Pharmaceutical compositions of dual GLP-1 and GIP receptor agonists and uses thereof

Abstract

A pharmaceutical composition of a GLP-1 and GIP receptor dual agonist and its use are provided. The pharmaceutical composition has good dissolution properties and stability.

Description

[Technical field]

[0001] This disclosure claims priority to a Chinese patent application filed on December 01, 2021 (application number CN202111454626.6).

[0002] The present disclosure relates to the field of pharmaceutical formulations, specifically to pharmaceutical compositions comprising GLP-1 and GIP receptor dual agonists and their pharmaceutical uses. [Background technology]

[0003] At present, there are many drugs of glucagon-like peptide-1 (GLP-1) class on the market, such as liraglutide, semaglutide and dulaglutide, which are mainly used for the treatment of type 2 diabetes mellitus (T2DM), among which liraglutide has also been approved for marketing by the FDA as an anti-obesity drug. Under physiological conditions, active GLP-1 consists of 30 amino acids and is secreted from intestinal L cells after a meal by cleaving glucagon proate with PC1 / 3 enzyme. In T2DM patients, the secretion of GLP-1 after a meal is significantly suppressed, but the response of GLP-1R of patients to GLP-1 at pharmacological concentrations is not significantly different from that of normal people, further demonstrating the relatively large therapeutic potential of this target. GLP-1R agonists have remarkable advantages in therapeutic effects such as glucose reduction and weight loss, but due to their action on the central nervous system and stomach, they cause nausea and vomiting, i.e., dose-dependent gastrointestinal side effects. The therapeutic dose of GLP-1 class drugs is limited, and by continuing to increase the dose, more significant glucose reduction, weight loss and other therapeutic effects cannot be achieved, so it is necessary to supplement other therapeutic plans to enhance the therapeutic effect or reduce the incidence of side effects of GLP-1 class drugs.

[0004] Glucose-dependent insulinotropic polypeptide (GIP) also belongs to incretin. Active GIP contains 42 amino acids. By cleaving the GIP precursor by PC1 / 3 enzyme in enteroendocrine K cells, it can simultaneously exert a comprehensive regulatory effect on the nervous system and endocrine system, and also plays a role in improving metabolism. GIP exerts its effect directly on the central nervous system, pancreas, and stomach, and indirectly on the liver, and can also exert its effect on fat and muscle tissues by superimposing active ingredients, which can exert a comprehensive metabolic improvement effect. Research has revealed that in the body of non-insulin-dependent diabetes patients, the incretin function of GIP polypeptide is greatly reduced, causing the patients to lack or lose the incretin effect. When blood sugar levels are restored to normal, the inhibitory effect of GIP polypeptide generated in these diabetes patients is greatly weakened.

[0005] Therefore, in order to restore the tolerance of non-insulin-dependent diabetes mellitus patients to GIP polypeptides and to obtain a stronger clinical hypoglycemic effect in accordance with the incretin effect of GIP polypeptides, a clinically effective combination of a treatment method for non-insulin-dependent diabetes mellitus using GIP polypeptides and a clinically effective hypoglycemic drug is required.

[0006] PCT / CN2021 / 096568 provides derivatives of GLP-1 analogs with dual agonistic effects on human GLP-1 receptors and human GIP receptors, and agonistic activity on human GIP receptors. Compared with GLP-1 receptor agonists known in the art, they have stronger therapeutic effects on blood glucose reduction and weight loss, have extremely high plasma stability, and have pharmacokinetic properties that allow them to be administered to human subjects by subcutaneous injection once a week. However, chemically modified polypeptide drugs have complex structures and are prone to instability due to degradation, polymerization, or undesirable chemical modification, etc., so that they are suitable for administration, maintain stability during storage and subsequent use, and exert higher therapeutic effects, and therefore it is particularly important to study stable formulations of chemically modified polypeptide drugs. Summary of the Invention

[0007] The present disclosure relates to (a) a GLP-1 analogue represented by general formula (I) or a medicamentous salt, amide or ester thereof; R1-X1-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -Glu-Phe-X 23 -X 24 -Trp-Leu-X 27 -X 28 -X 29 -X 30 -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (I) (SEQ ID NO: 19) Among them, R1 is hydrogen (H), an alkyl group, an acetyl group, a formyl group, a benzoyl group, a trifluoroacetyl group, pGlu, or is absent; R2 is -NH2, -OH, or absent; X1, X2, X 10 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 23 , X 24 , X 27 , X 28 , X 29 and X 30 are independently selected from any natural amino acid residue, any unnatural amino acid residue, or a peptide fragment consisting of natural amino acid residues and / or unnatural amino acid residues; and (b) providing a pharmaceutical composition comprising an absorption enhancer;

[0008] In some embodiments, the absorption enhancer is one or more selected from N-(8-(2-hydroxybenzoyl)amino)octanoate, sodium octanoate, sodium caprate, sodium taurodeoxycholate, lauroylcarnitine, dodecylphosphatidylcholine, amino acids, cyclodextrin and its derivatives, surfactants, laurocapram and its homologues, alcohol-based organic solvents, organic acids, and fatty alcohols.

[0009] In some embodiments, the amino acid includes, but is not limited to, one or more selected from isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, arginine, histidine, alanine, glycine, proline, serine, and salts thereof, such as one or more selected from arginine, histidine, leucine, lysine, and salts thereof.

[0010] In some embodiments, cyclodextrins and derivatives thereof include, but are not limited to, one or more selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutyl-β-cyclodextrin (SBE-β-CD), 2,6-dimethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, methylated-β-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, dimaltose-β-cyclodextrin, and carboxymethyl-β-cyclodextrin, such as β-cyclodextrin.

[0011] In some embodiments, surfactants include, but are not limited to, sodium dodecyl sulfate, polysorbates, betaines, quaternary ammonium salts, sorbitan esters, poloxamers, or any mixture thereof.

[0012] In some embodiments, the alcohol-based organic solvent includes, but is not limited to, ethanol, glycerin, polyethylene glycol, propylene glycol, or any mixture thereof.

[0013] In some embodiments, the organic acid includes, but is not limited to, stearic acid, palmitic acid, oleic acid, lauric acid, or any mixture thereof; and / or In some embodiments, fatty alcohols include, but are not limited to, lauryl alcohol, cetyl alcohol, stearyl alcohol, or any mixture thereof.

[0014] In some embodiments, the absorption enhancer is (1) N-(8-(2-hydroxybenzoyl)amino)octanoate, (2) sodium caprate, (3) N-(8-(2-hydroxybenzoyl)amino)octanoate and sodium octanoate, (4) N-(8-(2-hydroxybenzoyl)amino)octanoate and amino acid or its salt, (5) N-(8-(2-hydroxybenzoyl)amino)octanoate and β-cyclodextrin, (6) N-(8-(2-hydroxybenzoyl)amino)octanoate, amino acid or its salt, and sodium caprate, (7) Any one selected from the group consisting of N-(8-(2-hydroxybenzoyl)amino)octanoate, an amino acid or a salt thereof, and sodium octanoate.

[0015] In some embodiments, the N-(8-(2-hydroxybenzoyl)amino)octanoate comprises one monovalent cation, two monovalent cations, or one divalent cation. In some embodiments, the N-(8-(2-hydroxybenzoyl)amino)octanoate is selected from the sodium, potassium, and calcium salts of N-(8-(2-hydroxybenzoyl)amino)octanoic acid. The N-(8-(2-hydroxybenzoyl)amino)octanoate may be crystalline and / or amorphous. In some embodiments, the delivery agent comprises an anhydrate, monohydrate, dihydrate, trihydrate, solvate, or trihydrate of N-(8-(2-hydroxybenzoyl)amino)octanoate, and combinations thereof.

[0016] In some embodiments, the N-(8-(2-hydroxybenzoyl)amino)octanoate is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate, also known as sodium 8-(salicylamido)octanoate (also referred to herein as "SNAC").

[0017] In some embodiments, the absorption enhancer is (1) SNAC, (2) sodium caprate, (3) SNAC and sodium octanoate, (4) SNAC and arginine or a salt thereof, (5) SNAC and β-cyclodextrin, (6) SNAC, arginine or its salts, and sodium caprate, (7) SNAC, arginine or a salt thereof, and leucine or a salt thereof, (8) SNAC, arginine or a salt thereof, and lysine or a salt thereof, and (9) Any one selected from the group consisting of SNAC, arginine or a salt thereof, and sodium octanoate. In some embodiments, the absorption enhancer accounts for at least 20% of the total mass of the composition.

[0018] In some embodiments, the absorption enhancer comprises at least 50% of the total weight of the composition.

[0019] In some embodiments, the absorption enhancer comprises at least 70% of the total weight of the composition.

[0020] In some embodiments, the absorption enhancer comprises at least 80% or at least 90% of the total weight of the composition.

[0021] In some embodiments, the absorption enhancer is SNAC, and SNAC comprises at least 20%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the total weight of the composition.

[0022] In some embodiments, the absorption enhancer is sodium caprate, and the sodium caprate comprises at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% of the total weight of the composition.

[0023] In some embodiments, the absorption enhancers are SNAC and sodium octanoate, and the combined weight of the SNAC and sodium octanoate comprises at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC and sodium octanoate, and the SNAC comprises 70%-90% of the total weight of the composition, and the sodium octanoate comprises 5%-10% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC and sodium octanoate, and the SNAC comprises 50%-70% or 50%-85% of the total weight of the composition, and the sodium octanoate comprises 10%-45% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC and sodium octanoate, and the SNAC comprises 20%-50% of the total weight of the composition and the sodium octanoate comprises 10%-75% or 40%-75% of the total weight of the composition.

[0024] In some embodiments, the absorption enhancer is SNAC and arginine or a salt thereof, and the combined weight of SNAC and arginine or a salt thereof constitutes at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the total weight of the composition. In some embodiments, the absorption enhancer is SNAC and arginine or a salt thereof, and SNAC constitutes 70%-90% of the total weight of the composition, and arginine or a salt thereof constitutes 5%-10% of the total weight of the composition. In some embodiments, the absorption enhancer is SNAC and arginine or a salt thereof, and SNAC constitutes 70%-90% of the total weight of the composition, and arginine or a salt thereof constitutes 1%-20% of the total weight of the composition. In some embodiments, the absorption enhancer is SNAC and arginine or a salt thereof, and SNAC comprises 70%-90% of the total weight of the composition, and arginine or a salt thereof comprises 5%-25% of the total weight of the composition. In some embodiments, the absorption enhancer is SNAC and arginine or a salt thereof, and SNAC comprises 50%-70% or 50%-85% of the total weight of the composition, and arginine or a salt thereof comprises 10%-45% of the total weight of the composition. In some embodiments, the absorption enhancer is SNAC and arginine or a salt thereof, and SNAC comprises 20%-50% of the total weight of the composition, and arginine or a salt thereof comprises 10%-75% or 40%-75% of the total weight of the composition.

[0025] In some embodiments, the absorption enhancers are SNAC and β-cyclodextrin, and the combined weight of the SNAC and β-cyclodextrin constitutes at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC and β-cyclodextrin, and the SNAC constitutes 70%-90% of the total weight of the composition, and the β-cyclodextrin constitutes 5%-10% or 1%-20% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC and β-cyclodextrin, and the SNAC constitutes 50%-70% or 50%-85% of the total weight of the composition, and the β-cyclodextrin constitutes 10%-45% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC and β-cyclodextrin, and the SNAC comprises 20%-50% of the total weight of the composition and the β-cyclodextrin comprises 10%-75% or 40%-75% of the total weight of the composition.

[0026] In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and sodium caprate, and the combined weight of the SNAC, arginine or a salt thereof, and sodium caprate constitutes at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and sodium caprate, and the SNAC constitutes 50%-90% of the total weight of the composition, the arginine or a salt thereof constitutes 1%-30% of the total weight of the composition, and the sodium caprate constitutes 1%-30% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and sodium caprate, and SNAC comprises 20%-50% of the total weight of the composition, arginine or a salt thereof comprises 10%-35% of the total weight of the composition, and sodium caprate comprises 15%-40% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and sodium caprate, and SNAC comprises 50%-70% of the total weight of the composition, arginine or a salt thereof comprises 10%-35% of the total weight of the composition, and sodium caprate comprises 10%-35% of the total weight of the composition.

[0027] In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and leucine or a salt thereof, and the combined weight of SNAC, arginine or a salt thereof, and leucine or a salt thereof constitutes at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and leucine or a salt thereof, and SNAC constitutes 50%-90% of the total weight of the composition, arginine or a salt thereof constitutes 1%-30% of the total weight of the composition, and leucine or a salt thereof constitutes 1%-30% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and leucine or a salt thereof, and SNAC comprises 20%-50% of the total weight of the composition, arginine or a salt thereof comprises 10%-35% of the total weight of the composition, and leucine or a salt thereof comprises 15%-40% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and leucine or a salt thereof, and SNAC comprises 50%-70% of the total weight of the composition, arginine or a salt thereof comprises 10%-35% of the total weight of the composition, and leucine or a salt thereof comprises 10%-35% of the total weight of the composition.

[0028] In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and lysine or a salt thereof, and the combined weight of SNAC, arginine or a salt thereof, and lysine or a salt thereof constitutes at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and lysine or a salt thereof, and SNAC constitutes 50%-90% of the total weight of the composition, arginine or a salt thereof constitutes 1%-30% of the total weight of the composition, and lysine or a salt thereof constitutes 1%-30% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and lysine or a salt thereof, and SNAC comprises 20%-50% of the total weight of the composition, arginine or a salt thereof comprises 10%-35% of the total weight of the composition, and lysine or a salt thereof comprises 15%-40% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and lysine or a salt thereof, and SNAC comprises 50%-70% of the total weight of the composition, arginine or a salt thereof comprises 10%-35% of the total weight of the composition, and lysine or a salt thereof comprises 10%-35% of the total weight of the composition.

[0029] In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and sodium octanoate, and the combined weight of SNAC, arginine or a salt thereof, and sodium octanoate constitutes at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and sodium octanoate, and the SNAC constitutes 50%-90% of the total weight of the composition, the arginine or a salt thereof constitutes 1%-30% of the total weight of the composition, and the sodium octanoate constitutes 1%-30% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and sodium octanoate, and SNAC comprises 20%-50% of the total weight of the composition, arginine or a salt thereof comprises 15%-40% of the total weight of the composition, and sodium octanoate comprises 10%-35% of the total weight of the composition. In some embodiments, the absorption enhancers are SNAC, arginine or a salt thereof, and sodium octanoate, and SNAC comprises 50%-70% of the total weight of the composition, arginine or a salt thereof comprises 10%-35% of the total weight of the composition, and sodium octanoate comprises 10%-35% of the total weight of the composition.

[0030] In some embodiments, the GLP-1 analogue or a medicamentable salt, amide or ester thereof comprises 0.1%-30%, 1%-20%, 1%-10%, or 1%-5% of the total weight of the composition.

[0031] In some embodiments, in the GLP-1 analogues shown in general formula (I), X1 is Tyr or His, X2 is Aib or D-Ala, and X 10 is Val or Tyr, and X 12 is Ser or Ile, and X 13 is Tyr or Ala, and X 14 is Leu or Nle, and X 15 is Asp or Glu, and X 16is Arg, Glu, Gly, Lys or Aib, and X 17 is Glu, Ile or Gln, and X 18 is Ala, Aib or His, and X 19 is Ala, Aib or Gln, and X 20 is Gln, Glu, Lys, and X 23 is Ile or Val, and X 24 is Ala, Asn or Gln, and X 27 is Val or Leu, and X 28 is Arg or Ala, and X 29 is Gly or Gln, and X 30 are Gly and Lys.

[0032] In some embodiments, X1 is Tyr or His, X2 is Aib or D-Ala, and X 10 is Val or Tyr or Y1, and X 12 is Ser or Ile or Y1, and X 13 is Tyr or Ala or Y1, and X 14 is Leu or Nle or Y1, and X 15 is Asp or Glu, and X 16 is Arg, Glu, Gly, Lys, Aib, or Y1, and X 17 is Glu, Ile, Gln, or Y1, and X 18 is Ala, Aib or His, and X 19 is Ala, Aib or Gln, and X 20 is Gln, Glu, Lys, and X 23 is Ile or Val, and X 24 is Ala, Asn or Gln, and X 27 is Val or Leu, and X 28 is Arg or Ala, and X 29 is Gly or Gln, and X 30 is Gly, Lys, and Y1 is a substituted Lys, Orn, Dap, Dab, or Cys residue, for example having a modifying group in the side chain of the Lys, Orn, Dap, Dab, or Cys residue.

[0033] In some embodiments, Y1 is a Lys, Orn, Dap, Dab, or Cys residue having a substituent at its side chain, the substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c It is a structure represented by -COOH, in which a is an integer of 1 to 3 (including 1, 2, and 3), b is 1 or 2, and c is an integer of 10 to 30 (including 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30).

[0034] In some embodiments, X1 is Tyr, X2 is Aib, and X 10 is Tyr, and X 12 is Ile, and X 13 is Tyr, and X 14 is Y1 and X 15 is Asp or Glu, and X 16 is Arg or Lys, and X 17 is Ile, and X 18 is Ala, and X 19 is Ala, and X 20 is Gln, and X 23 is Ile or Val, and X 24 is Asn, and X 27 is Ile or Leu, and X 28 is Ala, and X 29 is Gly, and X 30 is Gly, and Y1 has a side chain of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c It is a Lys, Orn, Dap, Dab or Cys residue linked to a substituent having —COOH, wherein a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0035] In some embodiments, X1 is Tyr, X2 is Aib, and X 10 is Tyr, and X 12 is Ile, and X13 is Tyr, and X 14 is Y1 and X 15 is Asp or Glu, and X 16 is Lys, and X 17 is Ile, and X 18 is Ala, and X 19 is Ala, and X 20 is Gln, and X 23 is Val and X 24 is Asn, and X 27 is Leu, and X 28 is Ala, and X 29 is Gly, and X 30 is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue having a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c In this structure, a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0036] In some embodiments, X1 is Tyr, X2 is Aib or D-Ala, and X 10 is Y1 and X 12 is Ile, and X 13 is Tyr, and X 14 is Leu or Nle, and X 15 is Glu, and X 16 is Arg or Lys, and X 17 is Ile, and X 18 is Ala, and X 19 is Ala, and X 20 is Gln or Lys, and X 23 is Ile or Val, and X 24 is Asn or Gln, and X 27 is Ile or Leu, and X 28 is Ala, and X 29 is Gly, and X 30is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue having a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c In this structure, a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0037] In some embodiments, X1 is Tyr, X2 is Aib or D-Ala, and X 10 is Tyr, and X 12 is Y1 and X 13 is Tyr, and X 14 is Leu or Nle, and X 15 is Glu, and X 16 is Arg or Lys, and X 17 is Ile, and X 18 is Ala, and X 19 is Ala, and X 20 is Gln or Lys, and X 23 is Ile or Val, and X 24 is Asn or Gln, and X 27 is Ile or Leu, and X 28 is Ala, and X 29 is Gly, and X 30 is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue having a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c In this structure, a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0038] In some embodiments, X1 is Tyr, X2 is Aib or D-Ala, and X 10 is Tyr, and X 12 is Ile, and X 13 is Y1 and X 14is Leu or Nle, and X 15 is Glu, and X 16 is Arg or Lys, and X 17 is Ile, and X 18 is Ala, and X 19 is Ala, and X 20 is Gln or Lys, and X 23 is Ile or Val, and X 24 is Asn or Gln, and X 27 is Ile or Leu, and X 28 is Ala, and X 29 is Gly, and X 30 is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue having a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c In this structure, a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0039] In some embodiments, X1 is Tyr, X2 is Aib or D-Ala, and X 10 is Tyr, and X 12 is Ile, and X 13 is Tyr, and X 14 is Y1 and X 15 is Glu, and X 16 is Arg or Lys, and X 17 is Ile, and X 18 is Ala, and X 19 is Ala, and X 20 is Gln or Lys, and X 23 is Ile or Val, and X 24 is Asn or Gln, and X 27 is Ile or Leu, and X 28 is Ala, and X 29 is Gly, and X 30is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue having a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c In this structure, a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0040] In some embodiments, X1 is Tyr, X2 is Aib, and X 10 is Tyr, and X 12 is Ile, and X 13 is Tyr, and X 14 is Y1 and X 15 is Glu, and X 16 is Arg or Lys, and X 17 is Ile, and X 18 is Ala, and X 19 is Ala, and X 20 is Gln, and X 23 is Ile or Val, and X 24 is Asn, and X 27 is Ile or Leu, and X 28 is Ala, and X 29 is Gly, and X 30 is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue having a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c In this structure, a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0041] In some embodiments, X1 is Tyr, X2 is Aib or D-Ala, and X 10 is Tyr, and X 12 is Ile, and X 13 is Tyr, and X 14 is Leu or Nle, and X 15 is Glu, and X16 is Y1 and X 17 is Ile, and X 18 is Ala, and X 19 is Ala, and X 20 is Gln or Lys, and X 23 is Ile or Val, and X 24 is Asn or Gln, and X 27 is Ile or Leu, and X 28 is Ala, and X 29 is Gly, and X 30 is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue having a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c In this structure, a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0042] In some embodiments, X1 is Tyr, X2 is Aib or D-Ala, and X 10 is Tyr, and X 12 is Ile, and X 13 is Tyr, and X 14 is Leu or Nle, and X 15 is Glu, and X 16 is Arg or Lys, and X 17 is Y1 and X 18 is Ala, and X 19 is Ala, and X 20 is Gln or Lys, and X 23 is Ile or Val, and X 24 is Asn or Gln, and X 27 is Ile or Leu, and X 28 is Ala, and X 29 is Gly, and X 30 is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue having a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu)b -CO-(CH2) c In this structure, a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0043] In some embodiments, X 10 , X 12 , X 13 , X 14 , X 16 and X 17 are each independently selected from Y1, where Y1 is a Lys, Orn, Dap, Dab or Cys residue having a substituent at the side chain, the substituent being represented by the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c In this structure, a is an integer of 1 to 3, b is 1 or 2, and c is an integer of 10 to 30.

[0044] In some embodiments, a is 2, b is 1 or 2, and c is an integer from 16 to 20 (eg, c is 16, 17, 18, 19, 20).

[0045] In some embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20.

[0046] In some embodiments, X 10 is Y1, Y1 is Lys having a substituent at the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c -COOH, where a is 2, b is 1 or 2, and c is 16 or 18.

[0047] In some embodiments, X 12 is Y1, Y1 is Lys having a substituent at the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2)c -COOH, where a is 2, b is 1 or 2, and c is 16 or 18.

[0048] In some embodiments, X 13 is Y1, Y1 is Lys having a substituent at the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c -COOH, where a is 2, b is 1 or 2, and c is 16 or 18.

[0049] In some embodiments, X 14 is Y1, Y1 is Lys having a substituent at the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c -COOH, where a is 2, b is 1 or 2, and c is 16 or 18.

[0050] In some embodiments, X 16 is Y1, Y1 is Lys having a substituent at the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c -COOH, where a is 2, b is 1 or 2, and c is 16 or 18.

[0051] In some embodiments, X 17 is Y1, Y1 is Lys having a substituent at the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c -COOH, where a is 2, b is 1 or 2, and c is 16 or 18.

[0052] In some embodiments, the side chain amino group of a Lys residue in Y1 is covalently linked to the substituent by forming an amide bond.

[0053] In some embodiments, Y is K(-OEG-OEG-γGlu-C18-OH) or K(-OEG-OEG-γGlu-C20-OH), wherein K(-OEG-OEG-γGlu-C18-OH) has the structure: [ka] , K(-OEG-OEG-γGlu-C20-OH) has the following structure: [ka] .

[0054] In some embodiments, Y is K(-OEG-OEG-γGlu-C18-OH) or K(-OEG-OEG-γGlu-C20-OH), wherein: K(-OEG-OEG-γGlu-C18-OH) has the following structure: [ka] , K(-OEG-OEG-γGlu-C20-OH) has the following structure: [ka] .

[0055] In some embodiments, the ε-amino group of the Lys residue in Y1 is covalently linked to the substituent via an amide bond and the α-amino group of the Lys residue is linked to the peptide chain.

[0056] In some embodiments, X1 is selected from Tyr, X2 is selected from Aib, and X 10 is chosen from Tyr, and X 12 Ile, X 13 is chosen from Tyr, and X14 is selected from Y1, and X 15 is selected from Asp or Glu, and X 16 is selected from Arg or Lys, and X 17 is chosen from Ile, and X 18 is chosen from Ala, and X 19 is chosen from Ala, and X 20 is selected from Gln, and X 23 is selected from Ile or Val, and X 24 is selected from Asn, and X 27 is selected from Ile or Leu, and X 28 is chosen from Ala, and X 29 is selected from Gly, and X 30 is selected from Gly, Y1 is K(-OEG-OEG-γGlu-C18-OH) or K(-OEG-OEG-γGlu-C20-OH), wherein K(-OEG-OEG-γGlu-C18-OH) has the following structure: [ka] , K(-OEG-OEG-γGlu-C20-OH) has the following structure: [ka] .

[0057] In some embodiments, X1 is selected from Tyr, X2 is selected from Aib, and X 10 is chosen from Tyr, and X 12 Ile, X 13 is chosen from Tyr, and X 14 is selected from Y1, and X 15 is selected from Asp or Glu, and X 16 is selected from Arg or Lys, and X 17 is chosen from Ile, and X 18 is chosen from Ala, and X 19 is chosen from Ala, and X 20 is selected from Gln, and X 23 is selected from Ile or Val, and X 24 is selected from Asn, and X 27is selected from Ile or Leu, and X 28 is chosen from Ala, and X 29 is selected from Gly, and X 30 is selected from Gly, Y1 is K(-OEG-OEG-γGlu-C18-OH) or K(-OEG-OEG-γGlu-C20-OH), wherein K(-OEG-OEG-γGlu-C18-OH) has the following structure: [ka] , K(-OEG-OEG-γGlu-C20-OH) has the following structure: [ka] .

[0058] In some embodiments of the present disclosure, the GLP-1 analog is shown in general formula (II) (SEQ ID NO: 20): H-YAibEGTFTSDYSIYX 14 X 15 X 16 IAAQEFX 23 NWLX 27 AGGPSSGAPPPS-NH2(II), of which X 14 is K or L, X 15 D, E, X 16 is K, R, X 23 is V, I, X 27 is I or L.

[0059] In some embodiments of the present disclosure, the GLP-1 analog is selected from the compounds numbered 1 to 18 below: [Table 1] . In some embodiments of the present disclosure, the GLP-1 analog is selected from the compounds shown below in numbers 1# to 18#: [Table 2] . In some embodiments, the GLP-1 analog of the present disclosure is selected from compounds shown in Figure 3 as 7#, 12#, 13#, 14#, 15#, 16#, 17#, or 18#.

[0060] In some embodiments, the GLP-1 analogs of the present disclosure are amphoteric compounds, and their medicamentable salts include salts formed by reaction with acidic or basic compounds. In some embodiments, the acidic compounds are selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. The basic compounds are selected from ammonium, alkali metal or alkaline earth metal hydroxides, and carbonates and bicarbonates, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, and potassium carbonate.

[0061] In some embodiments, the C-terminus of the GLP-1 analog has a carboxy-protecting group. In some embodiments, the C-terminus of the GLP-1 analog forms an amide or ester. In some embodiments, the pharmaceutical composition of the present disclosure comprises: Composition (a) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, and N-(8-(2-hydroxybenzoyl)amino)octanoate; Composition (b) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate and sodium octanoate; A composition (c) comprising the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate and an amino acid or a salt thereof (e.g., one or more selected from histidine, arginine, leucine and lysine or a salt thereof); A composition (d) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate and β-cyclodextrin; A composition (e) comprising the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, and sodium caprate; A composition (f) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or its salt, and sodium caprate; A composition (g) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate and histidine or its salt; A composition (h) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate and arginine or its salt; A composition (i) comprising the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, and leucine or a salt thereof; Composition (j) comprising the compound shown in 18# of FIG. 3 or a medicamentous salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof and lysine or a salt thereof; and It is any one selected from the compound shown in 18# of Figure 3 or its medicinal salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or its salt, and composition (k) comprising sodium octanoate.

[0062] In some embodiments, the pharmaceutical composition of the present disclosure comprises: A composition (a1) containing 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, and at least 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, based on the total mass of the composition; A composition (b1) containing 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate and 5% to 75% of sodium octanoate based on the total mass of the composition; A composition (c1) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 75% of an amino acid (e.g., one or more selected from histidine, arginine, leucine, and lysine, or a salt thereof); A composition (d1) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 75% of β-cyclodextrin; A composition (e1) containing 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, and at least 50% of sodium caprate, based on the total mass of the composition; A composition (f1) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 60% of arginine or a salt thereof, and 1% to 50% of sodium caprate; A composition (g1) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 75% of arginine or a salt thereof; A composition (h1) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 50% of arginine or a salt thereof, and 1% to 50% of leucine or a salt thereof; A composition (i1) containing, relative to the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 50% of arginine or a salt thereof, and 1% to 50% of lysine or a salt thereof; The composition is any one selected from composition (j1) containing, relative to the total mass of the composition, 1% to 20% of the compound shown in 18# of Figure 3 or a medicinal salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 50% of arginine or a salt thereof, and 1% to 50% of sodium octanoate.

[0063] In some embodiments, the pharmaceutical composition of the present disclosure comprises: A composition (a2) comprising 1% to 5% of the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, and at least 70%, for example at least 90%, of N-(8-(2-hydroxybenzoyl)amino)octanoate, based on the total weight of the composition; A composition (b2) containing 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate and 5% to 10% of sodium octanoate based on the total mass of the composition; A composition (b3) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 45% of sodium octanoate; A composition (b4) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 75% or 40% to 75% of sodium octanoate; A composition (c2) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 10% or 1% to 20% of arginine or a salt thereof; A composition (c3) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 45% of arginine or a salt thereof; A composition (c4) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 75% or 40% to 75% of arginine or a salt thereof; A composition (c5) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 25% of arginine or a salt thereof; A composition (d2) containing 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate and 5% to 10% or 1% to 20% of β-cyclodextrin based on the total mass of the composition; A composition (d3) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 45% of β-cyclodextrin; A composition (d4) containing, relative to the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 75% or 40% to 75% of β-cyclodextrin; A composition (e2) containing 1% to 5% of the compound shown in 18# of Figure 3 or a medicinal salt, amide or ester thereof, and 70% to 80% of sodium caprate, based on the total mass of the composition; A composition (f1) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, and 1% to 30% of sodium caprate; A composition (f2) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, and 15% to 40% of sodium caprate; A composition (f3) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, and 10% to 35% of sodium caprate; A composition (g1) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, and 1% to 30% of leucine or a salt thereof; A composition (g2) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, and 15% to 40% of leucine or a salt thereof; A composition (g3) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, and 10% to 35% of leucine or a salt thereof; A composition (h1) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, and 1% to 30% of lysine or a salt thereof; A composition (h2) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, and 15% to 40% of lysine or a salt thereof; A composition (h3) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, and 10% to 35% of lysine or a salt thereof; A composition (i1) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, and 1% to 30% of sodium octanoate; A composition (i2) containing, based on the total mass of the composition, 1% to 20% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 15% to 40% of arginine or a salt thereof, and 10% to 35% of sodium octanoate; and The composition is any one selected from the group consisting of composition (i3) containing, relative to the total mass of the composition, 1% to 20% of the compound shown in 18# of Figure 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, and 10% to 35% of sodium octanoate.

[0064] In some embodiments, the pharmaceutical compositions of the present disclosure further comprise one or more excipients selected from fillers, adhesives, disintegrants, lubricants, glidants, coating agents, and protease inhibitors.

[0065] In some embodiments, a filler does not necessarily function as a filler in the compositions of the present disclosure, an adhesive does not necessarily function as an adhesive in the compositions of the present disclosure, a disintegrant does not necessarily function as a disintegrant in the compositions of the present disclosure, a lubricant does not necessarily function as a lubricant in the compositions of the present disclosure, a glidant does not necessarily function as a glidant in the compositions of the present disclosure, a coating agent does not necessarily function as a coating agent in the compositions of the present disclosure, and a protease inhibitor does not necessarily function as a protease inhibitor in the compositions of the present disclosure.

[0066] In some embodiments, fillers include, but are not limited to, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, calcium hydrogen phosphate, sorbitol, or any mixture thereof.

[0067] In some embodiments, adhesives include, but are not limited to, povidone and its congeners, hydroxypropyl cellulose, hydroxypropyl methylcellulose and its congeners, or any mixture thereof.

[0068] In some embodiments, disintegrants include, but are not limited to, microcrystalline cellulose, alginic acid, alginates, potassium polyacrylate, calcium hydrogen phosphate, corn starch, pregelatinized starch, sodium carboxymethyl starch, sodium starch glycolate, crospovidone, cellulose powder, and cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and croscarmellose sodium.

[0069] In some embodiments, lubricants include, but are not limited to, magnesium stearate, glyceryl behenate, sodium stearoyl fumarate, stearic acid, palmitic acid, calcium stearate, talc powder, carnauba wax, or any mixture thereof.

[0070] In some embodiments, the glidant is selected from colloidal silica or talc powder.

[0071] In some embodiments, the coating agent includes, but is not limited to, a water-soluble polymer, a water-insoluble polymer, a gastrosoluble polymer, and an enteric polymer. The water-soluble polymer is a natural polymer or polysaccharide and a derivative thereof, such as gum arabic powder, gelatin, pullulan, dextrin, sodium carboxymethyl starch, sodium alginate, etc., a cellulose derivative, such as sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, carboxymethylcellulose, etc., and a water-soluble vinyl derivative, such as polyvinylpyrrolidone and polyvinyl alcohol, and the water-insoluble polymer is ethylcellulose (ethylcellulose aqueous dispersion (e.g., trade name: AQUACOAT, manufactured by FMC)), vinyl acetate polymer (e.g., trade name: Kollicoat SR30D, manufactured by BASF), aminoalkyl methacrylate copolymer (particularly its aqueous dispersion (AmmonioMethacrylate Copolymer Dispersion) (e.g., trade names: EUDRAGITRL30D, EUDRAGITRS30D, manufactured by EVONIC), ethyl acrylate-methyl methacrylate copolymer dispersion (e.g., trade name: EUDRAGITNE30D, manufactured by EVONIC), and the gastric-soluble polymer is an aminoacetal compound such as polyvinyl acetal-diethylaminoacetate (e.g., trade name: AEA, manufactured by Mitsubishi-Kagaku Foods Corporation), aminoalkyl methacrylate copolymer E (e.g., trade name: EUDRAGITE, manufactured by EVONIC), and mixtures thereof.The enteric polymer is an enteric cellulose ester such as cellulose acetate propionate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate (hypromellose phthalate), hydroxymethylethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate, or phthalate; an enteric methacrylic acid copolymer LD (e.g., trade name: EUDRAGITL30D-55, manufactured by EVONIC; trade name: POLYQUIDPA30, manufactured by Sanyo Chemical Industries; trade name: KollicoatMAE30DP, manufactured by BASF; trade name: Acryl-Eze (Acrylase, lot number 93O18508), manufactured by Colorcon); methacrylic acid copolymer L (e.g., trade name: EUDRAGITL, manufactured by EVONIC); or methacrylic acid copolymer S (e.g., trade name: EUDRAGITS100, EUDRAGITFS30D, manufactured by EVONIC).

[0072] In some embodiments, the coating agent is one or more selected from sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, methacrylic resin copolymer, and ethylcellulose.

[0073] In some embodiments, protease inhibitors include, but are not limited to, phenylmethylsulfonyl fluoride (PSMF), soybean trypsin inhibitor, soybean trypsin-chymotrypsin inhibitor, colicin, sunflower trypsin inhibitor, leupeptin, citric acid, ethylenediaminetetraacetic acid, sodium glycocholate, and 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride.

[0074] In some embodiments, the composition comprises, based on the total weight of the composition, 10%-30% or 15%-45% filler, 1%-5% adhesive, 0.5%-5% glidant, 0.5%-5% lubricant, and / or 10%-30% protease inhibitor.

[0075] In some embodiments, the pharmaceutical composition of the present disclosure comprises: A composition (i) comprising the compound shown in FIG. 3 #18 or its medicinal salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate, and one or more selected from fillers, adhesives and lubricants; A composition (ii) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate, sodium octanoate, a glidant and a lubricant; A composition (iii) comprising a compound shown in 18# of FIG. 3 or a medicamentable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, an amino acid (e.g., one or more selected from histidine, arginine, leucine and lysine or a salt thereof, e.g., arginine or a salt thereof), a glidant and a lubricant; A composition (iv) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate, β-cyclodextrin, a glidant and a lubricant; A composition (v) comprising the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, sodium caprate, and a protease inhibitor; A composition (vi) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or its salt, sodium caprate, a glidant and a lubricant; A composition (vii) comprising a compound shown in FIG. 3 #18 or a medicamentable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, leucine or a salt thereof, a glidant and a lubricant; A composition (viii) comprising the compound shown in FIG. 3 #18 or a medicamentable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, lysine or a salt thereof, a glidant and a lubricant; A composition (ix) comprising the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, a glidant, a lubricant, a filler and / or an adhesive; The composition is selected from the group consisting of a compound shown in 18# of Figure 3 or a medicamentous salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sodium octanoate, a glidant and a lubricant.

[0076] In some embodiments, the pharmaceutical composition of the present disclosure comprises: A composition (i-1) comprising the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, and one or more selected from microcrystalline cellulose, povidone and magnesium stearate; Composition (ii-1) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate, sodium octanoate, colloidal silica and magnesium stearate; A composition (iii-1) comprising the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, an amino acid (e.g., one or more selected from histidine, arginine, leucine and lysine or a salt thereof, e.g., arginine or a salt thereof), colloidal silica and magnesium stearate; Composition (iv-1) comprising the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, N-(8-(2-hydroxybenzoyl)amino)octanoate, β-cyclodextrin, colloidal silica and magnesium stearate; A composition (v-1) comprising the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, sodium caprate, and PMSF; Composition (vi-1) comprising the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sodium caprate, colloidal silica and magnesium stearate; A composition (vii-1) comprising the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, leucine or a salt thereof, colloidal silica and magnesium stearate; A composition (viii-1) comprising the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, lysine or a salt thereof, colloidal silica and magnesium stearate; Composition (ix-1) comprising the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sorbitol, colloidal silica and magnesium stearate; A composition (ix-2) comprising the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sorbitol, povidone, colloidal silica and magnesium stearate; A composition (ix-3) comprising the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sorbitol, hydroxypropylcellulose, colloidal silica and magnesium stearate; and The composition (x-1) is any one selected from the group consisting of the compound shown in 18# of Figure 3 or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sodium octanoate, colloidal silica and magnesium stearate.

[0077] In some embodiments, the pharmaceutical composition of the present disclosure comprises: A composition (i-2) containing, based on the total mass of the composition, 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 80% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 20% of a filler, about 2% of an adhesive and 0.5% to 5% of a lubricant; A composition (i-3) containing 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, at least 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate and 0.5% to 5% of a lubricant based on the total mass of the composition; A composition (ii-2) comprising, based on the total mass of the composition, 1%-20%, for example 1%-5% of the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, 70%-90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5%-10% of sodium octanoate, 1%-1.5% of a glidant and 0.5%-5% of a lubricant; A composition (ii-3) comprising, based on the total mass of the composition, 1%-20%, for example 1%-5% of the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, 50%-70% or 50%-85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10%-45% of sodium octanoate, 1%-1.5% of a glidant and 0.5%-5% of a lubricant; A composition (ii-4) comprising, based on the total mass of the composition, 1%-20%, for example 1%-5% of the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, 20%-50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10%-75% or 40%-75% of sodium octanoate, 1%-1.5% of a glidant and 0.5%-5% of a lubricant; A composition (iii-2) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 10% or 1% to 20% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (iii-3) comprising, based on the total mass of the composition, 1%-20%, for example 1%-5% of the compound shown in FIG. 3 #18 or its medicinal salt, amide or ester, 50%-70% or 50%-85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10%-45% of arginine, 1%-1.5% of a glidant and 0.5%-5% of a lubricant; A composition (iii-4) comprising, based on the total mass of the composition, 1%-20%, for example 1%-5% of the compound shown in FIG. 3 #18 or its medicinal salt, amide or ester, 20%-50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10%-75% or 40%-75% of arginine, 1%-1.5% of a glidant and 0.5%-5% of a lubricant; A composition (iii-5) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 25% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (iv-2) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicamentous salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 10% or 1% to 20% of β-cyclodextrin, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (iv-3) comprising, based on the total mass of the composition, 1%-20%, for example 1%-5% of the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, 50%-70% or 50%-85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10%-45% of β-cyclodextrin, 1%-1.5% of a glidant and 0.5%-5% of a lubricant; A composition (iv-4) comprising, based on the total mass of the composition, 1%-20%, for example 1%-5% of the compound shown in FIG. 3 #18 or its medicamentous salt, amide or ester, 20%-50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10%-75% or 40%-75% of β-cyclodextrin, 1%-1.5% of a glidant and 0.5%-5% of a lubricant; A composition (v-2) comprising, based on the total mass of the composition, 1%-2% or 1%-5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70%-80% of sodium caprate, and 15%-25% of a protease inhibitor; A composition (v-3) comprising 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 65% to 80% of sodium caprate, and 15% to 30% of a protease inhibitor, based on the total mass of the composition; A composition (vi-2) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of sodium caprate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (vi-3) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 15% to 40% of arginine or a salt thereof, 10% to 35% of sodium caprate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (vi-4) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of sodium caprate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (vii-2) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of leucine or a salt thereof, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (vii-3) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 15% to 40% of leucine or a salt thereof, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (vii-4) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of leucine or a salt thereof, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (viii-2) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of lysine or a salt thereof, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (viii-3) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 15% to 40% of lysine or a salt thereof, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (viii-4) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of lysine or a salt thereof, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (ix-4) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 25% of arginine or a salt thereof, 1% to 1.5% of a glidant, 0.5% to 5% of a lubricant, 1% to 20% of a filler and / or 0.5% to 5% of an adhesive; A composition (ix-5) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 40% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, 5% to 35% of a filler and / or 0.5% to 5% of an adhesive; A composition (ix-6) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, 1% to 40% of a filler and / or 0.5% to 5% of an adhesive; A composition (x-2) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of sodium octanoate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant; A composition (x-3) containing, relative to the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 15% to 40% of arginine or a salt thereof, 5% to 30% of sodium octanoate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, and The composition is any one selected from compositions (x-4) containing, relative to the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of Figure 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of sodium octanoate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant.

[0078] In some embodiments, the pharmaceutical composition of the present disclosure comprises: A composition (i-4) containing, based on the total mass of the composition, 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 80% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 20% of microcrystalline cellulose, about 2% of povidone and 0.5% to 5% of magnesium stearate; A composition (i-5) containing 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, at least 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate and 0.5% to 5% of magnesium stearate based on the total mass of the composition; A composition (ii-5) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 10% of sodium octanoate, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (ii-6) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 45% of sodium octanoate, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (ii-7) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% or 40% to 75% of sodium octanoate, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (iii-6) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 10% or 1% to 20% of arginine, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; Composition (iii-7) comprising, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 45% of arginine, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (iii-8) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% or 40% to 75% of arginine, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (iii-9) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 25% of arginine, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (iv-5) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 10% or 1% to 20% of β-cyclodextrin, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (iv-6) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 45% or 50% to 85% of β-cyclodextrin, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (iv-7) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% or 40% to 75% of β-cyclodextrin, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate, and A composition (v-4) containing 1% to 2% of the compound shown in 18# of Figure 3 or a medicinal salt, amide or ester thereof, 70% to 80% of sodium caprate, and 15% to 25% of PMSF based on the total mass of the composition; A composition (v-5) containing 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 65% to 80% of sodium caprate, and 15% to 30% of PMSF, based on the total mass of the composition; A composition (vi-5) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of sodium caprate, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (vi-6) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 15% to 40% of arginine or a salt thereof, 10% to 35% of sodium caprate, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (vi-7) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of sodium caprate, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (vii-5) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of leucine or a salt thereof, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (vii-6) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 15% to 40% of leucine or a salt thereof, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (vii-7) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of leucine or a salt thereof, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (viii-5) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of lysine or a salt thereof, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (viii-6) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 15% to 40% of lysine or a salt thereof, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (viii-7) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of lysine or a salt thereof, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (ix-7) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 25% of arginine or a salt thereof, 1% to 1.5% of colloidal silica, 0.5% to 5% of magnesium stearate, and 1% to 20% of sorbitol; A composition (ix-8) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 40% of arginine, 1% to 1.5% of colloidal silica, 0.5% to 5% of magnesium stearate, and 5% to 35% of sorbitol; A composition (ix-9) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% of arginine, 1% to 1.5% of colloidal silica, 0.5% to 5% of magnesium stearate, and 1% to 40% of sorbitol; A composition (ix-10) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 25% of arginine or a salt thereof, 1% to 1.5% of colloidal silica, 0.5% to 5% of magnesium stearate, 1% to 20% of sorbitol, and 0.5% to 5% of povidone or hydroxypropylcellulose; A composition (ix-11) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 40% of arginine, 1% to 1.5% of colloidal silica, 0.5% to 5% of magnesium stearate, 5% to 35% of sorbitol, and 0.5% to 5% of povidone or hydroxypropylcellulose; A composition (ix-12) containing, relative to the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% of arginine, 1% to 1.5% of colloidal silica, 0.5% to 5% of magnesium stearate, 1% to 40% of sorbitol, and 0.5% to 5% of povidone or hydroxypropylcellulose; and A composition (x-5) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of sodium octanoate, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; A composition (x-6) containing, based on the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 15% to 40% of arginine or a salt thereof, 10% to 35% of sodium octanoate, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate; The composition is any one selected from compositions (x-7) containing, relative to the total mass of the composition, 1% to 20%, for example 1% to 5% of the compound shown in 18# of Figure 3 or a medicinal salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of sodium octanoate, 1% to 1.5% of colloidal silica and 0.5% to 5% of magnesium stearate.

[0079] In some embodiments, the pharmaceutical composition of the present disclosure comprises: A composition (1) containing, based on the total mass of the composition, 1% to 2% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, about 75% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 20% of microcrystalline cellulose, about 2% of povidone and about 0.5% or about 2.5% of magnesium stearate; Composition (2) containing 3% to 3.5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 94% to 95% of N-(8-(2-hydroxybenzoyl)amino)octanoate and about 2.5% of magnesium stearate based on the total mass of the composition; A composition (3) comprising, based on the total mass of the composition, about 8% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 80% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 9% of sodium octanoate, about 1% of colloidal silica and about 2.5% of magnesium stearate; A composition (4) comprising, based on the total mass of the composition, about 3% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica and about 2.5% of magnesium stearate; A composition (5) comprising, based on the total weight of the composition, about 1.5% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica and about 2.5% of magnesium stearate; A composition (6) comprising, based on the total mass of the composition, about 3% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica and about 2.5% of magnesium stearate; A composition (7) comprising, based on the total mass of the composition, about 5% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica and about 2.5% of magnesium stearate; A composition (8) containing, based on the total mass of the composition, about 5.5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, 80% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica and about 2.5% of magnesium stearate; A composition (9) comprising, based on the total mass of the composition, about 15% of the compound shown in FIG. 3 #18 or a medicinal salt, amide or ester thereof, 70% to 75% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 8% to 10% of sodium octanoate, about 1% of colloidal silica, and about 2.5% of magnesium stearate; A composition (10) comprising, based on the total mass of the composition, about 3% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of arginine or a salt thereof, about 1.5% of colloidal silica, and about 1.5% of magnesium stearate; A composition (11) comprising, based on the total mass of the composition, about 3% of the compound shown in FIG. 3 #18 or a medicinal salt, amide or ester thereof, about 60% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 35% of arginine or a salt thereof, about 1.5% of colloidal silica, and about 1% of magnesium stearate; A composition (12) comprising, based on the total mass of the composition, about 2.5% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 45% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 50% of arginine or a salt thereof, about 1.5% of colloidal silica, and about 1% of magnesium stearate; A composition (13) comprising, based on the total mass of the composition, about 4% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 75% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 18% of arginine or a salt thereof, about 1% of colloidal silica, and about 2% of magnesium stearate; A composition (14) comprising, based on the total weight of the composition, about 2% to about 5% or 5% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, about 58% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 35% of arginine or a salt thereof, about 1% of colloidal silica, and about 2% of magnesium stearate; A composition (15) comprising, based on the total mass of the composition, about 3% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of histidine or a salt thereof, about 1.5% of colloidal silica, and about 1.5% of magnesium stearate; A composition (16) comprising, based on the total mass of the composition, about 3% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of β-cyclodextrin, about 0.5% of colloidal silica, and about 2.5% of magnesium stearate; A composition (17) comprising about 1.5% of the compound shown in FIG. 3 #18 or a medicament salt, amide or ester thereof, about 80% of sodium caprate, and about 20% of PMSF, based on the total mass of the composition; A composition (18) comprising, based on the total mass of the composition, about 2.5% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 28% of arginine or a salt thereof, about 20% of sodium caprate, about 1% of colloidal silica, and about 2% of magnesium stearate; A composition (19) comprising, based on the total mass of the composition, about 4% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 19% of arginine or a salt thereof, about 28% of sodium caprate, about 1% of colloidal silica, and about 2% of magnesium stearate; A composition (20) comprising, based on the total mass of the composition, about 5% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 58% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 23% of arginine or a salt thereof, about 12% of sodium caprate, about 1% of colloidal silica, and about 2% of magnesium stearate; A composition (21) comprising, based on the total mass of the composition, about 4% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 19% of arginine or a salt thereof, about 28% of leucine, about 1% of colloidal silica, and about 2% of magnesium stearate; A composition (22) comprising, based on the total mass of the composition, about 4% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 19% of arginine or a salt thereof, about 28% of lysine or a salt thereof, about 1% of colloidal silica, and about 2% of magnesium stearate; A composition (23) comprising, based on the total mass of the composition, about 2% to about 4% of the compound shown in 18# of FIG. 3 or a medicinal salt, amide or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 28% of arginine or a salt thereof, about 20% of sorbitol, about 1% of colloidal silica, and about 2% of magnesium stearate; A composition (24) comprising, based on the total mass of the composition, about 4% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 45% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 20% of arginine or a salt thereof, about 28% of sorbitol, about 1% of colloidal silica, and about 2% of magnesium stearate; A composition (25) comprising, based on the total weight of the composition, about 4% of the compound shown in FIG. 3 #18 or a medicamentous salt, amide or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 20% of arginine or a salt thereof, about 25% of sorbitol, about 1.5% of povidone or hydroxypropylcellulose, about 1% of colloidal silica, and about 2% of magnesium stearate; and The composition is any one selected from composition (26) containing, relative to the total mass of the composition, about 2.5% of the compound shown in 18# of Figure 3 or a medicinal salt, amide or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 28% of arginine or a salt thereof, about 20% of sodium octanoate, about 1% of colloidal silica, and about 2% of magnesium stearate.

[0080] In some embodiments, the pharmaceutical compositions of the present disclosure are administered orally.

[0081] In some embodiments, the pharmaceutical composition of the present disclosure is a powder, granule, tablet, capsule, or lyophilized formulation.

[0082] In some embodiments, the pharmaceutical composition of the present disclosure is a tablet or capsule.

[0083] In some embodiments, the capsule is an immediate release or enteric coated formulation.

[0084] In some embodiments, the pharmaceutical compositions of the present disclosure are in tablet form.

[0085] In some embodiments, the tablet has a weight of 100 mg to 1000 mg, for example, 100 mg to 800 mg, 100 mg to 600 mg, or 100 mg to 300 mg. In some embodiments, the tablet has a weight of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg.

[0086] In some embodiments, the pharmaceutical compositions described herein have good dissolution characteristics.

[0087] In some embodiments, a dissolution test is performed using a phosphate buffer solution of pH 6.8 containing 0.1% Tween 80 as a dissolution medium at a rotation speed of 50 rpm, and the dissolution rate % of the GLP-1 agonist and / or absorption enhancer in the pharmaceutical composition of the present disclosure after 15 minutes is ≧80%, ≧85%, ≧90%, ≧95%, ≧98%, or ≧99%.

[0088] In some embodiments, a dissolution test is performed using a phosphate buffer solution of pH 6.8 containing 0.1% Tween 80 as a dissolution medium at a rotation speed of 50 rpm, and the dissolution rate % of the GLP-1 agonist and / or absorption enhancer in the pharmaceutical composition of the present disclosure after 30 minutes is ≧80%, ≧85%, ≧90%, ≧95%, ≧98%, or ≧99%.

[0089] In some embodiments, the dissolution of the active ingredient in the pharmaceutical composition described herein essentially coincides with that of the absorption enhancer SNAC.

[0090] In some embodiments, the pharmaceutical compositions described herein have good in vivo exposure and / or oral bioavailability, e.g., in vivo exposure and / or oral bioavailability that is better than or comparable to LY3298176.

[0091] In some embodiments, the pharmaceutical compositions described herein have good stability.

[0092] In some embodiments, the pharmaceutical composition of the present disclosure is stored under conditions of 40° C. and RH 75% for 2 months, and the total impurity content in the pharmaceutical composition is 10.0% or less, for example, 9.0%, 8.0%, 7.0%, 6.0%, 5.0%, 4.0%, 3.0%, 2.0% or less.

[0093] In some embodiments, the pharmaceutical composition of the present disclosure is stored at 25° C. and RH 60% for 2 months, and the total impurities content in the pharmaceutical composition is 6.0% or less, e.g., 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0% or less.

[0094] In some embodiments, the pharmaceutical composition of the present disclosure is stored at 5° C.±3° C. for 1 month, and the total impurity content in the pharmaceutical composition is 6.0% or less, e.g., 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0% or less.

[0095] The present disclosure further provides a method for preparing any one of the above pharmaceutical compositions, comprising mixing the GLP-1 analog or its medicament salt, amide or ester with the absorption enhancer.

[0096] In some embodiments, the process includes a tableting, granulation, or capsule filling step.

[0097] In some embodiments, the method comprises the steps of direct powder compression, wet granulation, dry granulation, or enteric capsule shell filling.

[0098] The disclosure further provides a use of any one of the above pharmaceutical compositions in the preparation of a medicament for treating non-insulin dependent diabetes mellitus, insulin dependent diabetes mellitus, obesity, non-alcoholic fatty liver disease, hepatic steatosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, dyslipidemia associated with insulin resistance, and / or dyslipidemia associated with diabetes.

[0099] The GLP-1 analogues provided by the present disclosure are synthesized by the method of solid phase synthesis. In one example, the synthesis vector is Rink-amide MBHA (Xi'an Lanxiao Technology) resin. In the synthesis process, the α-amino group of the amino acid derivative used is protected with Fmoc group. For example, the side chains of amino acids are protected with protecting groups selected from the following depending on the functional group: the mercapto group of the cysteine ​​side chain, the amino group of the asparagine and glutamine side chains, and the imidazolyl group of the histidine side chain are protected with Trt (trityl group); the guanidine group of the arginine side chain is protected with Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group); the indolyl group of the tryptophan side chain and the amino group of the lysine side chain are protected with Boc (tert-butoxycarbonyl group); and the carboxy group of the aspartic acid and glutamic acid side chains, the hydroxy group of the threonine side chain, the phenol group of the tyrosine side chain, and the hydroxy group of the serine side chain are protected with t-Bu (tert-butyl group). For example, in the synthesis process, the carboxyl group of the C-terminal amino acid residue of the polypeptide is first condensed to the polymeric insoluble Rink-amide MBHA resin in the form of an amide bond, and then the Fmoc protecting group at the α-amino group is removed with a N,N-dimethylformamide (DMF) solution containing 20% ​​4-methylpiperidine, and if in excess, the solid-phase vector is condensed with the next amino acid derivative in the polypeptide sequence to form an amide bond to extend the peptide chain. The length of the synthesized polypeptide chain is obtained by repeating the operation of "condensation → washing → deprotection → washing → next amino acid condensation", and finally the polypeptide is decomposed from the solid-phase vector by reacting the resin with a mixed solution of trifluoroacetic acid: water: triisopropylsilane (for example, 90: 5: 5, v: v: v), and then precipitated with 5 volumes of frozen methyl tert-butyl ether to obtain a solid crude product of GLP-1 analog. The solid crude polypeptide product is dissolved in a mixed solution of acetonitrile / water containing 0.1% trifluoroacetic acid, and then purified and separated on a C-18 reverse phase preparative chromatography column to obtain a pure GLP-1 analog.

[0100] According to some embodiments, the present disclosure provides a method for producing a cellular membrane comprising: - a GLP-1 analogue according to the present disclosure or a medicamentable salt, amide or ester thereof; -Another therapeutic agent selected from the group consisting of anti-obesity agents, anti-diabetic agents, anti-hypertensive agents, and lipid-lowering agents, or a combination thereof; Also provided are pharmaceutical kits (kit-of-parts) in which the GLP-1 analog or its medicament salt, amide or ester is in a separate container from the other therapeutic agent. In some embodiments, the GLP-1 analog or its medicament salt, amide or ester is administered to a subject separately or in combination with the other therapeutic agent (e.g., administered simultaneously or sequentially). [Brief description of the drawings]

[0101] [Figure 1] 1 shows the effect of compounds of the present disclosure on the rate of weight change in diet-induced obese mice. [Diagram 2] FIG. 1 shows the effect of compounds of the present disclosure on daily food intake in diet-induced obese mice. [Diagram 3] 1 shows structures of exemplary compounds of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0102] In order that the present disclosure may be more readily understood, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art.

[0103] The amino acid sequences of the present disclosure include the standard one-letter or three-letter codes for the 20 amino acids, and unless otherwise indicated, the preferred configuration for all amino acid residues in the present disclosure is L-, where Aib is alpha aminoisobutyric acid, D-Ala is D-alanine, Orn is ornithine, Dap is 2,3-diaminopropionic acid, and Dab is 2,4-diaminobutyric acid.

[0104] The term "agonist" is defined as a substance that has an activating effect on the GLP-1 receptor or the GIP receptor.

[0105] The term "GLP-1 / GIP dual agonist" refers to a substance or ligand capable of activating the GLP-1 receptor and the GIP receptor.

[0106] The term "treatment" includes inhibiting, alleviating, halting, or reversing the progression or severity of an existing condition or disease.

[0107] The term "natural amino acid" refers to the twenty common amino acids, namely, alanine (A), cysteine ​​(C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y).

[0108] The term "unnatural amino acid" refers to a non-naturally encoded amino acid, or an amino acid that is not expressed in the genetic code of any organism. For example, an unnatural amino acid may be a purely synthetic compound. Illustrative examples of unnatural amino acids include hydroxyproline, γ-carboxyglutamic acid, O-phosphoserine, azetidine carboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid (Dap), desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid (Dab), N-ethylglycine, N-methylglycine, N- Examples of amino acids include, but are not limited to, ethylasparagine, pipecolic acid, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloisoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthylalanine, norvaline, norleucine, ornithine (Orn), D-ornithine, D-arginine, p-aminophenylalanine, pentylglycine, pipecolic acid, and thioproline. The term also includes derivatives obtained by chemically modifying the C-terminal carboxyl group (or the N-terminal amino group and / or its side chain functional group) of a natural amino acid (or an unnatural amino acid).

[0109] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, such as an alkyl group containing from 1 to 8 carbon atoms, such as an alkyl group containing from 1 to 6 carbon atoms, such as an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 20-methylhexyl, 21-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42-methylhexyl, 43-methylhex Examples of such groups include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.An alkyl group can be, for example, a lower alkyl group containing from 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any accessible attachment site, and may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylic acid ester groups. The substituted alkyl groups of the present disclosure may be methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkyl substituted with an alkoxy group, or alkyl substituted with a hydroxy group.

[0110] In this disclosure, various terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, and C" all mean the same thing, i.e., X may be any one or more of A, B, and C.

[0111] An amino acid "modification" as described in this disclosure refers to the substitution, addition or deletion of an amino acid, including the substitution or addition of any one or more of the 20 naturally occurring amino acids.

[0112] The term "native GLP-1" refers to a naturally occurring molecule of the glucagon or exendin family of peptides, where the glucagon family of peptides is encoded by the proglucagon gene and includes three small highly homologous peptides, glucagon(1-29), GLP-1(1-37) and GLP-2(1-33), and exendin is a peptide expressed in lizards that is similar to GLP-1 and promotes insulin secretion. In some embodiments, the term "native GLP-1" also refers to human GLP-1(7-37) and human GLP-1(7-36).

[0113] The term "GLP-1 analogue" refers to having 25 or less, 24 or less, 23 or less, 22 or less, 21 or less, 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, or 1 amino acid or chemical modification compared to native GLP-1 (particularly compared to human GLP-1(7-37) and human GLP-1(7-36)), said amino acid modification may be an amino acid substitution, addition and / or deletion, said chemical modification may be a chemical modification selected from amides, carbohydrates, alkyl groups, acyl groups, esters, polyethylene glycol (PEG) groups, sialyl groups, glycosylation groups, and the like.

[0114] An amino acid "substitution" described in this disclosure refers to the replacement of one amino acid residue with another.

[0115] The term "polyethylene glycol" or "PEG" refers to a mixture of polycondensates of ethylene oxide and water, which exists in linear or branched form and has the general formula H(OCH2CH2) nOH, where n is at least equal to 9. Unless further explained, the term includes polymers of polyethylene glycol having an average total molecular weight selected from 5,000 daltons to 40,000 daltons.

[0116] The term "fatty acid" refers to a carboxylic acid having a long chain fatty acid tail, which may be saturated or unsaturated, and in this disclosure fatty acids are carboxylic acids having a C4 to C30 straight or branched aliphatic group.

[0117] The term "peptide" covers the range of peptides having modified amino and carboxy termini, for example, an amino acid chain in which the terminal carboxylic acid is replaced with an amide group is included in the amino acid sequence named for natural amino acids.

[0118] Any hydrogen atom described in the present disclosure may be replaced with its isotope (protium, deuterium, tritium), and any hydrogen atom in the compounds of the present disclosure according to the present disclosure may be replaced with an isotope atom.

[0119] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the phrase includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0120] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, being replaced independently by a substituent. Substituents are only located at their chemically possible sites, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0121] The term "agonist activity" refers to the activation ability of a compound according to the present disclosure at the human GIP receptor and the human GLP-1 receptor. In some examples, the "agonist activity" is expressed in terms of relative activity, specifically, the ratio of the activation ability of a compound according to the present disclosure at the GLP-1R to the activation ability of a compound according to the present disclosure at the GIP receptor.

[0122] The term "pharmaceutical salt" refers to salts of compounds according to the present disclosure, which are safe and effective when used in the mammalian body and have the desired biological activity. Commonly used acids that form acid addition salts are hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and salts include sulfate, pyrosulfate, trifluoroacetate, sulfite, bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, acetate, propionate, octanoate, acrylate, formate, isobutyrate, hexanoate, enanthate, propiolate, and oxalic acid. Salts include salts of malonates, succinates, suberates, fumarates, maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, mesylates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and the like, such as trifluoroacetates. Basic substances can also form salts with the GLP-1 analogs, and these basic substances include hydroxides of ammonium, alkali metals, or alkaline earth metals, and carbonates and hydrogen carbonates, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, and the like.

[0123] Semaglutide is a once-weekly GLP-1 receptor single agonist polypeptide drug developed by Novo Nordisk of Denmark, and is currently approved and commercially available in the United States, Japan, and the European Union.

[0124] LY3298176 refers to a once-weekly GIP receptor / GLP-1 receptor dual agonist polypeptide drug developed by Eli Lilly and Company, which is currently undergoing Phase III clinical trials in multiple countries. Its structure is as follows:

[0125] YAibEGTFTSDYSIAibLDKIAQ K AFVQWLIAGGPSSGAPPPS-NH2, of which the following fatty acids [ka] is modified at the 20th K.

[0126] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs, and other chemical components such as physiologically / pharmaceutical acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredient to further exert biological activity. In this application, the terms "pharmaceutical composition" and "formulation" may be used interchangeably.

[0127] The term "excipient" as used herein broadly refers to any ingredient other than the active therapeutic ingredient. An excipient may be an inactive, non-active, and / or non-pharmaceutical active substance. Excipients may be used for various purposes as vectors, fillers, adhesives, lubricants, glidants, disintegrants, flow control agents, crystallization retarders, solubilizers, stabilizers, colorants, flavorings, surfactants, emulsifiers, and / or to improve the administration and / or absorption of active agents. One of ordinary skill in the art may select one or more of the above excipients by routine experimentation and without undue burden based on the specific desired characteristics of the solid oral dosage form. The amount of each excipient used may vary within conventional ranges in the art. Techniques and excipients that can be used to prepare oral dosage forms are described in Handbook of Pharmaceutical Excipients, 6th edition, Rowe et al., Eds., published by the American Pharmaceuticals Association and the Pharmaceutical Press, a publishing division of the Royal Pharmaceutical Society of Great Britain (2009), and Remington: the Science and Practice of Pharmacy, 21st edition, Gennaro, Ed., published by Lippincott Williams & Wilkins (2005).

[0128] The term "about" or "approximately" as used herein refers to a numerical value that is within an acceptable error range of a specific value as determined by one of ordinary skill in the art, the numerical portion being determined by how it is measured or determined (i.e., the limitations of the measurement system). For example, in the practice of the art, "about" may mean within or more than 1 standard deviation. Alternatively, "about" or "essentially including" may mean a range of at most ±20%, e.g., a pH of about 5.5 means pH 5.5 ±1.1. Moreover, particularly for biological systems or processes, the term may mean at most an order of magnitude or at most 5 times the numerical value. Unless otherwise indicated, when a specific value appears in the present application and claims, the meaning of "about" or "essentially including" should be assumed to be within an acceptable error range of the specific value.

[0129] The pharmaceutical compositions described in the present disclosure can achieve a stable effect, i.e., the GLP-1 analog therein essentially retains its physical and / or chemical stability and / or biological activity after storage, e.g., the pharmaceutical composition essentially retains its physical and chemical stability and its biological activity after storage. The storage period is generally selected based on the desired shelf life of the pharmaceutical composition. Currently, there are several analytical techniques for measuring protein stability, which can measure stability after storage at a given temperature for a given period of time.

[0130] A stable drug formulation is one that does not show any significant change when stored at refrigerated temperatures (2°C-8°C) for at least 3 months, at least 6 months, at least 1 year, and even up to 2 years. Stable drug formulations also include formulations that exhibit the desired characteristics after storage at 25°C for periods including 1 month, 3 months, 6 months, or 1 month at 40°C. Typical acceptable criteria for stability are that typically no more than about 10%, e.g., no more than about 5%, of the GLP-1 analog monomer is degraded as measured by SEC-HPLC. Typically no more than about 10%, e.g., no more than about 5%, of cleavage is observed, and typically no more than about 10%, e.g., no more than about 5%, of aggregates are formed.

[0131] A GLP-1 analog "retains its physical stability" in a drug formulation if it does not exhibit significant increased aggregation, precipitation, and / or denaturation as determined by visual inspection of color and / or clarity or by UV light scattering, size exclusion chromatography (SEC) and dynamic light scattering (DLS). Changes in protein conformation may be assessed by fluorescence spectroscopy (which determines the tertiary structure of a protein) and by FTIR spectroscopy (which determines the secondary structure of a protein).

[0132] If the GLP-1 analogue does not show any significant chemical changes, it is said that the GLP-1 analogue "retains its chemical stability" in the drug formulation. Chemical stability can be evaluated by detecting and quantifying chemically altered proteins. Degradation processes that constantly change the chemical structure of proteins include hydrolysis or cleavage (assessed by methods such as size exclusion chromatography and SDS-PAGE), oxidation (assessed by methods such as peptide mapping combined with mass spectrometry or MALDI / TOF / MS), deamidation (assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, measurement of isoaspartic acid, etc.) and isomerization (assessed by measurement of isoaspartic acid content, peptide mapping, etc.).

[0133] A GLP-1 analog "retains its biological activity" in a drug formulation if the biological activity of the GLP-1 analog over a given time period is within a given range of the biological activity exhibited when the drug formulation was prepared. The biological activity of a GLP-1 analog can be determined, for example, by antigen binding assays.

[0134] The three-letter and one-letter codes for amino acids used in this disclosure are as described in J. Biol. Chem, 243, p3558 (1968). Working Example

[0135] In order to describe the present disclosure in more detail, the present specification provides the following embodiments for carrying out the present disclosure, but the embodiments of the present disclosure are not limited thereto. Experimental methods for which specific conditions are not specified in the examples of the present disclosure generally follow conventional conditions or conditions recommended by manufacturers of raw materials or products. Reagents for which a specific source is not specified are ordinary reagents that are commercially available.

[0136] [Table 3-1] [Table 3-2] [Table 4] Example 1. Chemical synthesis of compound 18#

[0137] 1. Synthesis of the polypeptide backbone Rink-amide MBHA resin (substitution degree: 0.48 mmol / g, 0.1 mmol) was weighed and placed in a polypropylene polypeptide synthesis solid-phase reaction tube, N,N-dimethylformamide (DMF, 10 mL) was added and the resin was swelled under nitrogen-blowing for 10 minutes, DMF was removed by vacuum, DMF (10 mL) was added to wash the resin, and the resin washing was repeated twice, after which the synthesis of the polypeptide solid phase was carried out by the Fmoc / tBu strategy on a Prelude-X polypeptide fully automated synthesizer, among which 10 equivalents of amino acid residues activated with HCTU and 4-methylmorpholine (HCTU, 4-methylmorpholine, amino acid residue molar ratio is 1:2:1) were used, and the coupling was realized by condensing the amide bond by reacting in DMF at room temperature for 25 minutes. The N-terminal Fmoc protecting group was deprotected by reacting twice (10 minutes each time) at room temperature using a DMF solution containing 20% ​​4-methylpiperidine. During the synthesis of the polypeptide backbone, the N-terminal amino acid residue was selected to be constructed as Boc-L-Tyr(tBu)-OH and a second condensation was carried out, which is necessary to improve the quality of the crude peptide.

[0138] 2. Selective deprotection of the resin peptide protecting group Mtt ​​and modification of side chain fatty acid After completion of the elongation of the polypeptide backbone (or resin peptide), a mixture of 30% hexafluoroisopropanol in dichloromethane (10 mL) was added, and the mixture was reacted at room temperature for 45 minutes by shaking, after which the mixture was removed. A further mixture of 30% hexafluoroisopropanol in dichloromethane (10 mL) was added, and the mixture was reacted at room temperature for 45 minutes by shaking, after which the mixture was removed. After the reaction was completed, the resin was washed six times with DMF. The 14th lysine side chain was elongated on a Prelude-X fully automated polypeptide synthesizer, and additional coupling / deprotection cycles involved the amino acid building blocks Fmoc-NH-PEG2-COOH and Fmoc-L-Glu-OtBu. For all couplings, 10 equivalents of HCTU and 4-methylmorpholine-activated amino acid residues (HCTU, 4-methylmorpholine, amino acid residue molar ratio 1:2:1) were used, and the couplings were performed in DMF at room temperature for 25 minutes. The N-terminal Fmoc protecting group was deprotected by reacting twice at room temperature for 10 minutes each time using a DMF solution containing 20% ​​4-methylpiperidine. Finally, the resin obtained was washed three times with DCM and three times with DMF, and then 10 equivalents of HOOC-(CH2) 18 A DMF mixture (8 mL) containing -COOtBu, 10 equivalents of HCTU, and 20 equivalents of diisopropylethylamine (DIEA) was added, and the reaction was carried out at room temperature for 4 hours to complete the modification of the fatty acid in the side chain.

[0139] 3. Decomposition of products The resin peptide obtained in the previous step was washed three times with DMF and DCM, then dried in vacuum, and then the newly prepared decomposition solution (trifluoroacetic acid: triisopropylsilane: water = 90: 5: 5, volume ratio) was added and the mixture was shaken at room temperature for 3 to 4 hours to react. After the reaction was completed, the mixture was filtered, the resin was washed twice with trifluoroacetic acid, and the filtrate was combined and a large amount of frozen methyl tert-butyl ether was added to precipitate the solid. After centrifugation, the supernatant was removed to obtain the crude polypeptide product of compound 18#.

[0140] 4. Purification by reverse phase liquid chromatography The crude polypeptide product of compound 18# was dissolved in a mixed solvent containing 0.1% trifluoroacetic acid, 20% acetonitrile, and 20% acetic acid / water, filtered through a 0.22 μm film, and separated by a WATERS Prep150 LC reversed-phase high-performance liquid chromatography system, with buffers A (0.1% trifluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). Among them, the chromatography column was an X-SELECT OBD C-18 reversed-phase chromatography column, and the detection wavelength of the chromatograph during purification was set to 220 nm, and the flow rate was 15 mL / min. The distillate related to the product was collected and lyophilized to obtain the pure polypeptide product of compound 1#, with a yield of 18%. The purity of the pure polypeptide product was confirmed by analytical high-performance liquid chromatography and ultra-high-performance liquid chromatography / mass spectrometry, of which the purity was 92.81%. Molecular structure of compound 18#: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2, the structural formula is shown in Figure 3, structure 18#. Example 2. Chemical synthesis of other compounds

[0141] The compounds in Table 3 were synthesized according to the experimental design of Example 1: [Table 5-1] [Table 5-2] The purity of the compounds was determined by analytical HPLC and ultra-HPLC / mass spectrometry, and the purity of some compounds is shown in Table 4 below: [Table 6] Biological Testing and Evaluation The present disclosure will be further described below in conjunction with test examples, but these examples are not intended to limit the scope of the present disclosure. Example 3. Evaluation of the agonist activity of compounds according to the present disclosure against the glucagon-like peptide-1 receptor (GLP-1R)

[0142] 1. Purpose of the experiment: The purpose of this test example is to measure the agonist activity of the compounds according to the present disclosure against the glucagon-like peptide-1 receptor (GLP-1R).

[0143] 2. Experimental method: The frozen CHO-K1 / GLP-1R / CRE-luc stable transformed cell line (which can be prepared by a common method in this field) is taken out of the liquid nitrogen container, put into a water bath at 37°C to rapidly melt, resuspended in DMEM / F12 medium, centrifuged, washed once, resuspended in DMEM / F12 medium containing 0.1% casein as an experimental buffer, adjusted the cell density with the experimental buffer, seeded in a 384-well plate (Sigma Cat# CLS4514) at a density of 2500 cells / 5μL / well, and added 2.5μL of IBMX working solution (Sigma Cat# I7018) with a final concentration of 0.5mM IBMX prepared with buffer and 2.5μL of gradient diluted polypeptide sample to each well, centrifuged at 1000rpm for 1 minute, shaken for 30 seconds to mix evenly, and left to incubate at room temperature for 30 minutes. Detected with Cisbio cAMP-Gs Dynamic kit (Cisbio Cat# 62AM4PEC), and cAMP-d2 and Anti-cAMP-Eu 3+ -Cryptate was diluted 20-fold with cAMP Lysis & Detection Buffer and mixed evenly. 5 μL of diluted cAMP-d2 solution was added to each well, and then diluted Anti-cAMP-Eu 3+ 5 μL of -Cryptate solution was further added, the mixture was mixed uniformly by shaking for 30 seconds, and the mixture was incubated at room temperature in the dark for 1 hour.

[0144] 3. Experimental data processing method: The HTRF signal was read using a Biotek Synergy H1 microplate reader, with an excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm. The signal ratio (665 nm / 620 nm × 10,000) was calculated, and the signal ratio and sample concentration were nonlinearly fitted with a four-variable equation in GraphPad Prism 6 to obtain the EC 50 The values ​​obtained are shown in Table 5 below. Example 4. Evaluation of the agonist activity of compounds according to the present disclosure at the glucose-dependent insulinotropic peptide receptor (GIPR)

[0145] 1. Purpose of the experiment: The compounds were tested for agonist activity at the glucose-dependent insulinotropic peptide receptor (GIPR).

[0146] 2. Experimental method: Wild-type CHO-K1 cells were harvested, the cell suspension was adjusted to an appropriate density, and seeded into 6-well plates at 2 mL per well, and placed in a 37°C, 5% CO2 incubator to attach to the wall overnight. The transfection mixture (hGIP receptor plasmid, Fugene HD (Promega Cat# E2311), OptiMEM (Gibco Cat# 31985070) was mixed evenly and incubated at room temperature for 15 min, then added to the corresponding cell wells in a volume of 100 μL, and transfected for 24 h to overexpress hGIP receptor on the CHO-K1 cell surface. After the transient transfection was finished, the cells in the 6-well plates were harvested and transferred to the experimental buffer, DMEM / F12 medium (Gibco Cat# C3400) containing 0.1% casein (Sigma Cat# C3400), for 24 h. The cells were washed once with 11330032), the cell density was adjusted with experimental buffer, and seeded at a density of 5000 cells / 5μL / well in a 384-well plate (Sigma Cat# CLS4514). Then, 2.5μL of IBMX working solution (Sigma Cat# I7018) with a final concentration of 0.5mM IBMX prepared with buffer and 2.5μL of gradient diluted polypeptide sample were added to each well, centrifuged at 1000rpm for 1 minute, shaken for 30 seconds to mix uniformly, and incubated at room temperature for 30 minutes. Detection was performed with Cisbio cAMP-Gs Dynamic kit (Cisbio Cat# 62 AM4PEC), and cAMP-d2 and Anti-cAMP-Eu3+-Cryptate were detected using cAMP Lysis & Detection kit (Cisbio Cat# 62 AM4PEC). The solution was diluted 20-fold with buffer and mixed uniformly. 5 μL of the diluted cAMP-d2 solution was added to each well, followed by 5 μL of the diluted Anti-cAMP-Eu3+-Cryptate solution, and then the wells were shaken for 30 seconds to mix uniformly. The wells were then incubated at room temperature in the dark for 1 hour.

[0147] 3. Experimental data processing method: The HTRF signal was read using a Biotek Synergy H1 microplate reader, with an excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm. The signal ratio (665 nm / 620 nm × 10,000) was calculated, and the signal ratio and sample concentration were nonlinearly fitted with a four-variable equation in GraphPad Prism 6 to obtain the EC 50 The values ​​obtained are shown in Tables 5 and 6 below.

[0148] [Table 7] [Table 8]

[0149] 4. Experimental conclusion: By designing the polypeptide backbone and subsequent site-specific modification of fatty acids, the compounds according to the present disclosure have stronger GLP-1 / GIPR agonist activity than many GLP-1 / GIPR dual agonist polypeptides in the field, and therefore have better potential for treating metabolic diseases. Furthermore, unlike LY3298176, which shows preferential activity against GIPR, compounds 12#-18# according to the present disclosure show preferential activity against GLP-1R. Example 5. Stability testing of some compounds according to the present disclosure

[0150] Plasma stability is important for therapeutic polypeptide drugs because they are likely to be sensitive to polypeptide hydrolases and proteases in plasma. Unstable polypeptides in plasma will affect their half-life and therapeutic efficacy.

[0151] 1. Purpose of the experiment: This experiment is aimed at testing the stability of some compounds according to the present disclosure in human plasma.

[0152] 2. Experimental method: 5μL of samples with concentrations of 20, 50, 100, 200, 500, 1000, 2000, 5000, 10000 ng / mL were added to 45μL of human plasma, and the content of the compounds therein was detected by LC-MS to prepare a standard curve. 5μL of a polypeptide solution with a concentration of 1mg / mL was added to 45μL of human plasma. Five samples were prepared for each test compound, and one sample was taken after 0 minutes, 30 minutes, 60 minutes, 120 minutes, and 240 minutes, and the content of the compounds remaining therein was detected by LC-MS, and the relative content of the compounds remaining in the samples at other times was calculated based on the time at 0 minutes (100%). The compound detection method by LC-MS is to prepare 5% acetonitrile solution as solution A, and 95% acetonitrile solution as solution B, and form a solution gradient at a flow rate of 0.6mL / min with the time and solution ratio shown in Table 9 below, inject 15μL of sample, and detect the compound content by Raptor Biphenyl 2.7 micron detection column, see Table 7.

[0153] [Table 9]

[0154] 3. Experimental results: Plasma stability data for some compounds of the present disclosure are shown in Table 8 below.

[0155] [Table 10] Test conclusion: Studies have revealed that compound 7# according to the present disclosure has similar stability in human plasma at 4 hours compared to compound LY3298176 (relative content >90%). Example 6. Pharmacokinetic properties of some compounds according to the present disclosure in mice

[0156] Plasma stability is one of the factors that affect the pharmacokinetics of a polypeptide drug, which is further influenced by factors such as its absorption and clearance in the body.

[0157] 1. Purpose of the experiment: The purpose of this experiment is to study the pharmacokinetic behavior in the mouse body (plasma) of a single intravenous injection of a compound according to the present disclosure using Balb / c mice as test animals.

[0158] 2. Experimental method: Male Balb / c mice weighing 18g-30g and aged 7-9 weeks were purchased from Shanghai Jiesijie Laboratory Animal Co.,Ltd. Compound 7# was prepared in a buffer solution (pH=7.0) containing 20mM citric acid, and then compound 7# was injected into the mouse body through the tail vein at a dose of 30nmol / kg body weight. 0.2mL of blood was collected at 0 hours, 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 32 hours. At a temperature of 4℃, the collected mouse blood was centrifuged at a speed of 6000rpm for 6 minutes to separate plasma. The content of compound 7# in mouse plasma was detected according to the experimental method of Example 3.3.

[0159] 3. Experimental results: According to the above experimental method, the specific data are shown in Table 9 below: [Table 11]

[0160] 4. Experimental conclusion: Research has shown that compound 7# of the present disclosure has good pharmacokinetic properties after intravenous administration in mice, which shows advantages in treating diseases, for example, it can support weekly subcutaneous administration in humans. Example 7. Pharmacokinetic properties of some compounds according to the present disclosure in mice

[0161] 1. Purpose of the experiment: The purpose of this experiment is to study the pharmacokinetic behavior of the compound according to the present disclosure in the mouse body (plasma) following a single subcutaneous injection using Balb / c mice as test animals.

[0162] 2. Experimental method: Male Balb / c mice weighing 18g-30g and aged 7-9 weeks were purchased from Shanghai Jiesijie Laboratory Animal Co., Ltd. Compound 7# was prepared in a buffer solution (pH=7.0) containing 20mM citric acid, and then compound 7# was injected subcutaneously into the left flank of the mouse at a dose of 30nmol / kg body weight. 0.2mL of blood was collected at 0 hours, 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 32 hours. At a temperature of 4℃, the collected mouse blood was centrifuged at a speed of 6000rpm for 6 minutes to separate plasma. The content of compound 7# in mouse plasma was detected according to the experimental method of Example 5.2.

[0163] 3. Experimental results: According to the above experimental method, the specific data are shown in Table 10 below: [Table 12]

[0164] 4. Experimental conclusion: Studies have shown that the compounds disclosed herein have good pharmacokinetic properties after subcutaneous administration in mice, which may be advantageous in treating diseases, and may support, for example, weekly subcutaneous administration in humans. Example 8. In vivo efficacy of some compounds according to the present disclosure

[0165] 1. Purpose of the experiment: The regulatory effect of some of the disclosed compounds and the compound LY3298176 on blood glucose in normal mice following a single subcutaneous administration is tested.

[0166] 2. Experimental method: Male C57BL / 6 mice aged 10-12 weeks were purchased from Shanghai Jieshijie Laboratory Animal Co., Ltd. C57BL / 6 mice were subcutaneously injected with compound 7# or compound LY3298176 (dose: 10 nmol / kg body weight) and control buffer, then fasted but not deprived of water, and 18 hours later, a glucose solution with a concentration of 0.2 g / mL was injected via the abdominal cavity. According to the experimental design, blood was collected from the tail of the mouse at 0 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes, and the blood glucose level was measured. The specific method was to fix the mouse by physical means, expose the tail, cut off a small part of the tail, press the tail to bleed, discard the first drop of blood, and detect blood glucose with a Roche Active blood glucose meter. The area under the blood glucose curve (AUC) was calculated based on the results at each time point.

[0167] 3. Experimental results: According to the above experimental method, the specific data are shown in Table 11 below: [Table 13]

[0168] 4. Experimental conclusion: In this experiment, at a dose of 10 nmol / kg body weight, compound 7# of the present disclosure exhibited a significant hypoglycemic effect in normal mice, with the area under the blood glucose curve in the compound 7# group being reduced by more than 60% compared with that in the placebo (i.e., blank solvent). Example 9. Weight-reducing effects of some compounds according to the present disclosure

[0169] 1. Purpose of the experiment: The numbered compounds are tested for their modulating effect on body weight in diet-induced obese mice by subcutaneous administration.

[0170] 2. Experimental method: Obese male C57BL / 6 mice (weight 35g-55g, age 10-12 weeks, purchased from Shanghai Jieshijie Laboratory Animal Co., Ltd.) induced by high fat diet were subcutaneously injected with compounds LY3298176 (10nmol / kg body weight), 7# (10nmol / kg body weight), and 18# (three doses, 3nmol / kg, 10nmol / kg, and 100nmol / kg body weight, respectively, administered once every 3 days). According to the experimental design, the weight of each mouse was weighed and recorded on days 0, 3, and 6 until day 27, and the average weight of each group of mice was calculated, and the weight change curve was drawn based on the weight on the first day. After the study, the fat and other organs of the mice were removed and weighed, and the fat / brain ratio of each part of each mouse was calculated. The effects of the drug on fat were determined by comparing the changes in fat, organ / brain ratios of different parts of the mice in each group.

[0171] 3. Experimental results: According to the above experimental method, the specific data are shown in Tables 12 to 14 and FIG. 1 below: [Table 14]

[0172] 4. Experimental conclusion: In this experiment, at doses of 3 nmol / kg, 10 nmol / kg and 100 nmol / kg, compounds 7# and 18# of the present disclosure exhibited significant weight-reducing effects on high-fat diet-induced obese mice, and showed significant dose-related effects. Compound 18# reduced the body weight of the 10 nmol / kg test group by more than 20.0% on the 27th day, while control compound LY3298176 reduced the body weight of the test group by about 13.4% under the same dose conditions. In addition, the fat content (except scapular fat) of each site of the test groups of different doses of compound 18# was significantly reduced compared to the placebo (i.e., blank solvent) group. [Table 15] [Table 16] [Table 17] Example 10. Effect of compounds of the present disclosure on food intake in mice

[0173] Food intake of the mice in each group was measured daily during the study, and the results are shown in Table 1 and FIG.

[0174] The model control group DIO (diet-induced obesity) mice had an average daily food intake of 2.5 g during the entire study, and after different doses of compound 18# or LY3298176 were subcutaneously injected, the food intake of the mice in each group decreased to different degrees.

[0175] On the first day after administration, the food intake of the mice in each administration group was significantly reduced. The food intake of the mice in the 3 nmol / kg, 10 nmol / kg, and 100 nmol / kg compound 18# groups was 0.6 g, 0.3 g, and 0.2 g, respectively, which was significantly different from the model control group (2.5 g) and showed a relatively good dose-response relationship.

[0176] The mice in the model control group had a cumulative food intake of 12.8 g over 5 days after administration, while the mice in the compound 18# groups administered 3 nmol / kg, 10 nmol / kg, and 100 nmol / kg had cumulative food intakes of 7.2 g, 3.9 g, and 1.8 g over 5 days after administration, which were significantly lower than those of the model control group and showed a relatively good dose-response relationship.

[0177] The daily food intake of each administration group began to decrease on the first day after administration, and recovered from the second and third days. The daily food intake showed an overall upward trend during administration. On the 28th day after administration, the cumulative food intake of the three dose groups of compound 18# was 58.2g, 46.8g, and 36.7g, respectively, which was obviously lower than that of the model control group (70.8g), and showed good dose-dependency. Therefore, compound 18# can obviously reduce the food intake of DIO mice. [Table 18] [Table 19] Example 11. Improvement effect of some compounds disclosed herein on the glucose metabolism level of db / db mice

[0178] 1. Purpose of the experiment: The improving effect of the numbered compounds on the glucose metabolism level of db / db mice by subcutaneous administration is examined.

[0179] 2. Experimental method: C57BL / KsJ-db / db mice were administered blank vehicle (20 mM sodium citrate + 0.05% Tween-80, pH 7.5), compound LY3298176 (100 nmol / kg body weight) and 18# (three doses, 10 nmol / kg, 30 nmol / kg, 100 nmol / kg body weight, respectively) by subcutaneous injection, and the administration times were 0, 3, 7, 10, 14, 17, 21, 24 and 27 days, respectively. Each administration group contained 10 db / db mice. According to the experimental design, tail vein blood was collected by needle on 0, 7, 14, 21 and 28 days to detect fasting blood glucose level by blood glucose meter and blood glucose test strip, and the mice were fasted for 6 hours before blood collection at each blood collection time point. On days 3, 10, 17, 24, and 27, blood was collected from the tail vein with a needle and random blood glucose levels were detected using a blood glucose meter. Finally, after the experiment was completed on day 28, animals in all treatment groups were anesthetized with 2% to 5% isoflurane inhalation, and 100 μL of EDTA-K2 anticoagulated whole blood was collected from the orbit and used to measure glycated hemoglobin.

[0180] 3. Experimental results: According to the above experimental method, the specific data are shown in Tables 16 to 18 below.

[0181] [Table 20] [Table 21] [Table 22]

[0182] 4. Experimental conclusion: In this experiment, at doses of 10 nmol / kg, 30 nmol / kg and 100 nmol / kg, compound 18# of the present disclosure exhibited excellent improving effects on the glucose metabolism level of db / db mice, and showed a significant dose-related relationship. Compound 18# showed a glycated hemoglobin level of 3.78% in the test group at 100 nmol / kg dose at the end of the experiment, while the control compound LY3298176 showed a glycated hemoglobin level of 4.58% in the test group under the same dose conditions, and the efficacy of compound 18# in improving the glucose metabolism level of db / db mice is significantly superior to that of the control compound LY3298176 under the same dose conditions.

[0183] The GLP-1 analog or API used in the following examples was all compound 18#. Example 12. Preparation and testing of pharmaceutical compositions

[0184] The pharmaceutical composition according to the present disclosure was prepared using dry granulation according to the process of homogeneously mixing the prescribed amount of API (compound 18# shown in FIG. 3) with other ingredients, dry granulating them together, and then compressing them into tablets.

[0185] Dissolution test: According to the dissolution rate measurement method, 500mL of phosphate buffer solution of pH 6.8 containing 0.1% Tween 80 was used as the dissolution medium, the rotation speed was 50 rpm, and the operation was performed according to the method. 5mL of solution was measured after 5 minutes, 10 minutes, 15 minutes, 30 minutes and 45 minutes, and 5mL of liquid was added. Each of the dissolution solutions was filtered through a 10μm polyethylene filter, and then further filtered through a Mebagite PVDF 0.22μm filter membrane. The filtrate was placed in a liquid phase vial, and the dissolution amount of API and SANC of each tablet at different time points was detected by HPLC.

[0186] 12.1 The prescribed amounts of SNAC, API, microcrystalline cellulose, povidone and magnesium stearate (internal addition) were mixed uniformly, then dry granulated, magnesium stearate was added externally, mixed uniformly and compressed into tablets. The tablets were subjected to a dissolution test in a phosphate buffer solution of pH 6.8 containing 0.1% Tween 80. The specific formulation and dissolution rate results are shown in Table 19.

[0187] [Table 23-1] [Table 23-2]

[0188] In the recipe, " / " indicates that no ingredient was added.

[0189] 12.2 The prescribed amounts of SNAC, API, sodium octanoate, colloidal silica (internal addition) and magnesium stearate (internal addition) were mixed uniformly, then dry granulated, colloidal silica and magnesium stearate were added externally, mixed uniformly and compressed into tablets. The tablets were subjected to a dissolution test in a phosphate buffer solution of pH 6.8 containing 0.1% Tween 80. The specific formulation and dissolution rate results are shown in Table 20. [Table 24] 12.3 The prescribed amounts of SNAC, API, amino acids, colloidal silica (internal addition) and magnesium stearate (internal addition) were mixed uniformly, then dry granulated, magnesium stearate was added externally, and the tablets were compressed. The tablets were subjected to a dissolution test in a phosphate buffer solution of pH 6.8 containing 0.1% Tween 80. The specific formulation and dissolution rate results are shown in Table 21.

[0190] [Table 25]

[0191] In the recipe, " / " indicates that no ingredient was added.

[0192] 12.4 The formulation amounts of SNAC, API, β-cyclodextrin, colloidal silica (internal addition) and magnesium stearate (internal addition) were mixed uniformly, then dry granulated, magnesium stearate was added externally, and then compressed into tablets. The tablets were subjected to a dissolution test in a phosphate buffer solution of pH 6.8 containing 0.1% Tween 80. The specific formulation and dissolution rate results are shown in Table 22.

[0193] [Table 26]

[0194] 12.5 The plain tablets prepared by Formulations 6, 11 and 12 were coated with a coating powder of hydroxypropyl methylcellulose film-forming material, and then left under accelerated test (40°C, RH 75%), long-term test (25°C, RH 60%) and refrigerated test (5°C) conditions to investigate the stability of the tablets. The results are shown in Table 23.

[0195] [Table 27]

[0196] 12.6 The formulation amount of API, sodium caprate and PMSF protease inhibitor were mixed uniformly and then filled into the corresponding capsule shell. The capsules were placed in a decane basket and subjected to dissolution test in pH 6.8 phosphate buffer containing 0.1% Tween 80. The specific formulation and dissolution rate results are shown in Table 24.

[0197] [Table 28]

[0198] 12.7 The prescribed amount of SNAC, API, amino acids, sodium caprate or sodium octanoate, colloidal silica (internal addition), and magnesium stearate (internal addition) were mixed uniformly, then dry granulated, magnesium stearate was added externally, and the tablets were compressed. The tablets were subjected to a dissolution test in a phosphate buffer solution of pH 6.8 containing 0.1% Tween 80, and the specific formulation and dissolution rate results are shown in Table 25.

[0199] [Table 29]

[0200] In the recipe, " / " indicates that no ingredient was added.

[0201] 12.8 The formulation amount of SNAC, API, amino acids, sorbitol, colloidal silica (internal addition), magnesium stearate (internal addition), and / or adhesive (povidone, hydroxypropylcellulose) were mixed uniformly, then dry granulated, magnesium stearate was added externally, and then compressed into tablets. The tablets were subjected to dissolution test in phosphate buffer solution of pH 6.8 containing 0.1% Tween 80, and the specific formulation and dissolution rate results are shown in Table 26.

[0202] [Table 30-1] [Table 30-2]

[0203] In the recipe, " / " indicates that no ingredient was added.

[0204] 12.9 The formulation amounts of SNAC, API, amino acids, colloidal silica (internal addition) and magnesium stearate (internal addition) were mixed uniformly, then dry granulated, magnesium stearate was added externally, and the tablets were compressed. The tablets were subjected to a dissolution test in a phosphate buffer solution of pH 6.8 containing 0.1% Tween 80. The specific formulation is shown in Table 27, and the formulation table and dissolution rate results are shown in Table 28.

[0205] [Table 31] [Table 32-1] [Table 32-2]

[0206] 12.10 The prescribed amounts of SNAC, API, amino acids, colloidal silica (internal addition) and magnesium stearate (internal addition) were mixed uniformly, then dry granulated, magnesium stearate was added externally, and the tablets were compressed. The tablets were subjected to a dissolution test in a phosphate buffer solution of pH 6.8 containing 0.1% Tween 80. The specific formulation and dissolution rate results are shown in Table 29.

[0207] [Table 33]

[0208] In the recipe, " / " indicates that no ingredient was added.

[0209] It will be clearly understood that while the foregoing invention has been described in detail by way of illustration and example, these descriptions and examples should not be construed as limiting the scope of the present disclosure, and the disclosures of all patent and scientific literature cited herein are hereby expressly incorporated by reference in their entirety.

Claims

1. (a) A GLP-1 analogue represented by general formula (I) or a medicinal salt, amide or ester thereof R １ -X １ -X ２ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X １０ -Ser-X １２ -X １３ -X １４ -X １５ -X １６ -X １７ -X １８ -X １９ -X ２０ -Glu-Phe-X ２３ -X ２４ -Trp-Leu-X ２７ -X ２８ -X ２９ -X ３０ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R ２ (I) (In the formula, R １ is H, an alkyl group, an acetyl group, a formyl group, a benzoyl group, a trifluoroacetyl group, pGlu, or is absent, and R ２ Ha-NH ２ , —OH or absent, X １ , X ２ , X １０ , X １２ , X １３ , X １４ , X １５ , X １６ , X １７ , X １８ , X １９ , X ２０ , X ２３ , X ２４ , X ２７ , X ２８ , X ２９ and X ３０ are independently selected from any natural or unnatural amino acid residue, and (b) an absorption enhancer, preferably one or more absorption enhancers selected from N-(8-(2-hydroxybenzoyl)amino)octanoate, sodium octanoate, sodium caprate, sodium taurodeoxycholate, lauroylcarnitine, dodecylphosphatidylcholine, amino acids, cyclodextrin and derivatives thereof, surfactants, laurocapram and its homologues, alcohol-based organic solvents, organic acids, and fatty alcohols; A pharmaceutical composition comprising:

2. The amino acid is one or more selected from isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, arginine, histidine, alanine, glycine, proline, serine, and salts thereof, and is preferably one or more selected from arginine, histidine, leucine, lysine, and salts thereof; The cyclodextrin and derivatives thereof are one or more selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutyl-β-cyclodextrin (SBE-β-CD), 2,6-dimethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, methylated-β-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, dimaltose-β-cyclodextrin, and carboxymethyl-β-cyclodextrin, and are preferably β-cyclodextrin; the surfactant is selected from sodium dodecyl sulfate, polysorbate, betaine, quaternary ammonium salt, sorbitan ester, poloxamer or any mixture thereof; The alcohol-based organic solvent is selected from ethanol, glycerin, polyethylene glycol, propylene glycol, or any mixture thereof; the organic acid is selected from stearic acid, palmitic acid, oleic acid, lauric acid or any mixture thereof; and / or The fatty alcohol is selected from lauryl alcohol, cetyl alcohol, stearyl alcohol or any mixture thereof. The pharmaceutical composition of claim 1.

3. The absorption enhancer is (1) N-(8-(2-hydroxybenzoyl)amino)octanoate, (2) sodium caprate, (3) N-(8-(2-hydroxybenzoyl)amino)octanoate and sodium octanoate, (4) N-(8-(2-hydroxybenzoyl)amino)octanoate and an amino acid or a salt thereof, (5) N-(8-(2-hydroxybenzoyl)amino)octanoate and β-cyclodextrin; (6) N-(8-(2-hydroxybenzoyl)amino)octanoate, an amino acid or a salt thereof, and sodium caprate, and (7) Any one selected from the group consisting of N-(8-(2-hydroxybenzoyl)amino)octanoate, an amino acid or a salt thereof, and sodium octanoate; Preferably, the N-(8-(2-hydroxybenzoyl)amino)octanoate is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate. The pharmaceutical composition of claim 1.

4. X １ is Tyr or His, and X ２ is Aib or D-Ala, and X １０ is Val or Tyr or Y1, and X １２ is Ser or Ile or Y1, and X １３ is Tyr or Ala or Y1, and X １４ is Leu or Nle or Y1, and X １５ is Asp or Glu, and X １６ is Arg, Glu, Gly, Lys, AiB, or Y1, and X １７ is Glu, Ile or Gln or Y1, and X １８ is Ala, Aib or His, and X １９ is Ala, AiB or Gln, and X ２０ is Gln, Glu, Lys, and X ２３ is Ile or Val, and X ２４ is Ala, Asn or Gln, and X ２７ is Val or Leu, and X ２８ is Arg or Ala, and X ２９ is Gly or Gln, and X ３０ is Gly, Lys, Y1 is a Lys, Orn, Dap, Dab or Cys residue containing a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} ａ -(γ-Glu) ｂ -CO-(CH ２ ) ｃ having —COOH, a is an integer from 1 to 3, b is 1 or 2; c is an integer from 10 to 30; The pharmaceutical composition of claim 1.

5. X １ is Tyr, and X ２ is Aib, and X １０ is Tyr, and X １２ is Ile, and X １３ is Tyr, and X １４ is Y1 and X １５ is Asp or Glu, and X １６ is Arg or Lys, and X １７ is Ile, and X １８ is Ala, and X １９ is Ala, and X ２０ is Gln, and X ２３ is Ile or Val, and X ２４ is Asn, and X ２７ is Ile or Leu, and X ２８ is Ala, and X ２９ is Gly, and X ３０ is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue containing a substituent in the side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO—(CH 2 ) c -COOH; a is an integer from 1 to 3, b is 1 or 2; c is an integer from 10 to 30; The pharmaceutical composition of claim 1.

6. X １６ is Lys, and X ２３ is Val, and X ２７ is Leu, The pharmaceutical composition according to claim 5.

7. X １ is Tyr, and X ２ is Aib or D-Ala, and X １０ is Y1 and X １２ is Ile, and X １３ is Tyr, and X １４ is Leu or Nle, and X １５ is Glu, and X １６ is Arg or Lys, and X １７ is Ile, and X １８ is Ala, and X １９ is Ala, and X ２０ is Gln or Lys, and X ２３ is Ile or Val, and X ２４ is Asn or Gln, and X ２７ is Ile or Leu, and X ２８ is Ala, and X ２９ is Gly, and X ３０ is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue containing a substituent in the side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO—(CH 2 ) c -COOH; a is an integer from 1 to 3, b is 1 or 2; c is an integer from 10 to 30; The pharmaceutical composition of claim 1.

8. X １ is Tyr, and X ２ is Aib or D-Ala, and X １０ is Tyr, and X １２ is Y1 and X １３ is Tyr, and X １４ is Leu or Nle, and X １５ is Glu, and X １６ is Arg or Lys, and X １７ is Ile, and X １８ is Ala, and X １９ is Ala, and X ２０ is Gln or Lys, and X ２３ is Ile or Val, and X ２４ is Asn or Gln, and X ２７ is Ile or Leu, and X ２８ is Ala, and X ２９ is Gly, and X ３０ is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue containing a substituent in the side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO—(CH 2 ) c -COOH; a is an integer from 1 to 3, b is 1 or 2; c is an integer from 10 to 30; The pharmaceutical composition of claim 1.

9. X １ is Tyr, and X ２ is Aib or D-Ala, and X １０ is Tyr, and X １２ is Ile, and X １３ is Y1 and X １４ is Leu or Nle, and X １５ is Glu, and X １６ is Arg or Lys, and X １７ is Ile, and X １８ is Ala, and X １９ is Ala, and X ２０ is Gln or Lys, and X ２３ is Ile or Val, and X ２４ is Asn or Gln, and X ２７ is Ile or Leu, and X ２８ is Ala, and X ２９ is Gly, and X ３０ is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue containing a substituent in the side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO—(CH 2 ) c -COOH; a is an integer from 1 to 3, b is 1 or 2; c is an integer from 10 to 30; The pharmaceutical composition of claim 1.

10. X １ is Tyr, and X ２ is Aib or D-Ala, and X １０ is Tyr, and X １２ is Ile, and X １３ is Tyr, and X １４ is Y1 and X １５ is Glu, and X １６ is Arg or Lys, and X １７ is Ile, and X １８ is Ala, and X １９ is Ala, and X ２０ is Gln or Lys, and X ２３ is Ile or Val, and X ２４ is Asn or Gln, and X ２７ is Ile or Leu, and X ２８ is Ala, and X ２９ is Gly, and X ３０ is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue containing a substituent in the side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO—(CH 2 ) c -COOH; a is an integer from 1 to 3, b is 1 or 2; c is an integer from 10 to 30; The pharmaceutical composition of claim 1.

11. X ２ is Aib, and X ２０ is Gln, and X ２４ is Asn, The pharmaceutical composition of claim 10.

12. X １ is Tyr, and X ２ is Aib or D-Ala, and X １０ is Tyr, and X １２ is Ile, and X １３ is Tyr, and X １４ is Leu or Nle, and X １５ is Glu, and X １６ is Y1 and X １７ is Ile, and X １８ is Ala, and X １９ is Ala, and X ２０ is Gln or Lys, and X ２３ is Ile or Val, and X ２４ is Asn or Gln, and X ２７ is Ile or Leu, and X ２８ is Ala, and X ２９ is Gly, and X ３０ is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue containing a substituent in the side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO—(CH 2 ) c -COOH; a is an integer from 1 to 3, b is 1 or 2; c is an integer from 10 to 30; The pharmaceutical composition of claim 1.

13. X ２ is Aib, and X １４ is Leu, and X ２０ is Gln, and X ２４ is Asn, The pharmaceutical composition of claim 12.

14. X １ is Tyr, and X ２ is Aib or D-Ala, and X １０ is Tyr, and X １２ is Ile, and X １３ is Tyr, and X １４ is Leu or Nle, and X １５ is Glu, and X １６ is Arg or Lys, and X １７ is Y1 and X １８ is Ala, and X １９ is Ala, and X ２０ is Gln or Lys, and X ２３ is Ile or Val, and X ２４ is Asn or Gln, and X ２７ is Ile or Leu, and X ２８ is Ala, and X ２９ is Gly, and X ３０ is Gly, Y1 is a Lys, Orn, Dap, Dab or Cys residue containing a substituent in the side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO—(CH 2 ) c -COOH; a is an integer from 1 to 3, b is 1 or 2; c is an integer from 10 to 30; The pharmaceutical composition of claim 1.

15. a is 2, b is 1 or 2, and c is an integer from 16 to 20; The pharmaceutical composition according to any one of claims 4 to 14.

16. c is 16, 18 or 20; 16. The pharmaceutical composition of claim 15.

17. Y1 is a Lys residue containing a substituent in the side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} ａ -(γ-Glu) ｂ -CO-(CH ２ ) ｃ having —COOH, a is 2, b is 1 or 2; c is 16 or 18; The pharmaceutical composition according to any one of claims 4 to 14.

18. the substituent is covalently bonded to the amino group on the side chain via an amide bond; The pharmaceutical composition according to any one of claims 4 to 14.

19. Y1 is K(—OEG-OEG-γGlu-C18-OH) or K(—OEG-OEG-γGlu-C20-OH), Among them, K(-OEG-OEG-γGlu-C18-OH) has the following structure: 【Chemistry 1】 、 Preferably it has the following structure: 【Chemistry 2】 K(-OEG-OEG-γGlu-C20-OH) has the following structure: 【Transformation 3】 、 Preferably it has the following structure: 【Chemistry 4】 The pharmaceutical composition according to any one of claims 4 to 14.

20. the substituent is covalently attached to the ε-amino group on the side chain via an amide bond; The pharmaceutical composition according to any one of claims 4 to 14.

21. The GLP-1 analog has the sequence shown in SEQ ID NO: 20, Preferably, the GLP-1 analogue is selected from the compounds numbered 1 to 18 below: The pharmaceutical composition of claim 1. Table 1

22. The GLP-1 analogue is selected from the compounds numbered 1# to 18# below: The pharmaceutical composition of claim 1. Table 2

23. the GLP-1 analogue is selected from compound 7#, 12#, 13#, 14#, 15#, 16#, 17#, or 18#; Compound 7# has the structure shown below: 【Transformation 5】 Compound 12# has the structure shown below: 【Transformation 6】 Compound 13# has the structure shown below: 【Transformation 7】 Compound 14# has the structure shown below: 【Transformation 8】 Compound 15# has the structure shown below: 【Chemistry 9】 Compound 16# has the structure shown below: 【Chemistry 10】 Compound 17# has the structure shown below: 【Chemistry 11】 Compound 18# has the structure shown below 【Chemistry 12】 The pharmaceutical composition of claim 1.

24. The GLP-1 analogue or its pharmaceutically acceptable salt, amide or ester has a higher agonist activity against GLP-1R than against GIP receptor; Preferably, the GLP-1 analogue has a ratio of agonist activity at the GLP-1R to agonist activity at the GIP receptor of 1.1:1 to 10:1, more preferably 3:1 to 6.5:1, and most preferably 4.5:1 to 6:

1. The pharmaceutical composition of claim 1.

25. Further comprising one or more selected from fillers, adhesives, disintegrants, lubricants, glidants, coating agents and protease inhibitors; The pharmaceutical composition of claim 1.

26. the filler is selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, calcium hydrogen phosphate, sorbitol or any mixture thereof; the adhesive is selected from povidone and its homologues, hydroxypropyl cellulose, hydroxypropyl methylcellulose and its homologues or any mixture thereof; the disintegrant is selected from microcrystalline cellulose, alginic acid, alginate salts, polycristine potassium, calcium hydrogen phosphate, corn starch, pregelatinized starch, sodium carboxymethyl starch, sodium starch glycolate, crospovidone, cellulose powder, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, croscarmellose sodium, or any mixture thereof; the lubricant is selected from magnesium stearate, glyceryl behenate, sodium stearoyl fumarate, stearic acid, palmitic acid, calcium stearate, talc powder, carnauba wax, or any mixture thereof; the glidant is selected from colloidal silica or talc powder; the coating agent is one or more selected from the group consisting of sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxymethylcellulose, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, methacrylic resin copolymer, and ethylcellulose; and / or The protease inhibitor is selected from phenylmethylsulfonyl fluoride (PSMF), soybean trypsin inhibitor, soybean trypsin-chymotrypsin inhibitor, colicin, sunflower trypsin inhibitor, leupeptin, citric acid, ethylenediaminetetraacetic acid, sodium glycocholate, and 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride; 26. The pharmaceutical composition of claim 25.

27. the absorption enhancer comprises at least 50% of the total weight of the composition; Preferably, the absorption enhancer comprises at least 70% of the total weight of the composition; More preferably, the absorption enhancer comprises at least 80% or at least 90% of the total weight of the composition. The pharmaceutical composition of claim 1.

28. the absorption enhancer is SNAC, and the SNAC comprises at least 20%, at least 50%, at least 70%, or at least 90% of the total weight of the composition; the absorption enhancer is sodium caprate, and the sodium caprate comprises at least 50%, or at least 60%, or at least 70% of the total weight of the composition; the absorption enhancers are SNAC and sodium octanoate, and SNAC accounts for 20% to 90% of the total weight of the composition, and sodium octanoate accounts for 5% to 75% of the total weight of the composition; the absorption enhancers are SNAC and arginine or a salt thereof, and SNAC accounts for 20% to 90% of the total weight of the composition, and arginine or a salt thereof accounts for 5% to 75% of the total weight of the composition; the absorption enhancers are SNAC and β-cyclodextrin, and SNAC accounts for 20% to 90% of the total weight of the composition, and β-cyclodextrin accounts for 5% to 75% of the total weight of the composition; the absorption enhancers are SNAC, arginine or a salt thereof, and sodium caprate, and SNAC accounts for 20% to 90% of the total weight of the composition, arginine or a salt thereof accounts for 5% to 60% of the total weight of the composition, and sodium caprate accounts for 1% to 50% of the total weight of the composition; the absorption enhancers are SNAC, arginine or a salt thereof, and leucine or a salt thereof, and SNAC accounts for 20% to 90% of the total weight of the composition, arginine or a salt thereof accounts for 5% to 60% of the total weight of the composition, and leucine or a salt thereof accounts for 1% to 50% of the total weight of the composition; the absorption enhancers are SNAC, arginine or a salt thereof, and lysine or a salt thereof, and SNAC accounts for 20% to 90% of the total weight of the composition, arginine or a salt thereof accounts for 5% to 60% of the total weight of the composition, and lysine or a salt thereof accounts for 1% to 50% of the total weight of the composition; or The absorption enhancers are SNAC, arginine or a salt thereof, and sodium octanoate, and SNAC accounts for 20% to 90% of the total weight of the composition, arginine or a salt thereof accounts for 5% to 60% of the total weight of the composition, and sodium octanoate accounts for 1% to 50% of the total weight of the composition. The pharmaceutical composition of claim 1.

29. the GLP-1 analogue or its pharmaceutically acceptable salt, amide or ester constitutes 0.1% to 30% of the total mass of the composition; Preferably, the GLP-1 analogue or its pharmaceutically acceptable salt, amide or ester constitutes 1% to 10% of the total mass of the composition; More preferably, the GLP-1 analogue or its pharmaceutically acceptable salt, amide or ester constitutes 1% to 5% of the total mass of the composition. The pharmaceutical composition of claim 1.

30. A composition (a) comprising compound 18# or a medicamentable salt, amide, or ester thereof, and N-(8-(2-hydroxybenzoyl)amino)octanoate, wherein compound 18# has the structure shown below: 【Chemistry 13】 Composition (a), Composition (b) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, and sodium octanoate, wherein compound 18# has the structure shown below: 【Chemistry 14】 composition (b), A composition (c) comprising compound 18# or a medicamentable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, and an amino acid or a salt thereof, wherein the amino acid is preferably one or more selected from histidine, arginine, leucine and lysine or a salt thereof, and compound 18# has the structure shown below. 【Chemistry 15】 composition (c), A composition (d) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate and β-cyclodextrin, wherein compound 18# has the structure shown below: 【Chemistry 16】 composition (d), A composition (e) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, and sodium caprate, wherein compound 18# has the structure shown below: 【Chemistry 17】 Composition (e), Composition (f) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, and sodium caprate, wherein compound 18# has the structure shown below. [Chemistry 18] Composition (f), A composition (g) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, and histidine or a salt thereof, wherein compound 18# has the structure shown below: 【Chemistry 19】 Composition (g), A composition (h) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, and arginine or a salt thereof, wherein compound 18# has the structure shown below. 【Chemistry 20】 composition (h), Composition (i) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, and leucine or a salt thereof, wherein compound 18# has the structure shown below. 【Chemistry 21】 Composition (i), A composition (j) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, and lysine or a salt thereof, wherein compound 18# has the structure shown below: 【Chemistry 22】 Composition (j), and A composition (k) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, and sodium octanoate, wherein compound 18# has the structure shown below. 【Chemistry 23】 Composition (k) Any one selected from The pharmaceutical composition of claim 1.

31. A composition (a1) comprising, relative to the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, and at least 20% or at least 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, wherein compound 18# has the structure shown below. 【Chemistry 24】 Composition (a1), A composition (b1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 75% of sodium octanoate, wherein compound 18# has the structure shown below. 【Chemistry 25】 Composition (b1), A composition (c1) comprising, based on the total mass of the composition, 1% to 20% of compound 18# or a medicamentable salt, amide, or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 75% of an amino acid (e.g., one or more selected from histidine, arginine, leucine, and lysine, or salts thereof), wherein compound 18# has the structure shown below: 【Chemistry 26】 Composition (c1), A composition (d1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 75% of β-cyclodextrin, wherein compound 18# has the structure shown below: 【Chemistry 27】 Composition (d1), A composition (e1) comprising 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, and at least 50% of sodium caprate, based on the total weight of the composition, wherein compound 18# has the structure shown below: 【Chemistry 28】 Composition (e1), A composition (f1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a medicament salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 60% of arginine or a salt thereof, and 1% to 50% of sodium caprate, wherein compound 18# has the structure shown below. 【Chemistry 29】 Composition (f1), A composition (g1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or its pharmaceutically acceptable salt, amide or ester, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 75% of arginine or its salt, wherein compound 18# has the structure shown below: 【Transformation 30】 Composition (g1), A composition (h1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 50% of arginine or a salt thereof, and 1% to 50% of leucine or a salt thereof, wherein compound 18# has the structure shown below. 【Chemistry 31】 Composition (h1), A composition (i1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 50% of arginine or a salt thereof, and 1% to 50% of lysine or a salt thereof, wherein compound 18# has the structure shown below. 【Chemistry 32】 Composition (i1), and A composition (j1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a medicament salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 50% of arginine or a salt thereof, and 1% to 50% of sodium octanoate, wherein compound 18# has the structure shown below. 【Transformation 33】 Composition (j1) Any one selected from Preferably, the pharmaceutical composition comprises: A composition (a2) comprising, based on the total weight of the composition, 1% to 5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, and at least 70%, for example at least 90%, of N-(8-(2-hydroxybenzoyl)amino)octanoate, wherein compound 18# has the structure shown below: 【Transformation 34】 Composition (a2), A composition (b2) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 10% of sodium octanoate, wherein compound 18# has the structure shown below: 【Chemistry 35】 composition (b2), A composition (b3) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or its pharmaceutically acceptable salt, amide or ester, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 45% of sodium octanoate, wherein compound 18# has the structure shown below: 【Transformation 36】 composition (b3), A composition (b4) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 75% or 40% to 75% of sodium octanoate, wherein compound 18# has the structure shown below: 【Chemistry 37】 composition (b4), A composition (c2) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a medicament salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 10% or 1% to 20% of arginine or a salt thereof, wherein compound 18# has the structure shown below. 【Transformation 38】 Composition (c2), A composition (c3) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a medicament salt, amide or ester thereof, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 45% of arginine or a salt thereof, wherein compound 18# has the structure shown below. 【Chemistry 39】 composition (c3), A composition (c4) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a medicament salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 75% or 40% to 75% of arginine or a salt thereof, wherein compound 18# has the structure shown below. 【Chemistry 40】 composition (c4), A composition (c5) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a medicament salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 25% of arginine or a salt thereof, wherein compound 18# has the structure shown below. 【Chemistry 41】 composition (c5), A composition (d2) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or its pharmaceutically acceptable salt, amide or ester, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 10% or 1% to 20% of β-cyclodextrin, wherein compound 18# has the structure shown below: 【Chemistry 42】 Composition (d2), A composition (d3) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or its pharmaceutically acceptable salt, amide or ester, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 45% of β-cyclodextrin, wherein compound 18# has the structure shown below: 【Chemistry 43】 Composition (d3), A composition (d4) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 10% to 75% or 40% to 75% of β-cyclodextrin, wherein compound 18# has the structure shown below: 【Chemistry 44】 Composition (d4), and A composition (e2) comprising, based on the total weight of the composition, 1% to 5% of compound 18# or its pharmaceutically acceptable salt, amide or ester, and 70% to 80% of sodium caprate, wherein compound 18# has the structure shown below: 【Chemistry 45】 Composition (e2), A composition (f1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a medicament salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 60% of arginine or a salt thereof, and 1% to 50% of sodium caprate, wherein compound 18# has the structure shown below. 【Chemistry 46】 Composition (f1), A composition (g1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or its pharmaceutically acceptable salt, amide or ester, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 5% to 75% of arginine or its salt, wherein compound 18# has the structure shown below: 【Chemistry 47】 Composition (g1), A composition (h1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 50% of arginine or a salt thereof, and 1% to 50% of leucine or a salt thereof, wherein compound 18# has the structure shown below. 【Chemistry 48】 Composition (h1), A composition (i1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 50% of arginine or a salt thereof, and 1% to 50% of lysine or a salt thereof, wherein compound 18# has the structure shown below. 【Chemistry 49】 Composition (i1), and A composition (j1) comprising, based on the total weight of the composition, 1% to 20% of compound 18# or a medicament salt, amide or ester thereof, 20% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 50% of arginine or a salt thereof, and 1% to 50% of sodium octanoate, wherein compound 18# has the structure shown below. [Transformation 50] Composition (j1) Any one selected from The pharmaceutical composition of claim 1.

32. A composition (i) comprising compound 18# or a medicamentable salt, amide, or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, and one or more selected from fillers, adhesives, and lubricants, wherein compound 18# has the structure shown below: 【Chemistry 51】 Composition (i), A composition (ii) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, sodium octanoate, a glidant and a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 52】 Composition (ii), (iii) a composition comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, an amino acid (e.g., one or more selected from histidine, arginine, leucine and lysine or salts thereof, e.g., arginine or a salt thereof), a glidant, and a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 53】 composition (iii), A composition (iv) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, β-cyclodextrin, a glidant and a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 54】 composition (iv), A composition (v) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, sodium caprate, and a protease inhibitor, wherein compound 18# has the structure shown below: 【Transformation 55】 composition (v), A composition (vi) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sodium caprate, a glidant and a lubricant, wherein compound 18# has the structure shown below. 【Transformation 56】 composition (vi), A composition (vii) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, leucine or a salt thereof, a glidant, and a lubricant, wherein compound 18# has the structure shown below. 【Chemistry 57】 composition (vii), A composition (viii) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, lysine or a salt thereof, a glidant, and a lubricant, wherein compound 18# has the structure shown below: 【Transformation 58】 composition (viii), A composition (ix) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, a glidant, a lubricant, a filler and / or an adhesive, wherein compound 18# has the structure shown below. 【Chemistry 59】 Composition (ix), and A composition (x) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sodium octanoate, a glidant and a lubricant, wherein compound 18# has the structure shown below. 【Transformation 60】 Composition (x) Any one selected from Preferably, the pharmaceutical composition comprises: A composition (i-1) comprising compound 18# or a medicinal salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, and one or more selected from microcrystalline cellulose, povidone and magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 61】 Composition (i-1), A composition (ii-1) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, sodium octanoate, colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Transformation 62】 Composition (ii-1), A composition (iii-1) comprising compound 18# or a medicamentable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, an amino acid (e.g., one or more selected from histidine, arginine, leucine and lysine or salts thereof, e.g., arginine or a salt thereof), colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Transformation 63】 Composition (iii-1), A composition (iv-1) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, β-cyclodextrin, colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 64】 Composition (iv-1), A composition (v-1) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, sodium caprate, and PMSF, wherein compound 18# has the structure shown below. 【Transformation 65】 Composition (v-1), A composition (vi-1) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sodium caprate, colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Chemical Formula 66】 Composition (vi-1), A composition (vii-1) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, leucine or a salt thereof, colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Transformation 67】 Composition (vii-1), A composition (viii-1) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, lysine or a salt thereof, colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Transformation 68】 Composition (viii-1), A composition (ix-1) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sorbitol, colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Transformation 69】 Composition (ix-1), A composition (ix-2) comprising compound 18# or a medicamentable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sorbitol, povidone, colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Transformation 70】 Composition (ix-2), A composition (ix-3) comprising compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sorbitol, hydroxypropyl cellulose, colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 71】 Composition (ix-3), and A composition (x-1) comprising compound 18# or a medicamentable salt, amide or ester thereof, N-(8-(2-hydroxybenzoyl)amino)octanoate, arginine or a salt thereof, sodium octanoate, colloidal silica and magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 72】 Composition (x-1) Any one selected from 26. The pharmaceutical composition of claim 25.

33. Composition (i-2) comprising, based on the total weight of the composition, 1% to 5% of compound 18 or a pharmaceutically acceptable salt, amide or ester thereof, 70% to 80% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 20% of a filler, about 2% of an adhesive, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below. 【Transformation 73】 Composition (i-2), A composition (i-3) comprising, based on the total weight of the composition, 1% to 5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, at least 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 74】 Composition (i-3), A composition (ii-2) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a medicament salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 10% or 5% to 25% of sodium octanoate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 75】 Composition (ii-2), A composition (ii-3) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 45% of sodium octanoate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Transformation 76】 Composition (ii-3), A composition (ii-4) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a medicament salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% or 40% to 75% of sodium octanoate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below. 【Chemical 77】 Composition (ii-4), A composition (iii-2) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a medicament salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 10% or 1% to 20% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Transformation 78】 Composition (iii-2), A composition (iii-3) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a medicament salt, amide or ester thereof, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 45% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Transformation 79】 Composition (iii-3), A composition (iii-4) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a medicament salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% or 40% to 75% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 80】 Composition (iii-4), A composition (iii-5) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 25% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 81】 Composition (iii-5), A composition (iv-2) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 10% or 1% to 20% of β-cyclodextrin, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 82】 Composition (iv-2), A composition (iv-3) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 50% to 70% or 50% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 45% of β-cyclodextrin, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 83】 Composition (iv-3), A composition (iv-4) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% or 40% to 75% of β-cyclodextrin, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemical 84】 Composition (iv-4), A composition (v-2) comprising, based on the total weight of the composition, 1% to 2% or 1% to 5% of compound 18# or its pharmaceutically acceptable salt, amide or ester, 70% to 80% of sodium caprate, and 15% to 25% of a protease inhibitor, wherein compound 18# has the structure shown below: 【Chemical 85】 Composition (v-2), A composition (v-3) comprising, based on the total weight of the composition, 1% to 5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 65% to 80% of sodium caprate, and 15% to 30% of a protease inhibitor, wherein compound 18# has the structure shown below. 【Chemical 86】 Composition (v-3), A composition (vi-2) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of sodium caprate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 87】 Composition (vi-2), A composition (vi-3) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 15% to 40% of arginine or a salt thereof, 10% to 35% of sodium caprate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemical 88】 Composition (vi-3), A composition (vi-4) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of sodium caprate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 89】 Composition (vi-4), A composition (vii-2) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of leucine or a salt thereof, 1% to 1.5% of a glidant, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below. 【Chemistry 90】 Composition (vii-2), A composition (vii-3) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 15% to 40% of leucine or a salt thereof, 1% to 1.5% of a glidant, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 91】 Composition (vii-3), A composition (vii-4) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of leucine or a salt thereof, 1% to 1.5% of a glidant, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below. 【Chemistry 92】 Composition (vii-4), A composition (viii-2) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a medicament salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of lysine or a salt thereof, 1% to 1.5% of a glidant, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemistry 93】 Composition (viii-2), A composition (viii-3) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a medicament salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 15% to 40% of lysine or a salt thereof, 1% to 1.5% of a glidant, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemical 94】 Composition (viii-3), A composition (viii-4) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a medicament salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of lysine or a salt thereof, 1% to 1.5% of a glidant, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below: 【Chemical 95】 Composition (viii-4), A composition (ix-4) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a medicament salt, amide or ester thereof, 70% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 5% to 25% of arginine or a salt thereof, 1% to 1.5% of a glidant, 0.5% to 5% of a lubricant, 1% to 20% of a filler and / or 0.5% to 5% of an adhesive, wherein compound 18# has the structure shown below. 【Chemistry 96】 Composition (ix-4), A composition (ix-5) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a medicament salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 40% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, 5% to 35% of a filler and / or 0.5% to 5% of an adhesive, wherein compound 18# has the structure shown below: 【Chemistry 97】 Composition (ix-5), A composition (ix-6) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a medicament salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 75% of arginine, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, 1% to 40% of a filler and / or 0.5% to 5% of an adhesive, wherein compound 18# has the structure shown below: 【Chem.98】 Composition (ix-6), A composition (x-2) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a medicamentable salt, amide or ester thereof, 50% to 90% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 1% to 30% of arginine or a salt thereof, 1% to 30% of sodium octanoate, 1% to 1.5% of a glidant and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below. 【Chem.99】 Composition (x-2), A composition (x-3) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5% of compound 18# or a medicament salt, amide or ester thereof, 20% to 50% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 15% to 40% of arginine or a salt thereof, 10% to 35% of sodium octanoate, 1% to 1.5% of a glidant, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below. 【Chemistry 100】 Composition (x-3), A composition (x-4) comprising, based on the total weight of the composition, 1% to 20%, for example 1% to 5%, of compound 18# or a medicament salt, amide or ester thereof, 50% to 70% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 10% to 35% of arginine or a salt thereof, 10% to 35% of sodium octanoate, 1% to 1.5% of a glidant, and 0.5% to 5% of a lubricant, wherein compound 18# has the structure shown below. 【Chemistry 101】 Composition (x-4) Any one selected from 26. The pharmaceutical composition of claim 25.

34. A composition (1) comprising, based on the total weight of the composition, 1% to 2% of compound 18# or a medicament salt, amide, or ester thereof, about 75% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 20% of microcrystalline cellulose, about 2% of povidone, and about 0.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemical Engineering 102】 Composition (1), A composition (2) comprising, based on the total weight of the composition, 3% to 3.5% of compound 18# or a pharmaceutically acceptable salt, amide or ester thereof, 94% to 95% of N-(8-(2-hydroxybenzoyl)amino)octanoate, and about 2.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 103】 Composition (2), A composition (3) comprising, based on the total weight of the composition, about 8% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 80% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 9% of sodium octanoate, about 1% of colloidal silica, and about 2.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemical 104】 Composition (3), A composition (4) comprising, based on the total weight of the composition, about 3% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica, and about 2.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 105】 Composition (4), A composition (5) comprising, based on the total weight of the composition, about 1.5% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica, and about 2.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 106】 composition (5), A composition (6) comprising, based on the total weight of the composition, about 3% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica, and about 2.5% of magnesium stearate, wherein compound 18# has the structure shown below: 【Chemistry 107】 composition (6), A composition (7) comprising, based on the total weight of the composition, about 5% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica, and about 2.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 108】 composition (7), A composition (8) comprising, based on the total weight of the composition, about 5.5% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, 80% to 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of sodium octanoate, about 1% of colloidal silica, and about 2.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 109】 composition (8), A composition (9) comprising, based on the total weight of the composition, about 15% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, 70% to 75% of N-(8-(2-hydroxybenzoyl)amino)octanoate, 8% to 10% of sodium octanoate, about 1% of colloidal silica, and about 2.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemical 110】 composition (9), A composition (10) comprising, based on the total weight of the composition, about 3% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of arginine or a salt thereof, about 1.5% of colloidal silica, and about 1.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 111】 composition (10), A composition (11) comprising, based on the total weight of the composition, about 3% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 60% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 35% of arginine or a salt thereof, about 1.5% of colloidal silica, and about 1% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 112】 Composition (11), A composition (12) comprising, based on the total weight of the composition, about 2.5% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 45% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 50% of arginine or a salt thereof, about 1.5% of colloidal silica, and about 1% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 113】 Composition (12), A composition (13) comprising, based on the total weight of the composition, about 4% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 75% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 18% of arginine or a salt thereof, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemical 114】 Composition (13), A composition (14) comprising, based on the total weight of the composition, about 2% to about 5% or 5% of compound 18# or a medicamentable salt, amide, or ester thereof, about 58% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 35% of arginine or a salt thereof, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemical 115】 composition (14), A composition (15) comprising, based on the total weight of the composition, about 3% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of histidine, about 1.5% of colloidal silica, and about 1.5% of magnesium stearate, wherein compound 18# has the structure shown below: 【Chemistry 116】 composition (15), A composition (16) comprising, based on the total weight of the composition, about 3% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 85% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 10% of β-cyclodextrin, about 0.5% of colloidal silica, and about 2.5% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 117】 composition (16), A composition (17) comprising, based on the total weight of the composition, about 1.5% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 80% of sodium caprate, and about 20% of PMSF, wherein compound 18# has the structure shown below. 【Chemistry 118】 composition (17), A composition (18) comprising, based on the total weight of the composition, about 2.5% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 28% of arginine or a salt thereof, about 20% of sodium caprate, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemical 119】 composition (18), A composition (19) comprising, based on the total weight of the composition, about 4% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 19% of arginine or a salt thereof, about 28% of sodium caprate, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemical 120】 composition (19), A composition (20) comprising, based on the total weight of the composition, about 5% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 58% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 23% of arginine or a salt thereof, about 12% of sodium caprate, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 121】 composition (20), A composition (21) comprising, based on the total weight of the composition, about 4% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 19% of arginine or a salt thereof, about 28% of leucine or a salt thereof, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 122】 composition (21), A composition (22) comprising, based on the total weight of the composition, about 4% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 19% of arginine or a salt thereof, about 28% of lysine or a salt thereof, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemical 123】 composition (22), A composition (23) comprising, based on the total weight of the composition, about 2% to about 4% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 28% of arginine or a salt thereof, about 20% of sorbitol, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 124】 composition (23), A composition (24) comprising, based on the total weight of the composition, about 4% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 45% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 20% of arginine or a salt thereof, about 28% of sorbitol, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below. 【Chemistry 125】 composition (24), A composition (25) comprising, based on the total weight of the composition, about 4% of Compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 20% of arginine or a salt thereof, about 25% of sorbitol, about 1.5% of povidone or hydroxypropyl cellulose, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein Compound 18# has the structure shown below. 【Chemistry 126】 composition (25), A composition (26) comprising, based on the total weight of the composition, about 2.5% of compound 18# or a pharmaceutically acceptable salt, amide, or ester thereof, about 47% of N-(8-(2-hydroxybenzoyl)amino)octanoate, about 28% of arginine or a salt thereof, about 20% of sodium octanoate, about 1% of colloidal silica, and about 2% of magnesium stearate, wherein compound 18# has the structure shown below: 【Chemistry 127】 Composition (26) Any one selected from 26. The pharmaceutical composition of claim 25.

35. The pharmaceutical composition is a powder, granules, tablet, capsule or freeze-dried preparation, Preferably, the pharmaceutical composition is a tablet or capsule; More preferably, the pharmaceutical composition is an immediate release formulation or an enteric coated formulation. The pharmaceutical composition of claim 1.

36. A method for preparing the pharmaceutical composition of any one of claims 1 to 14 and 21 to 35, comprising the step of mixing the GLP-1 analogue or a pharmaceutically acceptable salt, amide or ester thereof with the absorption enhancer; Preferably, the process comprises the steps of granulation, tableting or capsule filling, More preferably, the process comprises the steps of direct powder compression, wet granulation, dry granulation, tabletting or enteric capsule shell filling.

37. 36. The pharmaceutical composition according to any one of claims 1 to 14 and 21 to 35, for treating non-insulin dependent diabetes mellitus, insulin dependent diabetes mellitus, obesity, non-alcoholic fatty liver disease, hepatic steatosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, dyslipidemia associated with insulin resistance, and / or dyslipidemia associated with diabetes.

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