add fillers, active ingredients, binders, and antioxidants to a hopper mixer for mixing; 2) Second premixing: Add the internal lubricant to the hopper mixer for mixing; 3) Granulation: After the second premixing, granulation is performed using a fixed vacuum granulator; 4) Third premixing: The granulated material is added to the hopper mixer for mixing; 5) Dry granulation: The premixed material is granulated using a dry granulation process; 6) General mixing: Add the prescribed amount of lubricant to the hopper mixer and perform general mixing; 7) Optionally, compress into tablets; 8) Choose any location, coat; 9) Packaging, optional.

15. A method for preparing the pharmaceutical composition according to any one of claims 1 to 13, characterized in that, Includes the following steps: 1) Premixing: The filler, active ingredient, binder, antioxidant, and pH adjuster are added to a wet formulation machine for premixing; 2) Granulation: Add an appropriate amount of anhydrous ethanol for speed I granulation and speed II granulation; 3) Drying: Transfer the wet granules to a fluidized bed granulator for drying; 4) Granulation: The dried granules are granulated. 5) Blending: Add the granulated material, the prescribed amount of filler, and the prescribed amount of binder to the hopper mixer for blending I, and add the prescribed amount of lubricant to the hopper mixer for blending II; 6) Optionally, compress the tablets; 7) Choose any location, coat; 8) Packaging, optional.

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