Oral pharmaceutical composition containing dual receptor agonist of gip and glp-1 and use thereof

Abstract

Provided are an oral pharmaceutical composition containing a compound of formula (I) and the use thereof. Specifically, provided is an oral pharmaceutical composition comprising a compound of formula (I), a complex molecule, a compound containing a nitrogen atom functional group, a medium chain fatty acid or a salt thereof, and N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof. The compound of formula (I) is as shown below.

Description

Oral pharmaceutical compositions containing dual receptor agonists of GIP and GLP-1 and their uses

[0001] Cross-reference declaration

[0002] This disclosure claims priority to Chinese Patent Application No. 2024115777064, filed on November 6, 2024, entitled "Oral Pharmaceutical Composition Containing a Bireceptor Agonist of GIP and GLP-1 and Use Therein", the entire contents of which are incorporated herein by reference.

[0003] This disclosure claims priority to Chinese Patent Application No. 2025110240550, filed on July 24, 2025, entitled “Oral Pharmaceutical Composition Containing a Bireceptor Agonist of GIP and GLP-1 and Use Therein”, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This disclosure relates to the biopharmaceutical field, specifically to an oral pharmaceutical composition containing a dual receptor agonist of GIP and GLP-1 and its use. Background Technology

[0005] Glucose-dependent insulinotropic peptide (GIP) is a 42-amino acid gastrointestinal regulatory peptide that plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic β-cells and protecting pancreatic β-cells in the presence of glucose. Glucagon-like peptide-1 (GLP-1) is a 37-amino acid peptide that stimulates insulin secretion, protects pancreatic β-cells, and inhibits glucagon secretion, gastric emptying, and food intake, leading to weight loss. GIP and GLP-1 are secreted by K cells and L cells of the small intestinal endothelium, respectively, and are collectively known as incretins. Incretin receptor signaling plays a crucial physiological role in glucose homeostasis.

[0006] Studies have found that if blood glucose is lowered to a certain level, sensitivity to GIP can be restored, indicating that co-activation of GLP-1R / GIPR can exert a synergistic hypoglycemic effect. Dual receptor agonists of GIP and GLP-1 may produce superior hypoglycemic effects and insulin secretion stimulation. Therefore, the development of dual receptor agonists of GIP and GLP-1 has become a hot topic. Currently, dual receptor agonists of GIP and GLP-1 have been developed; for example, existing technical literature WO 2022 / 199629 A1 discloses a series of dual receptor agonists of GIP and GLP-1. However, because dual receptor agonists of GIP and GLP-1 are easily degraded in the gastrointestinal tract, their absorption and stability are poor. Even if they successfully cross the gastrointestinal barrier, their large molecular weight makes it difficult to enter the bloodstream through the intestinal mucosa, thus making it difficult to achieve sufficient bioavailability via oral administration.

[0007] It is well known that oral administration offers better patient compliance, ease of use, and a lower risk of infection compared to injection. Furthermore, the drug's absorption through the intestines and subsequent entry into the intravenous system for systemic metabolism is more gradual, helping to reduce the likelihood of sudden side effects. Therefore, there is an urgent need in this field to develop oral formulations of dual-receptor agonists of GIP and GLP-1. Summary of the Invention

[0008] The purpose of this disclosure is to provide an oral pharmaceutical composition.

[0009] Another object of this disclosure is to provide the use of the above-described oral pharmaceutical composition.

[0010] In one aspect, this disclosure provides an oral pharmaceutical composition comprising:

[0011] (i) The compound represented by formula (I) or its pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label or prodrug;

[0012] (ii) Coordinating molecules;

[0013] (iii) Compounds containing nitrogen-containing functional groups;

[0014] (iv) medium-chain fatty acids or their salts; and

[0015] (v) N-(8-[2-hydroxybenzoyl]amino)octanoic acid or a salt thereof;

[0016] Wherein, the coordinating molecule is a C containing a hydrophilic group. 6-10 Aromatic rings or containing hydrophilic groups C 5-10 Mixed fragrance ring;

[0017] The compound containing a nitrogen-atom functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of the substituent groups selected from -S(O)2OH and -OH.

[0018] In one aspect of this disclosure, the pharmaceutical composition includes an active ingredient, which is a compound represented by formula (I).

[0019] In one technical solution of this disclosure, the coordinating molecule or the compound containing nitrogen-atom functional groups is not covalently bonded to the compound shown in formula (I).

[0020] In one embodiment of this disclosure, the molecular weight of the compound containing nitrogen-containing functional groups does not exceed about 500 Da.

[0021] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 0.5% w / w of a dual receptor agonist of GIP and GLP-1.

[0022] In one embodiment of this disclosure, the pharmaceutical composition comprises a dual receptor agonist of GIP and GLP-1 at a concentration of not less than about 0.5% w / w and not more than about 15.0% w / w.

[0023] In one embodiment of this disclosure, the pharmaceutical composition comprises a dual receptor agonist of GIP and GLP-1 at a concentration of not less than about 0.5% w / w and not more than about 10.0% w / w.

[0024] In one embodiment of this disclosure, the pharmaceutical composition comprises a dual receptor agonist of GIP and GLP-1 at a concentration of not less than about 0.5% w / w and not more than about 5.0% w / w.

[0025] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 20.0% w / w of medium-chain fatty acids or their salts.

[0026] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 25% w / w of medium-chain fatty acids or their salts.

[0027] In one embodiment of this disclosure, the pharmaceutical composition comprises no more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0028] In one embodiment of this disclosure, the pharmaceutical composition comprises no more than about 45% w / w of medium-chain fatty acids or their salts.

[0029] In one embodiment of this disclosure, the pharmaceutical composition comprises no more than about 40% w / w of medium-chain fatty acids or their salts.

[0030] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0031] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 25.0% w / w and not more than about 40% w / w of medium-chain fatty acids or their salts.

[0032] In one embodiment of this disclosure, the pharmaceutical composition comprises approximately 20% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 24.5% w / w, 24.8% w / w, 25% w / w, 25.1% w / w, 25.3% w / w, 25.5% w / w, 26% w / w, 26.5% w / w, and 26.8% w / w. , 26.9% w / w, 27% w / w, 27.1% w / w, 27.2% w / w, 27.4% w / w, 27.5% w / w, 27.6% w / w, 27.7% w / w, 27.9% w / w, 28% w / w, 28.5% w / w, 28.9% w / w, 29% w / w, 30% w / w, 35% w / w medium chain fatty acids or salts thereof.

[0033] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 20.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0034] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 25% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0035] In one embodiment of this disclosure, the pharmaceutical composition comprises no more than about 50.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0036] In one embodiment of this disclosure, the pharmaceutical composition comprises no more than about 45% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0037] In one embodiment of this disclosure, the pharmaceutical composition comprises no more than about 40% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0038] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0039] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 25.0% w / w and not more than about 40% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0040] In one embodiment of this disclosure, the pharmaceutical composition comprises about 20% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 24.5% w / w, 25% w / w, 25.1% w / w, 25.2% w / w, 25.3% w / w, 25.5% w / w, 26% w / w, 26.5% w / w, 27% w / w, 27.5% w / w, 27.7% w / w, 28% w / w, 28.3% w / w, 28.5% w / w, 29% w / w, 30% w / w, or 35% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0041] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 5.0% w / w of a compound containing a nitrogen-containing functional group.

[0042] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 7.0% w / w of a compound containing a nitrogen-containing functional group.

[0043] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 8.0% w / w of a compound containing a nitrogen-containing functional group.

[0044] In one embodiment of this disclosure, the pharmaceutical composition comprises not less than about 9.0% w / w of a compound containing a nitrogen-containing functional group.

[0045] In one aspect of this disclosure, the pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a rate not exceeding about 30.0 w / w; for example, not exceeding about 25% w / w; not exceeding about 24% w / w; not exceeding about 23% w / w; not exceeding about 22% w / w; not exceeding about 21% w / w; and not exceeding about 20% w / w.

[0046] In one embodiment of this disclosure, the pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 5.0% w / w and not more than about 30.0 w / w.

[0047] In one embodiment of this disclosure, the pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 9.0% w / w and not more than about 20.0 w / w.

[0048] In one embodiment of this disclosure, the pharmaceutical composition comprises approximately 5% w / w, 8% w / w, 9% w / w, 10% w / w, 13% w / w, 14% w / w, 15% w / w, 16% w / w, 16.2% w / w, 16.4% w / w, 16.5% w / w, 16.6% w / w, 16.7% w / w, 16.8% w / w, 16.9% w / w, 17% w / w, 17.1% w / w, and 17.5% w / w. w, 17.7% w / w, 17.9% w / w, 18.0% w / w, 18.1% w / w, 18.2% w / w, 18.3% w / w, 18.4% w / w, 18.5% w / w, 18.6% w / w, 18.7% w / w, 18.8% w / w, 18.9% w / w, 19% w / w, 19.5% w / w, 20% w / w, 25% w / w, 30% w / w compounds containing nitrogen atom functional groups.

[0049] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule of not less than about 5.0% w / w.

[0050] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule of not less than about 7.0% w / w.

[0051] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule of not less than about 8.0% w / w.

[0052] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule of not less than about 9.0% w / w.

[0053] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule of no more than about 30.0% w / w.

[0054] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule of no more than about 25% w / w.

[0055] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule of no more than about 18.0% w / w.

[0056] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule of no more than about 16.0% w / w.

[0057] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule of no more than about 15.0% w / w.

[0058] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule comprising not less than about 5.0% w / w and not more than about 30.0 w / w.

[0059] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule comprising not less than about 5.0% w / w and not more than about 20.0 w / w.

[0060] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule comprising not less than about 5.0% w / w and not more than about 15.0% w / w.

[0061] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule comprising not less than about 5.0% w / w and not more than about 10.0 w / w.

[0062] In one embodiment of this disclosure, the pharmaceutical composition comprises about 5% w / w, 6% w / w, 7% w / w, 8% w / w, 8.3% w / w, 8.4% w / w, 8.5% w / w, 8.6% w / w, 8.7% w / w, 8.8% w / w, 8.9% w / w, 9% w / w, 9.1% w / w, 9.2% w / w, 9.3% w / w, 9.4% w / w, 9.5% w / w, 9.6% w / w, 9.7% w / w, 9.8% w / w, 9.9% w / w, and 10% w / w of a coordinating molecule.

[0063] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule comprising not less than about 9.0% w / w and not more than about 30.0% w / w.

[0064] In one embodiment of this disclosure, the pharmaceutical composition comprises a complexing molecule comprising not less than about 9.0% w / w and not more than about 20.0% w / w.

[0065] In one embodiment of this disclosure, the pharmaceutical composition comprises about 1-50 parts by weight of the compound represented by formula (I).

[0066] In one embodiment of this disclosure, the pharmaceutical composition comprises about 1-20 parts by weight of the compound represented by formula (I).

[0067] In one embodiment of this disclosure, the pharmaceutical composition comprises about 1-10 parts by weight of the compound represented by formula (I).

[0068] In one embodiment of this disclosure, the pharmaceutical composition comprises about 5-10 parts by weight of the compound represented by formula (I).

[0069] In one embodiment of this disclosure, the pharmaceutical composition comprises about 10-40 parts by weight of the compound represented by formula (I).

[0070] In one embodiment of this disclosure, the pharmaceutical composition comprises about 10-200 parts by weight of a complexing molecule.

[0071] In one embodiment of this disclosure, the pharmaceutical composition comprises about 10-100 parts by weight of a complexing molecule.

[0072] In one embodiment of this disclosure, the pharmaceutical composition comprises about 30-100 parts by weight of a complexing molecule.

[0073] In one embodiment of this disclosure, the pharmaceutical composition comprises about 50-100 parts by weight of a complexing molecule.

[0074] In one embodiment of this disclosure, the pharmaceutical composition comprises about 10-500 parts by weight of a compound containing a nitrogen-atom functional group.

[0075] In one embodiment of this disclosure, the pharmaceutical composition comprises about 10-200 parts by weight of a compound containing a nitrogen-atom functional group.

[0076] In one embodiment of this disclosure, the pharmaceutical composition comprises about 30-200 parts by weight of a compound containing a nitrogen-atom functional group.

[0077] In one aspect of this disclosure, the pharmaceutical composition comprises about 50-150 parts by weight of a compound containing a nitrogen-atom functional group.

[0078] In one embodiment of this disclosure, the pharmaceutical composition comprises about 50-100 parts by weight of a compound containing a nitrogen-atom functional group.

[0079] In one embodiment of this disclosure, the pharmaceutical composition comprises about 100-500 parts by weight of a medium-chain fatty acid or a salt thereof.

[0080] In one embodiment of this disclosure, the pharmaceutical composition comprises about 100-300 parts by weight of a medium-chain fatty acid or a salt thereof.

[0081] In one embodiment of this disclosure, the pharmaceutical composition comprises about 100-200 parts by weight of a medium-chain fatty acid or a salt thereof.

[0082] In one embodiment of this disclosure, the pharmaceutical composition comprises about 150-200 parts by weight of a medium-chain fatty acid or a salt thereof.

[0083] In one embodiment of this disclosure, the pharmaceutical composition comprises about 100-500 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0084] In one embodiment of this disclosure, the pharmaceutical composition comprises about 100-300 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0085] In one embodiment of this disclosure, the pharmaceutical composition comprises about 100-200 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0086] In one embodiment of this disclosure, the pharmaceutical composition comprises about 150-200 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0087] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 5-150 mg of the compound represented by formula (I); for example, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg.

[0088] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 5-100 mg of the compound represented by formula (I); for example, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, or 100 mg.

[0089] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-200 mg of a complexing molecule.

[0090] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-100 mg of a complexing molecule.

[0091] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 30-100 mg of a complexing molecule.

[0092] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 30-70 mg of a complexing molecule; for example, 30 mg, 40 mg, 55 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, or 100 mg.

[0093] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-500 mg of a compound containing a nitrogen-containing functional group.

[0094] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-200 mg of a compound containing a nitrogen-containing functional group.

[0095] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 30-150 mg of a compound containing a nitrogen-containing functional group; for example, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 100 mg, 120 mg, or 150 mg.

[0096] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-500 mg of medium-chain fatty acids or salts thereof.

[0097] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-300 mg of medium-chain fatty acids or their salts.

[0098] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 130-180 mg of medium-chain fatty acids or their salts; for example, 100 mg, 110 mg, 130 mg, 150 mg, 160 mg, or 180 mg.

[0099] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-500 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0100] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-300 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0101] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 130-180 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof; for example, 100 mg, 110 mg, 130 mg, 150 mg, 160 mg, or 180 mg.

[0102] In one embodiment of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing a nitrogen-containing functional group or its salt in the pharmaceutical composition is 1:(1-2.5); for example, 1:2 or 1:1.

[0103] In one embodiment of this disclosure, the mass percentage ratio of the medium-chain fatty acid or its salt to the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the pharmaceutical composition is 1:(0.8-1.2); for example, 1:1.

[0104] In one technical solution of this disclosure, the mass percentage ratio of the medium-chain fatty acid or its salt, the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, the complexing molecule, and the compound containing the nitrogen-containing functional group in the pharmaceutical composition is 3:3:1:1 or 3:3:2:2 or 3:3:1:2 or 3:3:2:1.

[0105] In one technical solution of this disclosure, the mass percentage ratio of sodium decanoate, sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC), arginine or lysine, and nicotinamide in the pharmaceutical composition is 3:3:1:1, 3:3:2:2, 3:3:1:2, or 3:3:2:1.

[0106] In one embodiment of this disclosure, the pharmaceutical composition comprises, by mass percentage, the compound of formula (I), the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt, in the ratio of (1-10):(10-100):(10-100):(100-500):(100-500) (); preferably (1-10):(10-100):(10-100):(100-300):(100-300); preferably (4-10):(30-100):(50-100):(100-200):(100-200); for example 7:50:50:150:150, or 7:50:100:150:150 or 7:100:50:150:150.

[0107] In one embodiment of this disclosure, the pharmaceutical composition comprises, by mass percentage, the compound of formula (I), the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt, in the ratio of (5-100):(10-100):(10-150):(75-300):(75) -300); preferably (5-100):(30-100):(50-100):(100-200):(100-200); for example 10:50:100:150:150, 20:50:100:150:150, 40:50:100:150:150, 60:50:100:150:150 or 80:50:100:150:150.

[0108] In one embodiment of this disclosure, the compound containing a nitrogen-containing functional group contains an amino group and -C(O)OH, an amino group and -C(O)OH; or contains an amino group and -S(O)2OH, an amino group and -S(O)2OH; or contains a quaternary ammonium group and -C(O)O - It may contain quaternary ammonium groups and -OH; or it may contain quaternary ammonium groups and -C(O)O. - and -OH.

[0109] In one technical solution disclosed herein, the molecular weight of the compound containing nitrogen-atom functional groups ranges from 50 to 250 g / mol, wherein the molecular weight of the compound containing nitrogen-atom functional groups is in free form.

[0110] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is C. 1-8 Compounds containing amino, amine, or quaternary ammonium functional groups.

[0111] In one embodiment of this disclosure, the compound containing an amino or quaternary ammonium functional group is selected from at least one of amino acids, L-carnitine, taurine, betaine, choline, choline chloride, and carnitine. The amino acids are selected from natural or synthetic amino acids.

[0112] In one technical solution disclosed herein, the amino acid is selected from at least one of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, asparagine, glutamine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, sarcosine, γ-aminobutyric acid, ornithine, and citrulline.

[0113] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is an amino acid.

[0114] In one technical solution of this disclosure, the compound containing the nitrogen-atom functional group is arginine or lysine; arginine is preferred.

[0115] In one embodiment of this disclosure, the pharmaceutical composition contains 1, 2, 3, 4, or 5 of the compounds containing nitrogen-containing functional groups.

[0116] In one technical solution of this disclosure, the hydrophilic group in the complexing molecule is not a ribosome or a deoxyribosome.

[0117] In one technical solution disclosed herein, in the coordination molecule, C 6- C 10 Aromatic ring or C 5- C 10 The heteroaryl ring is not replaced by ribosyl or deoxyribosyl groups.

[0118] In one technical solution disclosed herein, the ligand is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0119] In one technical solution disclosed herein, the ligand is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide; more preferably, nicotinamide.

[0120] In one embodiment of this disclosure, the drug combination contains 1, 2, 3, 4, or 5 of the aforementioned ligand molecules.

[0121] In one technical solution of this disclosure, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is a sodium salt, potassium salt, or ammonium salt.

[0122] In one technical solution of this disclosure, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC).

[0123] In one technical solution disclosed herein, the medium-chain fatty acid or its salt is C 6-14 Carboxylic acid or C 6-14 Carboxylate; preferably C 8-14 Carboxylic acid or C 8-14 Carboxylates.

[0124] In one technical solution disclosed herein, the medium-chain fatty acid or its salt is a saturated C 8-12 Straight-chain carboxylic acids or their salts.

[0125] In one embodiment of this disclosure, the medium-chain fatty acid is selected from octanoic acid (C8) and decanoic acid (C9). 10 ), n-Undecanoic acid (C 11 ) and n-dodecanoic acid (C 12 Preferred to be decanoic acid (C); 10 ).

[0126] In one technical solution of this disclosure, the medium-chain fatty acid salt is a sodium salt, potassium salt, or ammonium salt; preferably, it is a sodium salt.

[0127] In one technical solution of this disclosure, the medium-chain fatty acid salt is sodium decanoate (SD).

[0128] In one embodiment of this disclosure, the pharmaceutical composition contains 1, 2, 3, 4, or 5 of the medium-chain fatty acids or their salts.

[0129] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0130] The compound represented by formula (I) – about 1-50 parts by weight;

[0131] Nicotinamide – approximately 10-200 parts by weight;

[0132] Arginine and / or lysine – approximately 10-500 parts by weight;

[0133] Sodium decanoate – approximately 100-500 parts by weight; and

[0134] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 100-500 parts by weight.

[0135] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0136] The compound represented by formula (I) – about 1-50 parts by weight;

[0137] Nicotinamide – 50 ± 10% by weight;

[0138] Arginine and / or lysine – 100 ± 10% by weight;

[0139] Sodium decanoate – 150 ± 10% by weight; and

[0140] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate—150±10% by weight.

[0141] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0142] The compound represented by formula (I) – about 1-50 parts by weight;

[0143] Nicotinamide – approximately 50 parts by weight;

[0144] Arginine and / or lysine – approximately 100 parts by weight;

[0145] Sodium decanoate – approximately 150 parts by weight; and

[0146] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate – approximately 150 parts by weight.

[0147] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0148] The compound represented by formula (I) – about 1-50 parts by weight;

[0149] Nicotinamide – approximately 10-100 parts by weight;

[0150] Arginine and / or lysine – approximately 50-150 parts by weight;

[0151] Sodium decanoate – approximately 100-300 parts by weight; and

[0152] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate – approximately 100-300 parts by weight.

[0153] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient, the content of which is not higher than about 20% w / w.

[0154] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient of no more than about 15% w / w.

[0155] In one technical solution of this disclosure, the excipient is selected from one or more of fillers, disintegrants, and lubricants.

[0156] In one embodiment of this disclosure, the excipient is selected from one or more of fillers, disintegrants, lubricants, and adhesives.

[0157] In one technical solution disclosed herein, the filler is selected from at least one of starch, powdered sugar, dextrin, lactose, microcrystalline cellulose, pregelatinized starch, mannitol, and calcium sulfate.

[0158] In one technical solution disclosed herein, the filler is microcrystalline cellulose.

[0159] In one technical solution disclosed herein, the lubricant is selected from at least one of magnesium stearate, micronized silica gel, talc, polyethylene glycol, and sodium dodecyl sulfate.

[0160] In one technical solution disclosed herein, the lubricant is sodium dodecyl sulfate.

[0161] In one technical solution disclosed herein, the lubricant is sodium dodecyl sulfate and magnesium stearate.

[0162] In one technical solution disclosed herein, the disintegrant is selected from at least one of dry starch, sodium carboxymethyl cellulose, low-substituted carboxymethyl cellulose, croscarmellose, croscarmellose sodium, and sodium carboxymethyl starch.

[0163] In one technical solution disclosed herein, the adhesive is selected from one or more of povidone, crospovidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

[0164] In one technical solution disclosed herein, the adhesive is polyvinyl chloride, more preferably polyvinyl chloride K90.

[0165] In one technical solution disclosed herein, the disintegrant is sodium carboxymethyl starch. In one aspect of this disclosure, the content of the filler is no higher than about 15.0% w / w, based on a pharmaceutical composition of 100% w / w; for example, 14.6% w / w, 14.5% w / w, 14.0% w / w, 13.5% w / w, 13.0% w / w, 12.7% w / w, 12.5% ​​w / w, 12.0% w / w, 11.8% w / w, 11.6% w / w, 10.0% w / w, 9.6% w / w, 9.5% w / w, 9.3% w / w, 9.2% w / w, 9.0% w / w, 8.9% w / w, 8.8% w / w, 8.5% w / w, 8.3% w / w, 7.5% w / w, 7.3% w / w, or 7.0% w / w.

[0166] In one aspect of this disclosure, the lubricant content is no higher than about 3.0% w / w, based on a pharmaceutical composition of 100% w / w; for example, 2.7% w / w, 2.4% w / w, 2.5% w / w, 2.2% w / w, 2.0%, 1.9% w / w, 1.7% w / w, 1.6% w / w, 1.4% w / w, 1.3% w / w, 1.2% w / w, 1.1% w / w, or 1.0% w / w.

[0167] In one embodiment of this disclosure, the content of the disintegrant is no higher than about 5.0% w / w, based on a pharmaceutical composition of 100% w / w; for example, 5.0% w / w, 4.9% w / w, 4.7% w / w, 4.5% w / w, 4.1% w / w, 4.0% w / w, 3.8% w / w, 3.3% w / w, 3.2% w / w, 3.0% w / w, 2.7% w / w, 2.6% w / w, 2.4% w / w, 2.3% w / w, 2.2% w / w, 2.1% w / w, 2.0% w / w, 1.8% w / w, 1.9% w / w, 1.6% w / w, or 1.5% w / w.

[0168] In one embodiment of this disclosure, the binder content is no higher than about 5.0% w / w, based on a pharmaceutical composition of 100% w / w; for example, 5.0% w / w, 4.0% w / w, 3.0% w / w, 2.7% w / w, 2.6% w / w, 2.4% w / w, 2.3% w / w, 2.2% w / w, 2.1% w / w, 2.0% w / w, 1%. 8%w / w, 1.9%w / w, 1.6%w / w, 1.4%w / w, 1.3%w / w, 1.2%w / w, 1.1%w / w, 1.0%w / w, 0.9%w / w, 0.8% w / w, 0.7% w / w, 0.6% w / w, 0.5% w / w, 0.4% w / w, 0.3% w / w, 0.2% w / w, 0.1% w / w.

[0169] In one embodiment of this disclosure, the excipients include microcrystalline cellulose, sodium dodecyl sulfate, and sodium carboxymethyl starch.

[0170] In one embodiment of this disclosure, the excipient comprises microcrystalline cellulose at a concentration of not less than about 5.0% w / w and not more than about 15.0 w / w, based on a pharmaceutical composition of 100% w / w.

[0171] In one embodiment of this disclosure, the excipient comprises sodium dodecyl sulfate at a concentration of not less than about 0.01% w / w and not more than about 3.0% w / w, based on a pharmaceutical composition of 100% w / w.

[0172] In one embodiment of this disclosure, the excipient comprises sodium carboxymethyl starch at a concentration of not less than about 0.1% w / w and not more than about 5.0% w / w, based on a pharmaceutical composition of 100% w / w.

[0173] In one embodiment of this disclosure, the excipients, based on a pharmaceutical composition of 100% w / w, comprise about 5.0-10.0% w / w microcrystalline cellulose, about 0.01-3.0% w / w sodium dodecyl sulfate, and about 0.1%-5.0% w / w sodium carboxymethyl starch.

[0174] In one embodiment of this disclosure, the excipients include microcrystalline cellulose, sodium dodecyl sulfate, sodium carboxymethyl starch, magnesium stearate, and povidone.

[0175] In one embodiment of this disclosure, the excipients, based on a pharmaceutical composition of 100% w / w, include about 5.0-10.0% w / w microcrystalline cellulose, about 0.01-3.0% w / w sodium dodecyl sulfate, about 0.1%-5.0% w / w sodium carboxymethyl starch, about 0.1-3.0% w / w magnesium stearate, and about 0.1%-5.0% w / w povidone.

[0176] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0177] The compound represented by formula (I) – about 1-50 parts by weight;

[0178] Nicotinamide – approximately 10-200 parts by weight;

[0179] Arginine and / or lysine – approximately 10-500 parts by weight;

[0180] Sodium decanoate – approximately 100-500 parts by weight; and

[0181] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — Approximately 100-500 parts by weight;

[0182] Excipients – approximately 12-150 parts by weight.

[0183] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0184] The compound represented by formula (I) – about 1-50 parts by weight;

[0185] Nicotinamide – approximately 10-100 parts by weight;

[0186] Arginine and / or lysine – approximately 50-150 parts by weight;

[0187] Sodium decanoate – approximately 100-300 parts by weight; and

[0188] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – approximately 100-300 parts by weight;

[0189] Excipients – approximately 12-150 parts by weight.

[0190] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0191] The compound represented by formula (I) – about 1-50 parts by weight (e.g., 10, 20, 40 parts by weight);

[0192] Nicotinamide – 50 ± 10% by weight;

[0193] Arginine and / or lysine – 100 ± 10% by weight;

[0194] Sodium decanoate – 150 ± 10% by weight; and

[0195] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate—150±10% by weight;

[0196] Excipients – approximately 12-150 parts by weight.

[0197] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0198] The compound represented by formula (I) – about 1-50 parts by weight (e.g., 10, 20, 40 parts by weight);

[0199] Nicotinamide – approximately 50 parts by weight;

[0200] Arginine and / or lysine – approximately 100 parts by weight;

[0201] Sodium decanoate – approximately 150 parts by weight; and

[0202] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – approximately 150 parts by weight;

[0203] Excipients – approximately 12-150 parts by weight.

[0204] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0205] The compound represented by formula (I) – about 1-50 parts by weight (e.g., 10, 20, 40 parts by weight);

[0206] Nicotinamide – 50 parts by weight;

[0207] Arginine and / or lysine – 100 parts by weight;

[0208] Sodium decanoate – 150 parts by weight; and

[0209] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – 150 parts by weight;

[0210] Excipients – 30-100 parts by weight.

[0211] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0212] The compound represented by formula (I) – about 1-50 parts by weight (e.g., 10, 20, 40 parts by weight);

[0213] Nicotinamide – approximately 50 parts by weight;

[0214] Arginine and / or lysine – approximately 100 parts by weight;

[0215] Sodium decanoate – approximately 150 parts by weight; and

[0216] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – approximately 150 parts by weight;

[0217] Excipients – approximately 40-90 parts by weight.

[0218] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0219] The compound shown in formula (I) – about 5-10 parts by weight;

[0220] Nicotinamide – approximately 50-100 parts by weight;

[0221] Arginine and / or lysine – approximately 50-100 parts by weight;

[0222] Sodium decanoate – approximately 150-200 parts by weight;

[0223] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate—approximately 150-200 parts by weight; and

[0224] Excipients – approximately 30-80 parts by weight.

[0225] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0226] The compound represented by formula (I) – about 1-50 parts by weight;

[0227] Nicotinamide – approximately 10-200 parts by weight;

[0228] Arginine and / or lysine – approximately 10-500 parts by weight;

[0229] Sodium decanoate – approximately 100-500 parts by weight; and

[0230] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — Approximately 100-500 parts by weight;

[0231] Filler – approximately 10-80 parts by weight;

[0232] Lubricant – approximately 1-15 parts by weight; and

[0233] Disintegrant – approximately 1-30 parts by weight.

[0234] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0235] The compound shown in formula (I) – about 5-10 parts by weight;

[0236] Nicotinamide – approximately 50-100 parts by weight;

[0237] Arginine and / or lysine – approximately 50-100 parts by weight;

[0238] Sodium decanoate – approximately 150-200 parts by weight;

[0239] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – approximately 150-200 parts by weight;

[0240] Filler – approximately 30-60 parts by weight;

[0241] Lubricant – approximately 1-10 parts by weight; and

[0242] Disintegrant – approximately 5-20 parts by weight.

[0243] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0244] The compound represented by formula (I) – about 1-50 parts by weight;

[0245] Nicotinamide – approximately 10-200 parts by weight;

[0246] Arginine – approximately 10-500 parts by weight;

[0247] Sodium decanoate – approximately 100-500 parts by weight; and

[0248] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — Approximately 100-500 parts by weight;

[0249] Filler – approximately 10-80 parts by weight;

[0250] Lubricant – approximately 1-15 parts by weight; and

[0251] Disintegrant – approximately 1-30 parts by weight.

[0252] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0253] The compound shown in formula (I) – about 5-10 parts by weight;

[0254] Nicotinamide – approximately 50-100 parts by weight;

[0255] Arginine – approximately 50-100 parts by weight;

[0256] Sodium decanoate – approximately 150-200 parts by weight;

[0257] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – approximately 150-200 parts by weight;

[0258] Filler – approximately 30-60 parts by weight;

[0259] Lubricant – approximately 1-10 parts by weight; and

[0260] Disintegrant – approximately 5-20 parts by weight.

[0261] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0262] The compound represented by formula (I) – about 1-50 parts by weight;

[0263] Nicotinamide – approximately 10-200 parts by weight;

[0264] Lysine – approximately 10-500 parts by weight;

[0265] Sodium decanoate – approximately 100-500 parts by weight; and

[0266] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — Approximately 100-500 parts by weight;

[0267] Filler – approximately 10-80 parts by weight;

[0268] Lubricant – approximately 1-15 parts by weight; and

[0269] Disintegrant – approximately 1-30 parts by weight.

[0270] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0271] The compound shown in formula (I) – about 5-10 parts by weight;

[0272] Nicotinamide – approximately 50-100 parts by weight;

[0273] Lysine – approximately 50-100 parts by weight;

[0274] Sodium decanoate – approximately 150-200 parts by weight;

[0275] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – approximately 150-200 parts by weight;

[0276] Filler – approximately 30-60 parts by weight;

[0277] Lubricant – approximately 1-10 parts by weight; and

[0278] Disintegrant – approximately 5-20 parts by weight.

[0279] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0280] The compound represented by formula (I) — 7 ± 10% by weight;

[0281] Nicotinamide – 50 ± 10% by weight;

[0282] Arginine or lysine – 50 ± 10% by weight;

[0283] Sodium decanoate – 150 ± 10% by weight;

[0284] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight; and

[0285] Excipients – approximately 30-80 parts by weight (e.g., 53 parts by weight).

[0286] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0287] The compound shown in formula (I) – approximately 7 parts by weight;

[0288] Nicotinamide – approximately 50 parts by weight;

[0289] Arginine or lysine – approximately 50 parts by weight;

[0290] Sodium decanoate – approximately 150 parts by weight;

[0291] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight; and

[0292] Excipients – approximately 30-80 parts by weight (e.g., 53 parts by weight).

[0293] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0294] The compound shown in formula (I) – approximately 7 mg;

[0295] Nicotinamide – approximately 50mg;

[0296] Arginine or lysine – approximately 50 mg;

[0297] Sodium decanoate – approximately 150 mg;

[0298] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 mg; and

[0299] Excipients – approximately 30-80 mg (e.g., 53 mg).

[0300] In one technical solution of this disclosure, the excipient includes:

[0301] Filler (preferably microcrystalline cellulose) – 39 ± 10% by weight;

[0302] Lubricant (preferably sodium dodecyl sulfate) – 5 ± 10% by weight; and

[0303] Disintegrant (preferably sodium carboxymethyl starch) – 9 ± 10% by weight.

[0304] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0305] The compound represented by formula (I) — 7 ± 10% by weight;

[0306] Nicotinamide – 50 ± 10% by weight;

[0307] Arginine – 50 ± 10% by weight;

[0308] Sodium decanoate – 150 ± 10% by weight;

[0309] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight;

[0310] Filler – 39 ± 10% by weight;

[0311] Lubricant – 5 ± 10% by weight; and

[0312] Disintegrant – 9 ± 10% by weight.

[0313] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0314] The compound shown in formula (I) – approximately 7 parts by weight;

[0315] Nicotinamide – approximately 50 parts by weight;

[0316] Arginine – approximately 50 parts by weight;

[0317] Sodium decanoate – approximately 150 parts by weight;

[0318] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight;

[0319] Filler – approximately 39 parts by weight;

[0320] Lubricant – approximately 5 parts by weight; and

[0321] Disintegrant – approximately 9 parts by weight.

[0322] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0323] The compound represented by formula (I) — 7 ± 10% by weight;

[0324] Nicotinamide – 50 ± 10% by weight;

[0325] Lysine – 50 ± 10% by weight;

[0326] Sodium decanoate – 150 ± 10% by weight;

[0327] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight;

[0328] Microcrystalline cellulose – 39 ± 10% by weight;

[0329] Sodium dodecyl sulfate—5 ± 10% by weight; and

[0330] Sodium carboxymethyl starch – 9 ± 10% by weight.

[0331] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0332] The compound shown in formula (I) – approximately 7 parts by weight;

[0333] Nicotinamide – approximately 50 parts by weight;

[0334] Lysine – approximately 50 parts by weight;

[0335] Sodium decanoate – approximately 150 parts by weight;

[0336] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight;

[0337] Microcrystalline cellulose – approximately 39 parts by weight;

[0338] Sodium dodecyl sulfate – approximately 5 parts by weight; and

[0339] Sodium carboxymethyl starch – approximately 9 parts by weight.

[0340] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0341] The compound represented by formula (I) — 7 ± 10% by weight;

[0342] Nicotinamide – 50 ± 10% by weight;

[0343] Arginine or lysine – 100 ± 10% by weight;

[0344] Sodium decanoate – 150 ± 10% by weight; and

[0345] N-(8-[2-hydroxybenzoyl]amino)octanoic acid sodium (SNAC) — 150 ± 10% by weight.

[0346] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0347] The compound shown in formula (I) – approximately 7 parts by weight;

[0348] Nicotinamide – approximately 50 parts by weight;

[0349] Arginine or lysine – approximately 100 parts by weight;

[0350] Sodium decanoate – approximately 150 parts by weight; and

[0351] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight.

[0352] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0353] Compounds of formula (I) in approximately 1.0%–10.0% w / w; and

[0354] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) at approximately 20.0%–40% w / w; and

[0355] Approximately 10.0%-20.0% w / w of arginine or lysine; and

[0356] Approximately 7.0%–25.0% w / w nicotinamide; and

[0357] Sodium decanoate, approximately 20.0%-40.0% w / w.

[0358] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0359] The compound represented by formula (I) at approximately 1.0%–2.0% w / w; and

[0360] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) at approximately 20.0%–40% w / w; and

[0361] Approximately 10.0%-20.0% w / w of arginine or lysine; and

[0362] Approximately 7.0%–25.0% w / w nicotinamide; and

[0363] Sodium decanoate, approximately 20.0%-40.0% w / w.

[0364] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0365] Compounds of formula (I) in approximately 1.0%–10.0% w / w; and

[0366] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) at approximately 20.0%–35% w / w; and

[0367] Approximately 10.0%-20.0% w / w of arginine or lysine; and

[0368] Approximately 7.0%-15.0% w / w nicotinamide; and

[0369] Sodium decanoate, approximately 20.0%-40.0% w / w.

[0370] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0371] The compound represented by formula (I) at approximately 1.0%–2.0% w / w; and

[0372] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) at approximately 20.0%–35% w / w; and

[0373] Approximately 10.0%-15.0% w / w of arginine or lysine; and

[0374] Approximately 7.0%-15.0% w / w nicotinamide; and

[0375] Sodium decanoate, approximately 20.0%-40.0% w / w.

[0376] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0377] The compound represented by formula (I) at approximately 1.0%–2.0% w / w; and

[0378] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) at approximately 20.0%-30% w / w; and

[0379] Approximately 10.0%-20.0% w / w of arginine or lysine; and

[0380] Approximately 7.0%-10.0% w / w nicotinamide;

[0381] Sodium decanoate, approximately 20.0%-30.0% w / w;

[0382] Approximately 5.0-10.0% w / w microcrystalline cellulose;

[0383] Sodium dodecyl sulfate, approximately 0.01-3.0% w / w; and

[0384] Sodium carboxymethyl starch, approximately 0.1%–5.0% w / w.

[0385] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0386] The compound of formula (I) is present in approximately 1.37%–1.52% w / w; and

[0387] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) contains approximately 29.41%–32.61% w / w; and

[0388] Approximately 9.8%–10.87% w / w of arginine or lysine; and

[0389] Approximately 9.8%–19.62% w / w nicotinamide;

[0390] Sodium decanoate, approximately 29.41%-32.61% w / w;

[0391] Approximately 7.69-8.52% w / w microcrystalline cellulose;

[0392] Sodium dodecyl sulfate, approximately 0.9-1% w / w; and

[0393] Sodium carboxymethyl starch, approximately 1.8%-2% w / w.

[0394] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0395] The compound represented by formula (I) — 10 ± 10% by weight;

[0396] Nicotinamide – 50 ± 10% by weight;

[0397] L-arginine – 100 ± 10% by weight;

[0398] Sodium decanoate – 150 ± 10% by weight;

[0399] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight; and

[0400] Excipients – 54 ± 10% by weight.

[0401] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0402] The compound shown in formula (I) – approximately 10 parts by weight;

[0403] Nicotinamide – approximately 50 parts by weight;

[0404] L-arginine – approximately 100 parts by weight;

[0405] Sodium decanoate – approximately 150 parts by weight;

[0406] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight; and

[0407] Excipients – approximately 54 parts by weight.

[0408] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0409] The compound shown in formula (I) – approximately 10 mg;

[0410] Nicotinamide – approximately 50mg;

[0411] L-arginine – approximately 100 mg;

[0412] Sodium decanoate – approximately 150 mg;

[0413] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 mg; and

[0414] Excipients – approximately 54 mg.

[0415] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0416] The compound represented by formula (I) — 10 ± 10% by weight;

[0417] Nicotinamide – 50 ± 10% by weight;

[0418] L-arginine – 100 ± 10% by weight;

[0419] Sodium decanoate – 150 ± 10% by weight;

[0420] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight;

[0421] Microcrystalline cellulose – 35.2 ± 10% by weight;

[0422] Sodium dodecyl sulfate – 4.6 ± 10% by weight;

[0423] Sodium carboxymethyl starch – 9.2 ± 10% by weight;

[0424] Povidone – 2 ± 10% by weight; and

[0425] Magnesium stearate – 3 ± 10% by weight.

[0426] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0427] The compound shown in formula (I) – approximately 10 parts by weight;

[0428] Nicotinamide – approximately 50 parts by weight;

[0429] L-arginine – approximately 100 parts by weight;

[0430] Sodium decanoate – approximately 150 parts by weight;

[0431] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight;

[0432] Microcrystalline cellulose – approximately 35.2 parts by weight;

[0433] Sodium dodecyl sulfate – approximately 4.6 parts by weight;

[0434] Sodium carboxymethyl starch – approximately 9.2 parts by weight;

[0435] Povidone – approximately 2 parts by weight; and

[0436] Magnesium stearate – approximately 3 parts by weight.

[0437] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0438] The compound represented by formula (I) — 20 ± 10% by weight;

[0439] Nicotinamide – 50 ± 10% by weight;

[0440] L-arginine – 100 ± 10% by weight;

[0441] Sodium decanoate – 150 ± 10% by weight;

[0442] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight; and

[0443] Excipients – 64 ± 10% by weight.

[0444] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0445] The compound shown in formula (I) – approximately 20 parts by weight;

[0446] Nicotinamide – approximately 50 parts by weight;

[0447] L-arginine – approximately 100 parts by weight;

[0448] Sodium decanoate – approximately 150 parts by weight;

[0449] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight; and

[0450] Excipients – approximately 64 parts by weight.

[0451] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0452] The compound represented by formula (I) – 20 mg;

[0453] Nicotinamide - 50mg;

[0454] L-arginine – 100mg;

[0455] Sodium decanoate – 150 mg;

[0456] N-(8-[2-hydroxybenzoyl]amino)octanoic acid sodium salt (SNAC) – 150 mg; and

[0457] Excipients – 64mg.

[0458] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0459] The compound represented by formula (I) — 20 ± 10% by weight;

[0460] Nicotinamide – 50 ± 10% by weight;

[0461] L-arginine – 100 ± 10% by weight;

[0462] Sodium decanoate – 150 ± 10% by weight;

[0463] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight;

[0464] Microcrystalline cellulose – 43.2 ± 10% by weight;

[0465] Sodium dodecyl sulfate – 4.6 ± 10% by weight;

[0466] Sodium carboxymethyl starch – 9.2 ± 10% by weight;

[0467] Povidone – 4 ± 10% by weight; and

[0468] Magnesium stearate – 3 ± 10% by weight.

[0469] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0470] The compound shown in formula (I) – approximately 20 parts by weight;

[0471] Nicotinamide – approximately 50 parts by weight;

[0472] L-arginine – approximately 100 parts by weight;

[0473] Sodium decanoate – approximately 150 parts by weight;

[0474] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight;

[0475] Microcrystalline cellulose – approximately 43.2 parts by weight;

[0476] Sodium dodecyl sulfate – approximately 4.6 parts by weight;

[0477] Sodium carboxymethyl starch – approximately 9.2 parts by weight;

[0478] Povidone – approximately 4 parts by weight; and

[0479] Magnesium stearate – approximately 3 parts by weight.

[0480] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0481] The compound represented by formula (I) – 40 ± 10% by weight;

[0482] Nicotinamide – 50 ± 10% by weight;

[0483] L-arginine – 100 ± 10% by weight;

[0484] Sodium decanoate – 150 parts by weight;

[0485] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight; and

[0486] Excipients – 84 ± 10% by weight.

[0487] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0488] The compound shown in formula (I) – approximately 40 parts by weight;

[0489] Nicotinamide – approximately 50 parts by weight;

[0490] L-arginine – approximately 100 parts by weight;

[0491] Sodium decanoate – approximately 150 parts by weight;

[0492] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight; and

[0493] Excipients – approximately 84 parts by weight.

[0494] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0495] The compound shown in formula (I) – approximately 40 mg;

[0496] Nicotinamide – approximately 50mg;

[0497] L-arginine – approximately 100 mg;

[0498] Sodium decanoate – approximately 150 mg;

[0499] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 mg; and

[0500] Excipients – approximately 84 mg.

[0501] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0502] The compound represented by formula (I) – 40 ± 10% by weight;

[0503] Nicotinamide – 50 ± 10% by weight;

[0504] L-arginine – 100 ± 10% by weight;

[0505] Sodium decanoate – 150 ± 10% by weight;

[0506] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight;

[0507] Microcrystalline cellulose – 59.2 ± 10% by weight;

[0508] Sodium dodecyl sulfate – 4.6 ± 10% by weight;

[0509] Sodium carboxymethyl starch – 9.2 ± 10% by weight;

[0510] Povidone – 8 ± 10% by weight; and

[0511] Magnesium stearate – 3 ± 10% by weight.

[0512] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0513] The compound shown in formula (I) – approximately 40 parts by weight;

[0514] Nicotinamide – approximately 50 parts by weight;

[0515] L-arginine – approximately 100 parts by weight;

[0516] Sodium decanoate – approximately 150 parts by weight;

[0517] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) – approximately 150 parts by weight;

[0518] Microcrystalline cellulose – approximately 59.2 parts by weight;

[0519] Sodium dodecyl sulfate – approximately 4.6 parts by weight;

[0520] Sodium carboxymethyl starch – approximately 9.2 parts by weight;

[0521] Povidone – approximately 8 parts by weight; and

[0522] Magnesium stearate – approximately 3 parts by weight.

[0523] In one embodiment of this disclosure, the pharmaceutical composition is a solid dosage form.

[0524] In one embodiment of this disclosure, the pharmaceutical composition is a tablet, capsule, granule, powder, powder, drop, or pill.

[0525] In one embodiment of this disclosure, the pharmaceutical composition is a tablet, capsule, or granule.

[0526] In one embodiment of this disclosure, the pharmaceutical composition is a tablet.

[0527] In one embodiment of this disclosure, the pharmaceutical composition is a coated tablet.

[0528] In one embodiment of this disclosure, the pharmaceutical composition is the core of a coated tablet.

[0529] In one embodiment of this disclosure, the pharmaceutical composition is a film-coated tablet.

[0530] In one embodiment of this disclosure, the pharmaceutical composition is a coated tablet, and the coating does not contain enteric material.

[0531] In one embodiment of this disclosure, the pharmaceutical composition is a coated tablet, and the coating is a gastrointestinal coating.

[0532] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises 5-150 mg of the compound shown in formula (I); preferably 5-100 mg. Examples include 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and 150 mg.

[0533] In one technical solution of this disclosure, the tablets are in the form of 1-150mg, for example, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 6.5mg, 6.8mg, 7mg, 7.1mg, 7.4mg, 7.5mg, 7.9mg, 8mg, 8.6mg, 9mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 100mg, and 150mg.

[0534] In one embodiment of this disclosure, the tablets are approximately 1-40 mg in size.

[0535] In one embodiment of this disclosure, the tablets are approximately 1-30 mg in size.

[0536] In one embodiment of this disclosure, the tablets are approximately 5-10 mg in size.

[0537] In one technical solution disclosed herein, the tablet has a specification of 10 mg.

[0538] In one embodiment of this disclosure, the tablet is 20 mg in size.

[0539] In one embodiment of this disclosure, the tablet is 40 mg in size.

[0540] On the other hand, this disclosure relates to the use of orally administered pharmaceutical compositions for:

[0541] (i) To prepare medicines for the treatment of diseases associated with GIP and / or GLP-1 receptor agonism; and / or

[0542] (ii) Treatment of diseases associated with GIP and / or GLP-1 receptor agonism.

[0543] In one technical solution of this disclosure, the disease associated with GIP and / or GLP-1 receptor agonism is selected from at least one of type 2 diabetes, obesity, hypertension, dyslipidemia, obstructive sleep apnea, non-alcoholic fatty liver disease, and cardiovascular disease.

[0544] In another aspect, this disclosure relates to a method for treating diseases associated with GIP and / or GLP-1 receptor agonism, the method comprising the step of administering a therapeutically effective amount of the oral pharmaceutical composition of this disclosure to a subject in need.

[0545] In one technical solution of this disclosure, the disease associated with GIP and / or GLP-1 receptor agonism is selected from at least one of type 2 diabetes, obesity, hypertension, dyslipidemia, obstructive sleep apnea, non-alcoholic fatty liver disease, and cardiovascular disease.

[0546] The oral pharmaceutical compositions disclosed herein contain compounds with amino or quaternary ammonium functional groups, complexing molecules, medium-chain fatty acids or their salts, and N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salts, which together can significantly increase oral blood drug concentrations.

[0547] The oral pharmaceutical composition disclosed herein, through the combined action of compounds containing nitrogen-containing functional groups and coordinating molecules, significantly increases the blood concentration of the drug compared to pharmaceutical compositions lacking compounds or coordinating molecules containing nitrogen-containing functional groups.

[0548] The oral pharmaceutical composition disclosed herein exhibits good stability in gastric juice.

[0549] The oral pharmaceutical compositions disclosed herein produce tablets with high dissolution, good stability, and high oral bioavailability. Attached Figure Description

[0550] Figure 1 is an absorption diagram of a tablet of the compound represented by formula (I) according to an embodiment of the present disclosure after oral administration in a beagle dog.

[0551] Figure 2 is a graph showing the change in the percentage of the prescription powder of the compound represented by formula (I) according to an embodiment of the present disclosure over time after treatment with gastric juice.

[0552] Figure 3 is a graph showing the dissolution results of the compound represented by formula (I) according to an embodiment of this disclosure. Detailed Implementation

[0553] Based on the above content of this disclosure, and in accordance with common technical knowledge and practices in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas of this disclosure.

[0554] I. Definition

[0555] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0556] In this disclosure, a range of numbers refers to individual integers within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C 1-3 "" means that the group can have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.

[0557] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0558] The terms "substituted" or "substituted" refer to the replacement of one or more hydrogen atoms on a particular atom or group with a substituent, provided that the valence state of the particular atom or group is normal and the resulting compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0559] The term "about" means approximately, close to, roughly, or roughly. When the term "about" is used in conjunction with a numerical range, it is modified by the limits above and below the stated value. Generally, the term "about" is used herein to modify a value by a deviation of 20% above or below a given value.

[0560] In this disclosure, amino acids and their abbreviations and English abbreviations are shown in Table 1 below.

[0561] Table 1

[0562] Pharmaceutical Composition

[0563] The terms “pharmaceutical acceptable” or “medicinal” refer to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0564] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound as a free acid or free base without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0565] The term "pharmaceutically acceptable ester" refers to an ester that retains the biological potency of the original specific compound without any adverse biological effects. Ester groups are typically introduced via organic acids and alcohol hydroxyl groups. In some embodiments, peptides are linked to fatty acids or derivatives thereof via ester bonds to obtain pharmaceutically acceptable esters.

[0566] The term "prodrug" refers to a compound that can be converted into an active drug substance in the body and exert its therapeutic effect. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. In embodiments of this disclosure, the prodrug may be an ester.

[0567] The terms "polypeptide" and "peptide" are used interchangeably and refer to a compound containing a series of amino acids linked together by amide (or peptide) bonds. Polypeptides typically contain at least 20 amino acid residues. In some embodiments, polypeptides contain 20-500 amino acid residues. In some embodiments, one or more modified amino acid residues and / or non-protein amino acid residues are also included.

[0568] The term "agonist" refers to a substance (ligand) that activates signal transduction by targeting a specific receptor type. For example, if the target receptor is the GLP-1 receptor, then the agonist has GLP-1 receptor activating activity, such as a GLP-1 peptide or an analogue thereof.

[0569] The term "dual receptor agonist of GIP and GLP-1" refers to a substance that has activating activity against both GIP and GLP-1 receptors.

[0570] in, Fa is attached to the C-terminal Ser carboxyl group.

[0571] In this disclosure, the preparation of the compound represented by formula (I) can be referred to prior art document WO 2022 / 199629A1.

[0572] The term "coordination molecule" refers to a molecule containing a hydrophilic group (C₁, C₂, C₃). 6- C 10 Aromatic ring or C 5- C 10 Heteroaromatic compounds, wherein a heteroaromatic ring refers to an aromatic ring compound containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The heteroaromatic ring can be monocyclic or polycyclic, such as bicyclic, wherein two or more rings exist in the form of fused rings, bridged rings, or spirocyclic rings, and at least one ring contains one or more heteroatoms. Specific examples of heteroaromatic rings include, but are not limited to, pyridine, thiophene, imidazole, pyrimidine, furan, pyrazine, thiazole, quinoline, isoquinoline, indole, benzimidazole, imidazopyridine, benzofuran, pyridazine, isoindole, and pyridinone. In some embodiments, the coordinating molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In some preferred embodiments, the coordinating molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide. In some preferred embodiments, the coordinating molecule is nicotinamide.

[0573] The term "hydrophilic group" refers to a group of atoms or functional groups in a molecule that can form hydrogen bonds with water molecules, thereby making the molecule readily soluble in water. These groups are typically polar or ionic and can form hydrogen bonds with polar oxygen atoms in water molecules, thus giving the molecule hydrophilicity. Examples of hydrophilic groups in this disclosure include, but are not limited to, hydroxyl, carboxyl, amino, sulfonic acid, phosphate, amide, ribosyl (or deoxyribosyl), and carboxyl groups.

[0574] The term "amino" refers to a compound consisting of one nitrogen atom (N) and two hydrogen atoms (H), which is often combined with other groups or molecular structures to form more complex compounds.

[0575] The term "amine group" is a broad chemical functional group that refers to a structure containing a nitrogen atom that can be attached to one or more hydrocarbon groups (such as methyl, ethyl, etc.). The amine group is the basis of amine compounds.

[0576] Primary amines: An amino group is attached to a hydrocarbon group (e.g., methylamine: CH3NH2).

[0577] Secondary amines: An amino group is attached to two hydrocarbon groups (e.g., dimethylamine: CH3NHCH3).

[0578] Tertiary amines: An amino group is attached to three hydrocarbon groups (e.g., trimethylamine: N(CH3)3).

[0579] The term "quaternary ammonium group" refers to -N + (R)3, wherein each R is independently a straight-chain or branched alkyl group, with an exemplary quaternary ammonium group being -N. + (CH3)3、-N + (CH2CH3)3.

[0580] In some embodiments, the compound containing the nitrogen-functional group is an amino acid, such as glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, asparagine, glutamine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, sarcosine, γ-aminobutyric acid, ornithine, and citrulline. In some preferred embodiments, the compound containing the nitrogen-functional group is a basic amino acid. In some preferred embodiments, the compound containing the nitrogen-functional group is an amino acid that carries a positive charge at physiological pH. In some embodiments, the compound containing the nitrogen-functional group is a quaternary ammonium cation complex, such as carnitine, L-carnitine, choline, choline chloride, and betaine. In some embodiments, the compound containing the nitrogen-functional group is taurine.

[0581] In some embodiments, the compound containing the nitrogen-containing functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, and γ-aminobutyric acid; preferably at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0582] The term "excipient" refers to a substance added to a pharmaceutical composition to impart a certain shape, size, or physical property to the drug. Examples of excipients include, but are not limited to, carriers, fillers, binders, disintegrants, lubricants, flow aids, flavor masking and flavoring agents, stabilizers, dispersants, film-forming agents, and preservatives. Suitable excipients can be selected based on factors such as the nature, type, route of administration, and therapeutic purpose of the drug. In this disclosure, the term "excipient" refers to any substance other than a complexing molecule, a compound containing an amino or quaternary ammonium functional group, a medium-chain fatty acid or its salt, or N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, used to impart a certain shape, size, or physical property to a drug. In some embodiments, the excipient is a filler, disintegrant, or lubricant. In some embodiments, the excipient is a filler, disintegrant, lubricant, or binder.

[0583] The term "filler" refers to excipients used to increase the weight and volume of tablets, facilitating tableting. Examples of fillers include, but are not limited to, starch, powdered sugar, dextrin, lactose, microcrystalline cellulose, pregelatinized starch, mannitol, and calcium sulfate. In one embodiment, the filler is microcrystalline cellulose.

[0584] The term "disintegrant" refers to an excipient that helps tablets break down into small particles in gastrointestinal fluids. Examples of disintegrants include, but are not limited to, dry starch, sodium carboxymethyl cellulose, low-substituted carboxymethyl cellulose, croscarmellose, croscarmellose sodium, and sodium carboxymethyl starch. In one embodiment, the disintegrant is sodium carboxymethyl starch.

[0585] The term "lubricant" refers to an excipient used to reduce friction between particles, prevent raw materials from adhering to the punch surface, or reduce friction between the tablet and the die cavity wall. Examples of lubricants include, but are not limited to, magnesium stearate, micronized silica gel, talc, polyethylene glycol, and sodium lauryl sulfate. In one embodiment, the lubricant is sodium lauryl sulfate. In another embodiment, the lubricant is a mixture of sodium lauryl sulfate and magnesium stearate.

[0586] The term "binder" refers to an excipient used to enhance the binding force between powder particles, such as an excipient used in tablet preparation to form a tablet with a certain mechanical strength and integrity during compression of loose drug powder. Examples of binders include, but are not limited to, starch paste, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, crospovidone, polyethylene glycol, etc. In one embodiment, the binder is povidone.

[0587] Any excipient disclosed herein may have one or more functions. For example, sodium dodecyl sulfate may also be used as a solubilizer in pharmaceutical compositions to improve solubility and promote dissolution.

[0588] The term "solid dosage form" refers to a solid pharmaceutical preparation with strong cohesiveness and shape stability. Solid dosage forms include, but are not limited to, tablets, capsules, granules, powders, and granules. Solid dosage forms can be conventional, sustained-release, or immediate-release preparations (e.g., osmotic pump tablets, sustained-release tablets, sustained-release capsules, rapidly disintegrating tablets, etc.). In some embodiments, the pharmaceutical composition of this disclosure is a tablet, capsule, or granule. In a preferred embodiment, the pharmaceutical composition of this disclosure is a tablet.

[0589] The term "tablet" refers to a round or irregularly shaped solid dosage form made from an active pharmaceutical ingredient and suitable excipients. Tablets are primarily oral conventional tablets (including sugar-coated tablets and film-coated tablets), but also include lozenges, sublingual tablets, oral patches, chewable tablets, dispersible tablets, soluble tablets, effervescent tablets, vaginal tablets, vaginal effervescent tablets, sustained-release tablets, controlled-release tablets, enteric-coated tablets (including enteric-coated tablets and colon-targeted enteric-coated tablets), and orally disintegrating tablets. The tablets of this disclosure can be coated using methods well known in the art. In one embodiment, the tablet is a non-enteric-coated tablet, such as a gastric-coated tablet.

[0590] The term "parts by weight" refers to the relative proportion of the weights of the ingredients in a prescription.

[0591] The term "w / w" refers to the percentage of a component by mass relative to the total mass of the mixture. In one embodiment of this disclosure, the pharmaceutical composition is an uncoated tablet comprising 1.52% w / w of the compound of formula (I), 10.87% w / w arginine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, and 32.61% w / w sodium decanoate. In one embodiment, the pharmaceutical composition is a core of a coated tablet comprising 1.52% w / w of the compound of formula (I), 10.87% w / w arginine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, and 32.61% w / w sodium decanoate. In one embodiment, the pharmaceutical composition is a coated tablet comprising 3.60% w / w the compound of formula (I), 18.01 w / w arginine, 27.01% w / w SNAC, 27.01% w / w sodium decanoate, and 9.00% w / w nicotinamide.

[0592] The term "specification" or "drug specification" refers to the amount of drug ingredient contained in a unit dosage form of a drug, usually expressed as the weight or content per tablet, capsule, or vial, etc., and includes indicators such as the content, potency, or fill volume of the active ingredient. In some embodiments of this disclosure, the tablet specifications are 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 6.5 mg, 6.8 mg, 7 mg, 7.1 mg, 7.4 mg, 7.5 mg, 7.9 mg, 8 mg, 8.6 mg, 9 mg, or 10 mg. In other embodiments of this disclosure, the tablet specifications may also be 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg.

[0593] The term "unit formulation" refers to the smallest unit of administration or the smallest unit of packaging in a pharmaceutical product that can be broken down, such as tablets, capsules, powders, injections, etc. These units can exist independently physically and can be precisely broken down in dosage. Unit formulations typically contain a predetermined amount of active ingredient to produce the desired therapeutic effect and are used in combination with appropriate pharmaceutical excipients.

[0594] The term "single-drug formulation" refers to a single dosage form in which a prescription contains only one drug or active ingredient.

[0595] The term "oral" refers to any method of oral administration, including but not limited to oral swallowing (e.g., swallowing directly or with warm water), oral dispensing (e.g., placing under the tongue or between the gums and cheeks), oral rehydration, and oral chewing.

[0596] The term "treatment" includes the suppression, relief, prevention, or elimination of one or more symptoms or side effects associated with the disease, condition, or disorder being treated. The term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, suppress, or reduce one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effect. Precise dosages will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment administered. The effect of an effective dose can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of the subject before or without administration of the drug or combination of drugs, or, in the case of a combination of drugs, the combined effect can be compared to the effect of administration of only one drug.

[0597] The term “object of need” refers to any object to which the pharmaceutical composition of this disclosure is administered, preferably a mammal, including but not limited to, domestic animals (e.g., cattle, sheep, cats, dogs and horses), primates (e.g., human and non-human primates such as monkeys), rabbits, and rodents (e.g. mice and rats).

[0598] The term "therapeutic effective amount" refers to the amount that, at the required dose and for the required duration, effectively achieves the desired therapeutic outcome. The therapeutic effective amount of the compounds or pharmaceutical compositions disclosed herein can vary depending on a variety of factors such as disease state, individual age, sex, weight, and the ability of the immune adjuvant or pharmaceutical composition to elicit the desired response in an individual.

[0599] II. Examples

[0600] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

[0601] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0602] The dual receptor agonists of GIP and GLP-1 used in the following examples are shown in Table 2 below.

[0603] Table 2

[0604] Example 1: Preparation of tablets of the compound shown in formula (I)

[0605] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0606] The oral pharmaceutical composition containing the compound shown in formula (I) is formulated as follows: 1.52% w / w of the compound shown in formula (I), 10.87% w / w of arginine, 10.87% w / w of nicotinamide, 32.61% w / w of SNAC, 32.61% w / w of sodium decanoate, 8.52% w / w of microcrystalline cellulose, 1% w / w of sodium dodecyl sulfate, and 2% w / w of sodium carboxymethyl starch. Wherein, the compound shown in formula (I) is: SNAC: sodium decanoate: arginine: nicotinamide = 7:150:150:50:50.

[0607] 2) Tableting: After mixing, the material is compressed into tablets using a flat die with a diameter of 10 mm. Each tablet contains 460 mg of material. The tablet is then removed from the die to obtain a 10 mm round flat tablet containing 7 mg of the compound shown in formula (I).

[0608] Example 2: Preparation of tablets of the compound shown in formula (I)

[0609] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0610] The oral pharmaceutical composition containing the compound shown in formula (I) is formulated as follows: 1.37% w / w of the compound shown in formula (I), 19.62% w / w of arginine, 9.8% w / w of nicotinamide, 29.41% w / w of SNAC, 29.41% w / w of sodium decanoate, 7.69% w / w of microcrystalline cellulose, 0.9% w / w of sodium dodecyl sulfate, and 1.8% w / w of sodium carboxymethyl starch. Wherein, the compound shown in formula (I) is: SNAC: sodium decanoate: arginine: nicotinamide = 7:150:150:100:50.

[0611] 2) Tableting: After mixing, the material is compressed into tablets using a flat die with a diameter of 10 mm. Each tablet contains 510 mg of material. The tablet is then removed from the die to obtain a 10 mm round flat tablet containing 7 mg of the compound shown in formula (I).

[0612] Example 3: Preparation of tablets of the compound shown in formula (I)

[0613] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0614] The pharmaceutical composition containing the compound shown in formula (I) is formulated as follows: 1.37% w / w of the compound shown in formula (I), 19.62% w / w of lysine, 9.8% w / w of nicotinamide, 29.41% w / w of SNAC, 29.41% w / w of sodium decanoate, 7.69% w / w of microcrystalline cellulose, 0.9% w / w of sodium dodecyl sulfate, and 1.8% w / w of sodium carboxymethyl starch. Wherein, the compound shown in formula (I) is expressed as follows: SNAC: sodium decanoate: lysine: nicotinamide = 7:150:150:100:50.

[0615] 2) Tableting: After mixing, the material is compressed into tablets using a flat die with a diameter of 10 mm. Each tablet contains 510 mg of material. The tablet is then removed from the die to obtain a 10 mm round flat tablet containing 7 mg of the compound shown in formula (I).

[0616] Example 4: Preparation of a formulation powder of the compound shown in formula (I)

[0617] 10 mg of the lyophilized powder of the compound shown in formula (I), 214 mg of SNAC, 214 mg of sodium decanoate, 71 mg of arginine, and 71 mg of nicotinamide were accurately weighed separately. The powders were mixed in an EP tube to obtain a formulation powder containing the compound shown in formula (I). In the mixed powder, the ratio of the compound shown in formula (I): SNAC: sodium decanoate: arginine: nicotinamide = 7:150:150:50:50.

[0618] Example 5: Preparation of tablets of the compound shown in formula (I)

[0619] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0620] The pharmaceutical composition containing the compound shown in formula (I) is formulated as follows: 1.37% w / w of the compound shown in formula (I), 9.80% w / w of arginine, 19.62% w / w of nicotinamide, 29.41% w / w of SNAC, 29.41% w / w of sodium decanoate, 7.69% w / w of microcrystalline cellulose, 0.9% w / w of sodium dodecyl sulfate, and 1.8% w / w of sodium carboxymethyl starch. Wherein, the compound shown in formula (I) is composed of SNAC: sodium decanoate: arginine: nicotinamide in a ratio of 7:150:150:50:100.

[0621] 2) Tableting: After mixing, the material is compressed into tablets using a flat die with a diameter of 10 mm. Each tablet contains 510 mg of material. The tablet is then removed from the die to obtain a 10 mm round flat tablet containing 7 mg of the compound shown in formula (I).

[0622] Comparative Example 1: Preparation of tablets of the compound shown in formula (I)

[0623] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0624] The pharmaceutical composition containing the compound shown in formula (I) is formulated as follows: 1.52% w / w of the compound shown in formula (I), 65.22% w / w of SNAC, 30.26% w / w of microcrystalline cellulose, 1% w / w of sodium dodecyl sulfate, and 2% w / w of sodium carboxymethyl starch. Wherein, the ratio of the compound shown in formula (I) to SNAC is 7:300.

[0625] 2) Tableting: After mixing, the material is compressed into tablets using a flat die with a diameter of 10 mm. Each tablet contains 460 mg of material. The tablet is then removed from the die to obtain a 10 mm round flat tablet containing 7 mg of the compound shown in formula (I).

[0626] Comparative Example 2: Preparation of tablets of the compound shown in formula (I)

[0627] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0628] The pharmaceutical composition containing the compound shown in formula (I) is formulated as follows: 1.52% w / w of the compound shown in formula (I), 10.87% w / w of arginine, 32.61% w / w of SNAC, 32.61% w / w of sodium decanoate, 19.39% w / w of microcrystalline cellulose, 1% w / w of sodium dodecyl sulfate, and 2% w / w of sodium carboxymethyl starch. Wherein, the ratio of the compound shown in formula (I) to SNAC to sodium decanoate to arginine is 7:150:150:50.

[0629] 2) Tableting: After mixing, the material is compressed into tablets using a flat die with a diameter of 10 mm. Each tablet contains 460 mg of material. The tablet is then removed from the die to obtain a 10 mm round flat tablet containing 7 mg of the compound shown in formula (I).

[0630] Comparative Example 3: Preparation of tablets of the compound shown in formula (I)

[0631] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0632] The pharmaceutical composition containing the compound shown in formula (I) is formulated as follows: 1.52% w / w the compound shown in formula (I), 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 19.39% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch. Wherein, the compound shown in formula (I) is composed of SNAC: sodium decanoate: nicotinamide in a ratio of 7:150:150:50.

[0633] 2) Tableting: After mixing, the material is compressed into tablets using a flat die with a diameter of 10 mm. Each tablet contains 460 mg of material. The tablet is then removed from the die to obtain a 10 mm round flat tablet containing 7 mg of the compound shown in formula (I).

[0634] Comparative Example 4: Preparation of lyophilized powder containing the compound shown in formula (I)

[0635] Accurately weigh 10 mg of the lyophilized powder of the compound shown in formula (I) and place it in an EP tube to obtain one portion of the lyophilized powder of the compound shown in formula (I).

[0636] Comparative Example 5: Preparation of a prescription powder containing the compound shown in formula (I)

[0637] Accurately weigh 10 mg of the lyophilized powder of the compound shown in formula (I), 214 mg of SNAC, 214 mg of sodium decanoate, and 71 mg of arginine. Mix the above powders in an EP tube to obtain one formulation powder of the compound shown in formula (I). In the mixed powder, the ratio of the compound shown in formula (I): SNAC: sodium decanoate: arginine is 7:150:150:50.

[0638] Test Example 1

[0639] The absorption of the compound tablets of formula (I) prepared above was tested in beagle dogs via oral administration. Specifically, 1 mL of blank blood was collected using an EDTA-K2 blood collection tube before administration as the zero-point blood sample. The tablets prepared in the comparative examples or embodiments were administered to beagle dogs via gavage, with three dogs per group and one tablet per dog. Subsequently, blood was collected from the forearm vein of the beagle dogs using an EDTA-K2 blood collection tube at the following time points after administration: 0.5 h, 1 h, 2 h, and 3 h, with 1 mL of blood collected at each point. The collected whole blood from the beagle dogs was centrifuged, and the supernatant plasma sample was collected and stored at -20°C for subsequent mass spectrometry analysis.

[0640] The mass spectrometry detection method is as follows: Take 20 μL of the plasma sample to be tested or the plasma sample containing the compound standard shown in formula (I), and add 200 μL of protein precipitant containing glibenclamide internal standard. Vortex mix and centrifuge the sample, and take 100 μL of the supernatant into a 96-well plate for analysis. The sample injection volume is 5 μL. The liquid chromatography column used is an ACQUITY UPLC Peptide BEH C18 Column (2.1 mm x 50 mm, 1.7 μm). Mobile phase A is 5% acetonitrile containing 0.1% formic acid, and mobile phase B is 95% acetonitrile containing 0.1% formic acid. The flow rate is set to 0.6 mL / min, and the liquid phase gradient (time / mobile phase B ratio) is set according to the following parameters: 0 min / 30%, 1.4 min / 75%, 1.6 min / 95%, 1.6 min / 30%, 1.8 min / 30%. The mass spectrometer used was a Waters Xevo TQ-S micro, with ESI+ ionization mode selected and MRM scanning mode chosen. The monitored ion pair for the compound shown in formula (I) was 1258.3 / 1837.9, and the monitored ion pair for the glibenclamide internal standard was 494.2 / 169.1.

[0641] The absorption results of the compound tablets shown in Formula (I) in beagle dogs via oral administration are shown in Table 3 and Figure 1 below. The results indicate that the absorption of the compound shown in Formula (I) in beagle dogs in Examples 1-3 is superior to that in the comparative examples.

[0642] Table 3

[0643] Test Example 2

[0644] Before the test, prepare sufficient reaction termination solution (methanol:acetonitrile = 1:1), artificial gastric fluid (prepared according to the Chinese Pharmacopoeia), and artificial gastric fluid (without pepsin). Add 1 mL of artificial gastric fluid (without pepsin) to one portion of the powder prepared in Comparative Example 4, Comparative Example 5, and Example 5, and vortex to obtain a stock solution of 10 mg / mL of the compound shown in formula (I). Take a certain amount of the stock solution and add it to the artificial gastric fluid at a ratio of 1:9, vortex to obtain a reaction system with a concentration of 1 mg / mL of the compound shown in formula (I). Prepare 3 portions for each group. Record the time and take a certain amount of the reaction system at time points of 1 min, 2 min, 5 min, 8 min, 10 min, 15 min, 30 min, 45 min, and 60 min. Add the mixture to the reaction termination solution at a ratio of 1:3, vortex to obtain the compound shown in formula (I), centrifuge the sample (10 min, 4℃, 10000 rpm), and then use HPLC to detect the content of the compound shown in formula (I).

[0645] Accurately weigh 20 mg of the compound shown in formula (I), dissolve it in 50% acetonitrile, sonicate for 5 min, and then dilute to 20 mL with 50% acetonitrile to obtain the reference stock solution. Measure 0.15 mL of the reference stock solution and dilute to 10 mL with pH 7.5 sodium salt buffer to obtain the reference sample. HPLC detection was performed using a Hungpu XBTC18 column (5 μm, 4.6*150 mm), with mobile phase A being 5% acetonitrile-0.1% TFA and mobile phase B being 95% acetonitrile-0.1% TFA. The HPLC parameters were set as follows: detection wavelength: 220 nm; column temperature: 50℃; flow rate: 1.0 mL / min; injection volume: 10 μL; isocratic elution for 12 min; mobile phase A:mobile phase B = 55:45.

[0646] The results of the gastric juice stability test in this case are shown in Table 4 and Figure 2. The results indicate that the excipient combination SNAC, sodium decanoate, arginine, and nicotinamide can further improve the stability of the compound shown in formula (I) in gastric juice compared to the excipient combination SNAC, sodium decanoate, and arginine.

[0647] Table 4 shows the proportions of compounds of formula (I) that were not degraded in the reaction system.

[0648] Test Example 3

[0649] Prepare sufficient dissolution medium (phosphate buffer, pH = 6.8) before testing. Tablets prepared in Comparative Example 2 and Example 1 were used for in vitro dissolution testing. 500 mL of dissolution medium was used, with a dissolution speed of 50 RPM and a temperature of 37℃ (±0.5℃). Time was recorded, and 1 mL samples were taken at time points of 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min. 1 mL of dissolution medium was added after each sample. The supernatant was collected after centrifugation and analyzed by HPLC.

[0650] Accurately weigh 20 mg of BGM0504, dissolve it in 50% acetonitrile, sonicate for 5 min, and then dilute to 20 mL with 50% acetonitrile to obtain the reference stock solution. Measure 0.15 mL of the reference stock solution and dilute to 10 mL with pH 7.5 sodium salt buffer to obtain the reference sample. HPLC detection was performed using a Hungpu XBTC18 column (5 μm, 4.6*150 mm), with mobile phase A being 5% acetonitrile-0.1% TFA and mobile phase B being 95% acetonitrile-0.1% TFA. The HPLC parameters were set as follows: detection wavelength: 220 nm; column temperature: 50℃; flow rate: 1.0 mL / min; injection volume: 10 μL; isocratic elution for 12 min; mobile phase A:mobile phase B = 55:45. The dissolution test results of this test example are shown in Table 5 and Figure 3. The results show that the dissolution of the formulation in Example 1 is significantly better than that in Comparative Example 2.

[0651] Dissolution rates of compounds represented by formula (I) in Table 5

[0652] Example 6: Preparation of tablets of the compound shown in formula (I)

[0653] 1.1 Prescription

[0654] Prepare tablets of the compounds shown in formula (I) according to the formulation in Table 6 below:

[0655] Table 6

[0656] 1.2 Process

[0657] After mixing, the material is compressed into tablets using a direct powder compression process to obtain tablets with a compound content of 20 mg as shown in formula (I).

[0658] Example 7: Preparation of tablets of the compound shown in formula (I)

[0659] 7.1 Prescription

[0660] Prepare tablets of the compounds shown in formula (I) according to the formulation in Table 7 below:

[0661] Table 7

[0662] 7.2 Process

[0663] The weighed blank granular excipients and drug-containing granular excipients were sieved and premixed to obtain blank granular premixed powder and drug-containing granular premixed powder, respectively.

[0664] The blank granule premix powder and the drug-containing granule premix powder are added to a granulator for granulation to obtain drug-containing granules and blank granules.

[0665] Calculate and weigh the amount of blank granules and magnesium stearate to be added based on the amount of medicated granules. Mix the medicated granules and the weighed blank granules, add magnesium stearate and continue mixing, then compress into tablets to obtain 20mg tablets.

[0666] The above tablets can be further coated to obtain 20mg coated tablets.

[0667] Example 8: Preparation of tablets of the compound shown in formula (I)

[0668] 1.1 Prescription

[0669] Prepare tablets of the compounds shown in formula (I) according to the formulation in Table 8 below:

[0670] Table 8

[0671] 1.2 Process

[0672] After mixing, the material is compressed into tablets using a direct powder compression process to obtain tablets with a compound content of 20 mg as shown in formula (I).

[0673] Example 9: Preparation of tablets of the compound shown in formula (I)

[0674] 1.1 Prescription

[0675] Prepare tablets of the compounds shown in formula (I) according to the formulation in Table 9 below:

[0676] Table 9

[0677] 1.2 Process

[0678] After mixing, the material was compressed into tablets using a direct powder compression process to obtain tablets with a compound content of 40 mg as shown in formula (I).

[0679] Example 10: Preparation of tablets of the compound shown in formula (I)

[0680] 1.1 Prescription

[0681] Prepare tablets of the compounds shown in formula (I) according to the formulation in Table 10 below:

[0682] Table 10

[0683] 1.2 Process

[0684] The weighed blank granular excipients and drug-containing granular excipients were sieved and premixed to obtain blank granular premixed powder and drug-containing granular premixed powder, respectively.

[0685] The blank granule premix powder and the drug-containing granule premix powder are added to a granulator for granulation to obtain drug-containing granules and blank granules.

[0686] Calculate and weigh the amount of blank granules and magnesium stearate based on the amount of medicated granules. Mix the medicated granules and the weighed blank granules, add magnesium stearate and continue mixing, then compress into tablets to obtain 40mg tablets.

[0687] The above tablets can be further coated to obtain 40mg film-coated tablets.

[0688] Example 11: Preparation of tablets of the compound shown in formula (I)

[0689] 1.1 Prescription

[0690] Prepare tablets of the compounds shown in formula (I) according to the formulation in Table 11 below:

[0691] Table 11

[0692] 1.2 Process

[0693] The weighed blank granular excipients and drug-containing granular excipients were sieved and premixed to obtain blank granular premixed powder and drug-containing granular premixed powder, respectively.

[0694] The blank granule premix powder and the drug-containing granule premix powder are added to a granulator for granulation to obtain drug-containing granules and blank granules.

[0695] Calculate and weigh the amount of blank granules and magnesium stearate to be added based on the amount of medicated granules. Mix the medicated granules and the weighed blank granules, add magnesium stearate and continue mixing, then compress into tablets to obtain 10mg tablets.

[0696] The above tablets can be further coated to obtain 10mg film-coated tablets.

[0697] Comparative Example 6: Preparation of tablets of the compound shown in formula (I)

[0698] 1.1 Prescription

[0699] Prepare tablets of the compounds shown in formula (I) according to the formulation in Table 12 below:

[0700] Table 12

[0701] 1.2 Process

[0702] After mixing, the material is compressed into tablets using a direct powder compression process to obtain tablets with a compound content of 20 mg as shown in formula (I).

[0703] Comparative Example 7: Preparation of tablets of the compound shown in formula (I)

[0704] 1.1 Prescription

[0705] Prepare tablets of the compounds shown in formula (I) according to the formulation in Table 13 below:

[0706] Table 13

[0707] 1.2 Process

[0708] After mixing, the material is compressed into tablets using a direct powder compression process to obtain tablets with a compound content of 20 mg as shown in formula (I).

[0709] Test Example 4

[0710] Pharmacokinetic studies were conducted using tablets prepared in Examples 6-11 and Comparative Examples 6 and 7. The experimental procedures are as follows:

[0711] 1) Animal Information

[0712] See Table 14 below.

[0713] Table 14

[0714] 2) Animal experiment design

[0715] See Table 15 below.

[0716] Table 15

[0717] 4) Sample collection

[0718] ① Blood collection time points: PO: 0h before drug administration, 15, 30min, 1, 2, 4, 6, 8, 24h after drug administration;

[0719] ② Blood collection site and volume: limb veins, 1 mL / time point;

[0720] ③ Blood collection tube anticoagulant: EDTA-2K;

[0721] ④ Blood collection: Collect blood samples at the above-set time points and place them in blood collection tubes. Place them temporarily on wet ice and centrifuge at 4000g for 5 minutes (4℃) within 30 minutes to separate the plasma. Dispense the plasma into labeled EP tubes. Place the dispensed samples in an ultra-low temperature freezer or dry ice at -70±10℃ within 30 minutes until transport and transfer.

[0722] 5) Test results

[0723] The samples were analyzed using an AB 6500 liquid chromatography-mass spectrometry (LC-MS) system. C was detected. max The results of the mean calculation are shown in Table 16 below.

[0724] Table 16 Note: NA in the table indicates not detected; / indicates that the item was not detected.

[0725] The results showed that, when tablets from Example 6, Comparative Example 6, and Comparative Example 7 were administered, the tablet from Example 6 had the highest Cmax value in beagle dogs. This indicates that, under the same specifications, the addition of SNAC and sodium decanoate to the formulation is beneficial for increasing the oral blood drug concentration in beagle dogs.

Claims

An oral pharmaceutical composition comprising: (i) The compound represented by formula (I) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label or prodrug thereof; (ii) Coordinating molecules; (iii) Compounds containing nitrogen-containing functional groups; (iv) Medium-chain fatty acids or their salts; and (v) N-(8-[2-hydroxybenzoyl]amino)octanoic acid or a salt thereof; Wherein, the coordinating molecule is a C containing a hydrophilic group. 6- C 10 Aromatic rings or C containing hydrophilic groups 5- C 10 Mixed fragrance ring; The compound containing a nitrogen-atom functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of the substituent groups selected from -S(O)2OH and -OH. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises: A dual receptor agonist of GIP and GLP-1 at a rate of not less than approximately 0.5% w / w; And / or, Not less than about 20.0% w / w of medium-chain fatty acids or their salts; and / or, Not less than about 20.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid or a salt thereof; and / or, Compounds containing nitrogen-containing functional groups at a rate of not less than about 5.0% w / w; and / or, The amount of coordinating molecules is not less than about 5.0% w / w. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises: A dual receptor agonist of GIP and GLP-1—approximately 1-50 parts by weight; Complex molecules – approximately 10-200 parts by weight; Compounds containing nitrogen-atom functional groups – approximately 10-500 parts by weight; Medium-chain fatty acids or their salts—approximately 100-500 parts by weight; and N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salts—about 100-500 parts by weight. The pharmaceutical composition according to any one of claims 1-3, wherein the nitrogen-containing functional group comprises an amino group and -C(O)OH, an amino group and -C(O)OH; or contains an amino group and -S(O)2OH, an amino group and -S(O)2OH; or contains a quaternary ammonium group and -C(O)O - It may contain quaternary ammonium groups and -OH; or it may contain quaternary ammonium groups and -C(O)O. - and -OH. According to claim 4, the pharmaceutical composition wherein the compound containing the nitrogen-containing functional group is selected from at least one of amino acids, L-carnitine, taurine, betaine, choline, choline chloride, and carnitine; wherein the amino acids are selected from natural amino acids or synthetic amino acids. According to claim 5, the pharmaceutical composition wherein the compound containing the nitrogen-containing functional group is an amino acid. According to the pharmaceutical composition of claim 6, the amino acid is selected from at least one of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, asparagine, glutamine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, sarcosine, γ-aminobutyric acid, ornithine, and citrulline. According to the pharmaceutical composition of claim 7, the compound containing the nitrogen-containing functional group is arginine or lysine; preferably arginine. The pharmaceutical composition according to any one of claims 1-3, wherein the coordinating molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. The pharmaceutical composition according to claim 9, wherein the coordinating molecule is nicotinamide. The pharmaceutical composition according to any one of claims 1-3, wherein the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid is a sodium salt, potassium salt or ammonium salt. According to the pharmaceutical composition of claim 11, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid is sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate. The pharmaceutical composition according to any one of claims 1-3, wherein the medium-chain fatty acid or its salt is C 6-14 Carboxylic acid or C 6-14 Carboxylates. According to claim 13, the medium-chain fatty acid or its salt is a saturated C4 fatty acid. 8-12 Straight-chain carboxylic acids or their salts. According to the pharmaceutical composition of claim 14, the medium-chain fatty acid is selected from caprylic acid (C8) and decanoic acid (C9). 10 ), n-Undecanoic acid (C 11 ) and n-dodecanoic acid (C 12 Preferred to be decanoic acid (C); 10 ). According to claim 14, the medium-chain fatty acid salt is sodium decanoate. The pharmaceutical composition according to any one of claims 1-16, wherein the pharmaceutical composition comprises: The compound represented by formula (I) – about 1-50 parts by weight; Nicotinamide – approximately 10-200 parts by weight; Arginine and / or lysine – approximately 10-500 parts by weight; Sodium decanoate – approximately 100-500 parts by weight; and Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – approximately 100-500 parts by weight; Preferably, the pharmaceutical composition comprises: The compound represented by formula (I) – about 1-50 parts by weight; Nicotinamide – approximately 10-100 parts by weight; Arginine and / or lysine – approximately 50-150 parts by weight; Sodium decanoate – approximately 100-300 parts by weight; and Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate – approximately 100-300 parts by weight. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition comprises: The compound represented by formula (I) – about 1-50 parts by weight; Nicotinamide – approximately 50 parts by weight; Arginine and / or lysine – approximately 100 parts by weight; Sodium decanoate – approximately 150 parts by weight; and Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate – approximately 150 parts by weight. The pharmaceutical composition according to any one of claims 1-18 further comprises an excipient, the content of which is not higher than about 20% w / w. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition comprises: The compound represented by formula (I) – about 1-50 parts by weight; Nicotinamide – approximately 10-200 parts by weight; Arginine and / or lysine – approximately 10-500 parts by weight; Sodium decanoate – approximately 100-500 parts by weight; and Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – approximately 100-500 parts by weight; Excipients – approximately 12-150 parts by weight. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition comprises: The compound represented by formula (I) – about 1-50 parts by weight; Nicotinamide – approximately 10-100 parts by weight; Arginine and / or lysine – approximately 50-150 parts by weight; Sodium decanoate – approximately 100-300 parts by weight; and Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate – approximately 100-300 parts by weight; Excipients – approximately 12-150 parts by weight. The pharmaceutical composition according to any one of claims 1-21, wherein, The mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group or its salt is 1:(1-2.5). The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition comprises: The compound represented by formula (I) – about 1-50 parts by weight (e.g., 10, 20, 40 parts by weight); Nicotinamide – 50 ± 10% by weight; Arginine and / or lysine – 100 ± 10% by weight; Sodium decanoate – 150 ± 10% by weight; and Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate—150±10% by weight; Excipients – approximately 12-150 parts by weight (or 30-100 parts by weight, or 40-90 parts by weight). The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition comprises: The compound represented by formula (I) — 10 ± 10% by weight; Nicotinamide – 50 ± 10% by weight; L-arginine – 100 ± 10% by weight; Sodium decanoate – 150 ± 10% by weight; Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight; Excipients – 54 ± 10% by weight. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition comprises: The compound represented by formula (I) — 20 ± 10% by weight; Nicotinamide – 50 ± 10% by weight; L-arginine – 100 ± 10% by weight; Sodium decanoate – 150 ± 10% by weight; Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight; Excipients – 64 ± 10% by weight. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition comprises: The compound represented by formula (I) – 40 ± 10% by weight; Nicotinamide – 50 ± 10% by weight; L-arginine – 100 ± 10% by weight; Sodium decanoate – 150 ± 10% by weight; Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) — 150 ± 10% by weight; Excipients – 84 ± 10% by weight. The pharmaceutical composition according to any one of claims 19-26, wherein the excipient is selected from one or more of fillers, disintegrants, lubricants, and binders; preferably, the filler is microcrystalline cellulose; and / or The lubricant is sodium dodecyl sulfate, magnesium stearate, or a combination thereof; and / or The disintegrant is sodium carboxymethyl starch; and / or The adhesive is polyvinyl chloride. The pharmaceutical composition according to claim 27, wherein the excipient comprises microcrystalline cellulose, sodium dodecyl sulfate, sodium carboxymethyl starch, magnesium stearate, and povidone. An oral pharmaceutical composition, wherein, The pharmaceutical composition comprises: The compound represented by formula (I) — 7 ± 10% by weight; Nicotinamide – 50 ± 10% by weight; Arginine or lysine – 100 ± 10% by weight; Sodium decanoate – 150 ± 10% by weight; and Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate—150±10% by weight; The compound represented by formula (I) has the following structure: An oral pharmaceutical composition, wherein, The pharmaceutical composition comprises: The compound represented by formula (I) — 7 ± 10% by weight; Nicotinamide – 50 ± 10% by weight; Arginine or lysine – 50 ± 10% by weight; Sodium decanoate – 150 ± 10% by weight; and Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate—150±10% by weight; The compound represented by formula (I) has the following structure: The pharmaceutical composition according to any one of claims 1-30 is a solid dosage form. The pharmaceutical composition according to claim 31 is a tablet, capsule, granule, powder, granule, drop pill, or pill. The pharmaceutical composition according to claim 32, wherein the pharmaceutical composition is a coated tablet. The pharmaceutical composition according to claim 33 is a non-enteric-coated tablet, preferably a gastric-coated tablet. According to claim 34, the pharmaceutical composition per unit dosage comprises 1-150 mg of the compound represented by formula (I). The use of the pharmaceutical composition according to any one of claims 1-35, for: (i) To prepare medicines for the treatment of diseases associated with GIP and / or GLP-1 receptor agonism; and / or (ii) Treatment of diseases associated with GIP and / or GLP-1 receptor agonism. According to the use of claim 36, the disease associated with GIP and / or GLP-1 receptor agonism is selected from at least one of type 2 diabetes, obesity, hypertension, dyslipidemia, obstructive sleep apnea, non-alcoholic fatty liver disease, and cardiovascular disease. A method for treating a disease associated with GIP and / or GLP-1 receptor agonism, the method comprising the step of administering to a subject in need a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1-35. According to the method of claim 38, the disease associated with GIP and / or GLP-1 receptor agonism is selected from at least one of type 2 diabetes, obesity, hypertension, dyslipidemia, obstructive sleep apnea, non-alcoholic fatty liver disease, and cardiovascular disease.

Images