Pharmaceutical composition

Abstract

Provided in the present disclosure is a pharmaceutical composition. Specifically provided in the present disclosure is a pharmaceutical composition containing a triple agonist targeting GLP-1, GIP and GCG receptors, and a buffer.

Description

A pharmaceutical composition

[0001] This disclosure claims priority to the following Chinese patent applications: CN202510062905.X, filed January 15, 2025, and CN202511990668.X, filed December 26, 2025. Technical Field

[0002] This disclosure pertains to the field of biomedicine and specifically relates to a pharmaceutical composition comprising a compound that has agonistic effects on human glucagon-like peptide-1 (GLP-1) receptor, human glucose-dependent insulinotropic peptide (GIP) receptor, and human glucagon (GCG) receptor. Background Technology

[0003] The broad mechanisms of action and physiological functions of glucagon-like peptide-1 (GLP-1) and its analogues suggest that GLP-1 peptides are ideal drugs for treating non-insulin-dependent diabetes mellitus (NIDM) and obesity-related diabetes. Similar to GLP-1, glucose-dependent insulinotropic peptide (GIP) can stimulate pancreatic β-cells to secrete insulin, thereby lowering plasma glucose levels and protecting β-cells to control glucose metabolism. In addition, GIP peptides also activate their GIP receptors in adipose tissue, promoting fat metabolism. Besides raising blood glucose levels, recent studies have shown that glucagon (GCG) can also promote fat and amino acid metabolism, increase energy expenditure, and suppress appetite. Therefore, activation of glucagon receptors also has the potential to treat metabolic diseases such as obesity and non-alcoholic steatohepatitis (NASH). When glucagon receptor activation is combined with the activation of GLP-1 and GIP receptors, it can have unparalleled efficacy in treating metabolic diseases. Currently, no triple agonist products targeting GLP-1, GIP, and GCG receptors have been approved for marketing.

[0004] WO2025016303 provides compounds that have agonist effects on human GLP-1 receptor, human GIP receptor and human GCG receptor, and have stronger weight-loss efficacy and extremely high plasma stability compared with other tri-agonists in the field.

[0005] Because chemically modified peptide drugs have complex structures, they are prone to degradation, polymerization, or undesirable chemical modifications, making them unstable. Therefore, research on stable formulations of chemically modified peptide drugs is particularly important in order to make them suitable for administration and to maintain stability during storage and subsequent use, thereby achieving better therapeutic effects. Summary of the Invention

[0006] This disclosure provides a pharmaceutical composition comprising a polypeptide or a pharmaceutically acceptable salt thereof and a buffer.

[0007] The buffer is selected from one or more of phosphate buffers, histidine buffers, tris(hydroxymethyl)aminomethane buffers (Tris), and 4-hydroxyethylpiperazine ethanesulfonic acid buffers (HEPES).

[0008] The polypeptide or its pharmaceutically acceptable salt comprises or has the structure shown by the compound represented by formula (I), formula (Ia) or formula (Ib).

[0009] This disclosure also provides, among other things, the discovery of pharmaceutical formulations for delivering the peptides described herein. In some embodiments, the provided formulations avoid problems commonly encountered in the formulation of peptide therapies, including degradation and precipitation during storage. For example, in some embodiments, the provided formulations exhibit stable physical properties and characteristics (e.g., no discoloration, no precipitation, or other degradation or formation of byproducts) upon exposure to accelerated conditions (e.g., storage at 40°C for 10 or 30 days). For example, benefits associated with the provided formulations can be seen in Examples 4-9, wherein colorless and clear formulations (including, in some embodiments, remaining colorless and clear after storage under accelerated conditions (e.g., storage at 40°C for 10 or 30 days)) are provided.

[0010] In some embodiments, a specific combination (e.g., molar ratio) of the peptide compound described herein with other excipients (e.g., divalent metal ions) can improve the stability of the formulation described herein. In some embodiments described herein, the stability of the pharmaceutical formulation can be understood as the absence of substantial changes in the formulation after storage under accelerated conditions (e.g., precipitation, peptide degradation).

[0011] In some embodiments, the polypeptide is as described in WO2025 / 016303.

[0012] The compound shown in formula (I)

[0013] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided:

[0014] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10-Ser-X 12 -X 13 -X 14 -Glu-X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40 -R2(SEQ ID NO: 145)

[0015] (I);

[0016] Wherein, R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0017] X1, X2, X3, X 10 X 12 X 13 X 14 X 16 X 17 X 18 X 19 X 20 X 21 X 27 X 28 X 29 Z, X 40 Each amino acid is independently selected from any natural amino acid, non-natural amino acid, or peptide segment composed of natural and / or non-natural amino acids.

[0018] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0019] R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pGlu, and R2 is -NH2 or -OH;

[0020] X1 is selected from amino acid residues of Tyr or His.

[0021] X2 represents an amino acid residue of Aib;

[0022] X3 is selected from amino acid residues of Gln or His.

[0023] X 10 Amino acid residues selected from Leu or Tyr;

[0024] X 12Amino acid residues selected from Lys, alpha-methyl-Lys, or Ile;

[0025] X 13 Amino acid residues selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr, or alpha-methyl-Leu;

[0026] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu;

[0027] X 16 Selected from amino acid residues of Glu, Lys, or Y1;

[0028] X 17 Selected from amino acid residues of Glu, Arg, homoArg, Ile, Lys, Gln, alpha-methyl-Lys, or Y1;

[0029] X 18 Amino acid residues selected from Ala or Aib;

[0030] X 19 Amino acid residues selected from Ala or Gln;

[0031] X 20 The amino acid residues selected from Gln, Aib, isovaleine, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0032] X 21 Selected from amino acid residues of Glu or Y1;

[0033] X 27 Amino acid residues selected from Ile or Leu;

[0034] X 28 Amino acid residues selected from Ala or Glu;

[0035] X 29 Amino acid residues selected from Gly or D-Glu;

[0036] X 40 Amino acid residues selected from Lys, Y1 or not present;

[0037] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149);

[0038] Y1 is a Lys, Orn, Dap, Dab, or Cys residue that is a side-chain substituent.

[0039] In some implementation schemes, X 16 X 17 and X 21 The amino acid at at least one position is Y1.

[0040] In some implementation schemes, X 16 For Y1. In some implementations, X 17 Y1.

[0041] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt thereof represented by formula (Ia):

[0042] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X 20 -Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40 -R2(SEQ ID NO: 151)

[0043] (Ia);

[0044] Wherein, R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0045] X1 is selected from amino acid residues of Tyr or His.

[0046] X2 represents an amino acid residue of Aib;

[0047] X3 is selected from amino acid residues of Gln or His.

[0048] X 10 Amino acid residues selected from Leu or Tyr;

[0049] X 12 Amino acid residues selected from Lys, alpha-methyl-Lys, or Ile;

[0050] X 13 Amino acid residues selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr, or alpha-methyl-Leu;

[0051] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu;

[0052] X 17 Amino acid residues selected from Glu, Arg, homoArg, Ile, Lys, Gln, or alpha-methyl-Lys;

[0053] X 18 Amino acid residues selected from Ala or Aib;

[0054] X 19 Amino acid residues selected from Ala or Gln;

[0055] X 20 The amino acid residues selected from Gln, Aib, isovaleine, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0056] X 27 Amino acid residues selected from Ile or Leu;

[0057] X 28 Amino acid residues selected from Ala or Glu;

[0058] X 29 Amino acid residues selected from Gly or D-Glu;

[0059] X 40 Amino acid residues selected from Lys or absent;

[0060] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149).

[0061] Y1 is a Lys, Orn, Dap, Dab, or Cys residue that is a side-chain substituent.

[0062] In some embodiments, the compound represented by formula (Ia) has R1 as hydrogen.

[0063] In some embodiments, the compound represented by formula (Ia) has R2 as -NH2 or -OH.

[0064] In some embodiments, the compound represented by formula (Ia) has R2 as -NH2.

[0065] In some embodiments, the compound represented by formula (Ia) is Z, which is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146).

[0066] In some embodiments, the compound shown in formula (Ia), X 40 It does not exist.

[0067] In some embodiments, in the compound of formula (Ia), Y1 is a Lys residue of a side-chain-linked substituent.

[0068] In some embodiments, this disclosure provides a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

[0069] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X 20 -Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150)

[0070] (Ib);

[0071] Wherein, R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0072] X1 is selected from amino acid residues of Tyr or His.

[0073] X2 represents an amino acid residue of Aib;

[0074] X3 is selected from amino acid residues of Gln or His.

[0075] X 10 Amino acid residues selected from Leu or Tyr;

[0076] X 12 Amino acid residues selected from Lys, alpha-methyl-Lys, or Ile;

[0077] X 13 Amino acid residues selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr, or alpha-methyl-Leu;

[0078] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu;

[0079] X 17 Amino acid residues selected from Ile, Lys, Gln, or alpha-methyl-Lys;

[0080] X 18 Amino acid residues selected from Ala or Aib;

[0081] X 19 Amino acid residues selected from Ala or Gln;

[0082] X 20 The amino acid residues selected from Gln, Aib, isovaleine, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0083] X 27 Amino acid residues selected from Ile or Leu;

[0084] X 28 Amino acid residues selected from Ala or Glu;

[0085] X29 Amino acid residues selected from Gly or D-Glu;

[0086] Y1 is a Lys, Orn, Dap, Dab, or Cys residue that is a side-chain substituent.

[0087] In some embodiments, the compound represented by formula (Ib) has R1 as hydrogen.

[0088] In some embodiments, the compound represented by formula (Ib) has R2 as -NH2 or -OH.

[0089] In some embodiments, the compound represented by formula (Ib) has R2 as -NH2.

[0090] In some embodiments, in the compound of formula (Ib), Y1 is a Lys residue of a side-chain-linked substituent.

[0091] In some embodiments, in compounds with the structure shown in any of the foregoing embodiments, X1, X2, and X3 are selected from any of the following:

[0092] X1 is His, X2 is Aib, and X3 is His;

[0093] X1 is Tyr, X2 is Aib, and X3 is Gln; or

[0094] X1 is His, X2 is Aib, and X3 is Gln.

[0095] In some implementations, compounds with the structure shown in any of the foregoing embodiments,

[0096] X1 is His, X2 is Aib, and X3 is His; or

[0097] X1 is His, X2 is Aib, and X3 is Gln.

[0098] In some embodiments, the compounds with the structures shown in any of the foregoing examples have X1, X2, and X3 as His, Aib, and His, respectively.

[0099] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 17 It is a Lys residue.

[0100] In some implementation schemes, X 17 X 18 X 19 and X 20 Choose from any of the following:

[0101] X 17 For Lys, X 18 For Ala, X 19For Ala and X 20 For Gln;

[0102] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 It is alpha-methyl-Ser;

[0103] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 It is isovalerine;

[0104] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 It is 1-aminocyclopropane-1-carboxylic acid;

[0105] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 It is 1-aminocyclobutane-1-carboxylic acid;

[0106] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 For Aib;

[0107] X 17 For Lys, X 18 For Aib, X 19 For Ala and X 20 For Gln; and

[0108] X 17 For Lys, X 18 For Ala, X 19 For Gln, and X 20 It is Gln.

[0109] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 17 For Gln residues. In some embodiments, X 17 X 18 X 19 and X 20 Choose from any of the following:

[0110] X 17 For Gln, X 18 For Ala, X 19For Ala and X 20 For Gln;

[0111] X 17 For Gln, X 18 For Ala, X 19 For Ala and X 20 It is isovalerine;

[0112] X 17 For Gln, X 18 For Ala, X 19 For Ala and X 20 It is 1-aminocyclopropane-1-carboxylic acid; and

[0113] X 17 For Gln, X 18 For Ala, X 19 For Ala and X 20 It is 1-aminocyclobutane-1-carboxylic acid.

[0114] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 17 It is alpha-methyl-Lys.

[0115] In some implementation schemes, X 17 X 18 X 19 and X 20 These are alpha-methyl-Lys, Ala, Ala, and Gln, respectively. In some embodiments, compounds with the structure shown in any of the preceding embodiments, wherein X... 17 For Ile. In some implementations, X 17 X 18 X 19 and X 20 They are Ile, Ala, Ala, and Gln, respectively.

[0116] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, X 12 It is an Ile residue.

[0117] In some implementation schemes, X 12 X 13 and X 14 Choose from any of the following:

[0118] X 12 For Ile, X 13 For Leu, and X 14 For Leu; or

[0119] X 12 For Ile, X 13For alpha-methyl-Leu, and X 14 For Leu.

[0120] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 12 It is a Lys residue.

[0121] In some implementation schemes, X 12 X 13 and X 14 Choose from any of the following:

[0122] X 12 For Lys, X 13 For alpha-methyl-Tyr, and X 14 For Leu;

[0123] X 12 For Lys, X 13 For Aib and X 14 For Leu;

[0124] X 12 For Lys, X 13 For Tyr, and X 14 For alpha-methyl-Leu; and

[0125] X 12 For Lys, X 13 For Tyr, and X 14 For Leu.

[0126] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 12 It is an alpha-methyl-Lys residue.

[0127] In some implementation schemes, X 12 X 13 and X 14 Choose from any of the following:

[0128] X 12 alpha-methyl-Lys, X 13 For Tyr, and X 14 For Leu;

[0129] X 12 alpha-methyl-Lys, X 13 For Leu, and X 14 For Leu; and

[0130] X 12 alpha-methyl-Lys, X 13 For Ile, and X 14 For Leu.

[0131] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X1 to X 29 Choose from any of the following groups:

[0132] (i) X1, X2, and X3 are selected from any of the following:

[0133] X1 is His, X2 is Aib, and X3 is His;

[0134] X1 is His, X2 is Aib, and X3 is Gln; or

[0135] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0136] X 10 Amino acid residues selected from Leu or Tyr.

[0137] X 12 Amino acid residues selected from Lys, alpha-methyl-Lys, or Ile

[0138] X 13 The amino acid residues selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr, or alpha-methyl-Leu

[0139] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu,

[0140] X 16 It's Y1.

[0141] X 17 Amino acid residues selected from Lys

[0142] X 18 Amino acid residues selected from Ala or Aib

[0143] X 19 Amino acid residues selected from Ala or Gln.

[0144] X 20 The amino acid residues selected from Gln, Aib, isovaleine, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid, or 1-aminocyclobutane-1-carboxylic acid

[0145] X 27 Amino acid residues selected from Ile or Leu.

[0146] X 28 amino acid residues selected from Ala or Glu, X 29 Amino acid residues selected from Gly or D-Glu;

[0147] In some implementation schemes,

[0148] X1 is His, X2 is Aib, and X3 is His; or

[0149] X1 is His, X2 is Aib, and X3 is Gln;

[0150] (ii) X1, X2, and X3 are selected from any of the following:

[0151] X1 is His, X2 is Aib, and X3 is His;

[0152] X1 is His, X2 is Aib, and X3 is Gln; or

[0153] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0154] X 10 Amino acid residues selected from Leu or Tyr.

[0155] X 12 Amino acid residues selected from Lys, alpha-methyl-Lys, or Ile

[0156] X 13 The amino acid residues selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr, or alpha-methyl-Leu

[0157] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu,

[0158] X 16 It is Y1, X 17 Amino acid residues selected from Lys

[0159] X 18 Amino acid residues selected from Ala or Aib

[0160] X 19 Amino acid residues selected from Ala or Gln.

[0161] X 20 Amino acid residues selected from Gln

[0162] X 27 Amino acid residues selected from Ile or Leu.

[0163] X 28 Amino acid residues selected from Ala or Glu,

[0164] X 29Amino acid residues selected from Gly or D-Glu;

[0165] (iii) X1, X2, and X3 are selected from any of the following:

[0166] X1 is His, X2 is Aib, and X3 is His;

[0167] X1 is His, X2 is Aib, and X3 is Gln; or

[0168] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0169] X 10 Amino acid residues selected from Leu or Tyr.

[0170] X 12 Amino acid residues selected from alpha-methyl-Lys or Ile

[0171] X 13 Amino acid residues selected from Ile, Leu, or alpha-methyl-Leu

[0172] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu,

[0173] X 16 It is Y1, X 17 Amino acid residues selected from Lys

[0174] X 18 Selected from amino acid residues of Ala.

[0175] X 19 Selected from amino acid residues of Ala.

[0176] X 20 The amino acid residues are selected from Aib, isovaleine, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid, or 1-aminocyclobutane-1-carboxylic acid.

[0177] X 27 Amino acid residues selected from Ile or Leu.

[0178] X 28 Amino acid residues selected from Ala or Glu,

[0179] X 29 Amino acid residues selected from Gly or D-Glu;

[0180] In some implementation schemes,

[0181] X1 is His, X2 is Aib, and X3 is His; or

[0182] X1 is His, X2 is Aib, and X3 is Gln;

[0183] (iv)X1 is His;

[0184] X2 is Aib;

[0185] X3 stands for His;

[0186] X 10 Amino acid residues selected from Tyr,

[0187] X 12 Amino acid residues selected from Lys or alpha-methyl-Lys,

[0188] X 13 Amino acid residues selected from Tyr,

[0189] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu,

[0190] X 16 It is Y1, X 17 Amino acid residues selected from Lys

[0191] X 18 Amino acid residues selected from Ala or Aib

[0192] X 19 Amino acid residues selected from Ala or Gln.

[0193] X 20 Amino acid residues selected from Gln

[0194] X 27 Amino acid residues selected from Ile or Leu.

[0195] X 28 Amino acid residues selected from Ala or Glu,

[0196] X 29 Amino acid residues selected from Gly;

[0197] (v)X1 is His;

[0198] X2 is Aib;

[0199] X3 is His or Gln;

[0200] X 10 Amino acid residues selected from Leu or Tyr.

[0201] X 12 Amino acid residues selected from Ile,

[0202] X 13 The amino acid residues selected from alpha-methyl-Leu,

[0203] X 14 The amino acid residues selected from Leu

[0204] X 16 It is Y1, X 17 Amino acid residues selected from Lys

[0205] X 18 Selected from amino acid residues of Ala.

[0206] X 19 Selected from amino acid residues of Ala.

[0207] X 20 Amino acid residues selected from Gln, Aib, 1-aminocyclobutane-1-carboxylic acid, or isovaleine.

[0208] X 27 The amino acid residues selected from Leu

[0209] X 28 Selected from amino acid residues of Ala.

[0210] X 29 Amino acid residues selected from Gly or D-Glu;

[0211] (vi) X1, X2, and X3 are selected from any of the following:

[0212] X1 is His, X2 is Aib, and X3 is His;

[0213] X1 is His, X2 is Aib, and X3 is Gln; or

[0214] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0215] X 10 Amino acid residues selected from Leu or Tyr.

[0216] X 12 Amino acid residues selected from alpha-methyl-Lys or Ile

[0217] X 13 The amino acid residues selected from Leu;

[0218] X 14 The amino acid residues selected from Leu

[0219] X 16 It is Y1, X 17Amino acid residues selected from Ile, Lys, or Gln.

[0220] X 18 Selected from amino acid residues of Ala.

[0221] X 19 Selected from amino acid residues of Ala.

[0222] X 20 The amino acid residues selected from Gln, Aib, isovaleine, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid, or 1-aminocyclobutane-1-carboxylic acid

[0223] X 27 Amino acid residues selected from Ile or Leu.

[0224] X 28 Amino acid residues selected from Ala or Glu,

[0225] X 29 Amino acid residues selected from Gly or D-Glu;

[0226] In some implementation schemes,

[0227] X1 is His, X2 is Aib, and X3 is His; or

[0228] X1 is His, X2 is Aib, and X3 is Gln;

[0229] (vii)X1 is His;

[0230] X2 is Aib;

[0231] X3 stands for His;

[0232] X 10 Amino acid residues selected from Tyr,

[0233] X 12 Amino acid residues selected from Lys

[0234] X 13 Amino acid residues selected from alpha-methyl-Tyr or Aib;

[0235] X 14 The amino acid residues selected from Leu

[0236] X 16 It's Y1.

[0237] X 17 Amino acid residues selected from Lys

[0238] X 18 Selected from amino acid residues of Ala.

[0239] X 19 Selected from amino acid residues of Ala.

[0240] X 20 Amino acid residues selected from Gln

[0241] X 27 The amino acid residues selected from Leu

[0242] X 28 Selected from amino acid residues of Ala.

[0243] X 29 Amino acid residues selected from Gly;

[0244] (viii) X1, X2, and X3 are selected from any one of the following:

[0245] X1 is His, X2 is Aib, and X3 is His; or

[0246] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0247] X 10 Amino acid residues selected from Leu or Tyr.

[0248] X 12 The amino acid residues selected from alpha-methyl-Lys

[0249] X 13 Amino acid residues selected from Ile;

[0250] X 14 The amino acid residues selected from Leu

[0251] X 16 It's Y1.

[0252] X 17 Amino acid residues selected from Lys

[0253] X 18 Selected from amino acid residues of Ala.

[0254] X 19 Selected from amino acid residues of Ala.

[0255] X 20 Amino acid residues selected from Gln or isovaleine.

[0256] X 27 Amino acid residues selected from Leu or Ile

[0257] X 28 Amino acid residues selected from Ala or Glu,

[0258] X 29 Amino acid residues selected from Gly;

[0259] In some implementations, X1 is His, X2 is Aib, and X3 is His;

[0260] (ix)X1 represents His;

[0261] X2 is Aib;

[0262] X3 stands for His;

[0263] X 10 Amino acid residues selected from Leu or Tyr.

[0264] X 12 Amino acid residues selected from Lys, alpha-methyl-Lys, or Ile

[0265] X 13 Amino acid residues selected from Ile, Leu, or Tyr

[0266] X 14 The amino acid residues selected from Leu

[0267] X 16 It is Y1, X 17 Amino acid residues selected from Ile, Gln, or alpha-methyl-Lys.

[0268] X 18 Selected from amino acid residues of Ala.

[0269] X 19 Selected from amino acid residues of Ala.

[0270] X 20 Amino acid residues selected from Gln, isovaleine, 1-aminocyclopropane-1-carboxylic acid, or 1-aminocyclobutane-1-carboxylic acid.

[0271] X 27 The amino acid residues selected from Leu

[0272] X 28 Selected from amino acid residues of Ala.

[0273] X 29 Amino acid residues selected from Gly or D-Glu;

[0274] (x)X1 is His;

[0275] X2 is Aib;

[0276] X3 stands for His;

[0277] X 10 Amino acid residues selected from Leu or Tyr.

[0278] X 12 Amino acid residues selected from alpha-methyl-Lys or Ile

[0279] X 13 Amino acid residues selected from Ile or Leu.

[0280] X 14 The amino acid residues selected from Leu

[0281] X 16 It's Y1.

[0282] X 17 Amino acid residues selected from Gln

[0283] X 18 Selected from amino acid residues of Ala.

[0284] X 19 Selected from amino acid residues of Ala.

[0285] X 20 Amino acid residues selected from Gln, isovaleine, 1-aminocyclopropane-1-carboxylic acid, or 1-aminocyclobutane-1-carboxylic acid.

[0286] X 27 The amino acid residues selected from Leu

[0287] X 28 Selected from amino acid residues of Ala.

[0288] X 29 Amino acid residues selected from Gly or D-Glu;

[0289] (xi)X1 represents His;

[0290] X2 is Aib;

[0291] X3 stands for His;

[0292] X 10 Amino acid residues selected from Tyr,

[0293] X 12 Amino acid residues selected from Lys or alpha-methyl-Lys,

[0294] X 13 Amino acid residues selected from Leu or Tyr.

[0295] X 14 The amino acid residues selected from Leu

[0296] X 16 It's Y1.

[0297] X 17 Amino acid residues selected from Ile or alpha-methyl-Lys.

[0298] X 18 Selected from amino acid residues of Ala.

[0299] X 19 Selected from amino acid residues of Ala.

[0300] X 20 Amino acid residues selected from Gln

[0301] X 27 The amino acid residues selected from Leu

[0302] X 28 Selected from amino acid residues of Ala.

[0303] X 29 The amino acid residues are selected from Gly.

[0304] In some embodiments, the amino acid combination as shown in any one of (i) to (xi) above, wherein Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148), or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149). In some embodiments, Z is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146).

[0305] In some embodiments, such as the amino acid combinations shown in any one of (i) to (xi) above, wherein X 40 The amino acid residues selected from Lys may be absent. In some embodiments, X 40 It does not exist.

[0306] In some embodiments, as shown in any of (i) to (xi) above, the amino acid combination, wherein Y1 is a Lys, Orn, Dap, Dab, or Cys residue of the side-chain-linked substituent. In some embodiments, Y1 is a Lys residue of the side-chain-linked substituent.

[0307] In some embodiments, as shown in any of (i) to (xi) above, R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pGlu, and R2 is -NH2 or -OH. In some embodiments, R1 is hydrogen and R2 is -NH2 or -OH. In some embodiments, R1 is hydrogen and R2 is -NH2.

[0308] In some embodiments, the compound represented by formula (I), formula (Ia), or formula (Ib) comprises (or is) any of the polypeptide sequences shown below:

[0309] Table 1

[0310] In Table 1, αK is alpha-methyl-Lys, αY is alpha-methyl-Tyr, αL is alpha-methyl-Leu, Iva is isovaline, e is D-Glu, Aib is α-aminoisobutyric acid, Ac3c is 1-aminocyclopropane-1-carboxylic acid, and Ac4c is 1-aminocyclobutane-1-carboxylic acid.

[0311] In some embodiments, the compound with the structure shown in any of the foregoing embodiments further comprises a substituent. In some embodiments, the substituent is linked to an amino acid residue at any position. In some embodiments, the substituent is covalently linked to the side chain of the amino acid residue. For example, the substituent is covalently linked to the ε-amino group of a Lys residue.

[0312] In some embodiments, the substituent comprises the following structure: -Z1-Z2.

[0313] In some implementations, Z2 includes (or is) C 12 -C 32 Fatty acids. For example, C 12 -C 32 Examples of fatty acids include, but are not limited to, palmitic acid (hexadecanoic acid) (C 16 Monoacids), hexadecanoic acid (C 16 diacid), pearlitic acid (heptadecanoic acid) (C 17 Monoacids), heptadecanedioic acid (C 17 diacid), stearic acid (C 18 Monoacids), octadecanoic acid (C 18 diacid), nonadecanoic acid (nonadecanoic acid) (C 19 Monoacids), nonadecanedioic acid (C 19 diacid), arachidic acid (eicosanoic acid) (C 20 Monoacids), eicosanoic acid (C 20 dicarboxylic acid), eicosanoic acid (eicosanoic acid) (C 21Monoacids), cocoedioic acid (C 21 Diacid), behenic acid (behenic acid) (C 22 Monoacids), docosanoic acid (C 22 Dicarboxylic acids, including their branched and substituted derivatives.

[0314] In some implementations, Z1 may contain amino acids, amino polyethylene glycol, or blends thereof.

[0315] In some embodiments, Z1 comprises (or is) 0-10 amino acid residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) independently selected from Gly, Glu, γGlu, and OEG.

[0316] Exemplarily, where the linker comprises at least one amino acid, the amino acid may be one to four Glu or γGlu amino acid residues. In some embodiments, the linker may comprise one or two Glu or γGlu amino acid residues, including their D form. For example, the linker may comprise one or two γGlu amino acid residues. Alternatively, the linker may comprise one to four amino acid residues (e.g., Glu or γGlu amino acids) used in combination with OEG.

[0317] For example, the linker may be a combination of 1 to 4 Glu or γGlu amino acids and 1 to 4 OEG. In other cases, the linker may be a combination of 1 or 2 γGlu amino acids and 1 or 2 OEG.

[0318] As described in this disclosure, the amino acid residue of “OEG” is [2-(2-amino-ethoxy)-ethoxy]-acetyl, and its structure is as follows:

[0319] As described in this disclosure, the structure of the "γGlu" amino acid residue is shown below:

[0320] As described in this disclosure, "pGlu" is polyglutamic acid with the structure Glu-(Glu)d-Glu. Exemplarily, the molecular weight of pGlu is 700,000 to 2,000,000 units (e.g., 100 units).

[0321] In some implementations, Z1 includes the following structure: -(OEG) a -(γGlu) b-; where a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), and b is any integer between 1 and 2 (e.g., 0, 1, or 2). In some specific embodiments, a is 1, 2, or 3, and b is 1 or 2. In some specific embodiments, a is 2 or 3, and b is 1 or 2. In some specific embodiments, a is 2, and b is 1 or 2. In some specific embodiments, a is 2, and b is 1.

[0322] In some implementations, Z2 comprises the following structure: -CO-(CH2) c -COOH, where c is any integer between 10 and 30 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30). In some specific embodiments, c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific embodiments, c is 16, 18, or 20. In some specific embodiments, c is 16 or 18.

[0323] In some embodiments, the substituent has the following structure: {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0324] Where a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 2 (e.g., 1 or 2), and c is any integer between 10 and 30 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30).

[0325] In some specific implementations, a is 1, 2, or 3, b is 1 or 2, and c is any integer from 16 to 20 (e.g., 16, 17, 18, 19, 20).

[0326] In some specific implementation schemes, a is 2 or 3, b is 1 or 2, and c is 16, 18, or 20.

[0327] In some specific implementation schemes, a is 2, b is 1 or 2, and c is 16, 18, or 20.

[0328] In some specific implementation schemes, a is 2, b is 1 or 2, and c is 16 or 18.

[0329] In some specific implementation schemes, a is 2, b is 1, and c is 16 or 18.

[0330] In some specific implementations, the substituents have the following structure:

[0331] In some embodiments, the compound with the structure shown in any of the foregoing embodiments, X 16 X 21 and X 40 Each was independently selected from Y1.

[0332] In some embodiments, Y1 is a Lys, Orn, Dap, Dab, or Cys residue of the side chain connecting the substituent. In some embodiments, the substituent has the structure -Z1-Z2, wherein Z1 contains 0-10 amino acid residues independently selected from Gly, Glu, γGlu, and OEG, and Z2 is selected from C. 12-32 Fatty acids.

[0333] In some implementations, Z1 includes (or is) the structure shown below: -(OEG) a -(γGlu) b -; where a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), and b is any integer between 1 and 2 (e.g., 1 or 2). In some embodiments, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, where c is any integer between 10 and 30 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30).

[0334] In some embodiments, the substituent comprises (or is) the structure shown below: {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0335] Where a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific implementations, a is 1, 2, or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific implementations, a is 2 or 3, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16 or 18. In some specific implementations, a is 2, b is 1, and c is 16 or 18.

[0336] In some embodiments, Y1 is a Lys residue with a side-chain-linked substituent, the substituent being covalently linked to the ε-amino group of the Lys residue via an amide bond.

[0337] In some implementations, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2)). 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH), or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0338] Wherein, K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH) has the following structure:

[0339] K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) has the following structure:

[0340] In some implementations, Y1 has the following structure:

[0341] In some embodiments, the compound has the structure shown in formula (I) or a pharmaceutically acceptable salt thereof.

[0342] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40 -R2(SEQ ID NO: 145)

[0343] (I);

[0344] in:

[0345] R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pGlu.

[0346] R2 is -NH2 or -OH;

[0347] X1 is selected from amino acid residues of Tyr or His.

[0348] X2 represents an amino acid residue of Aib;

[0349] X3 is selected from amino acid residues of Gln or His.

[0350] X 10 Amino acid residues selected from Leu or Tyr;

[0351] X 12 Amino acid residues selected from Lys, alpha-methyl-Lys, or Ile;

[0352] X 13 Amino acid residues selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr, or alpha-methyl-Leu;

[0353] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu;

[0354] X 16 Selected from amino acid residues of Glu, Lys, or Y1;

[0355] X 17 Selected from amino acid residues of Glu, Arg, homoArg, Ile, Lys, Gln, alpha-methyl-Lys, or Y1;

[0356] X 18 Amino acid residues selected from Ala or Aib;

[0357] X 19 Amino acid residues selected from Ala or Gln;

[0358] X 20 The amino acid residues selected from Gln, Aib, isovaleine, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0359] X 21 Selected from amino acid residues of Glu or Y1;

[0360] X 27 Amino acid residues selected from Ile or Leu;

[0361] X 28 Amino acid residues selected from Ala or Glu;

[0362] X 29Amino acid residues selected from Gly or D-Glu;

[0363] X 40 Amino acid residues selected from Lys, Y1 or not present;

[0364] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149).

[0365] Y1 is a Lys, Orn, Dap, Dab, or Cys residue with a side chain connecting to a substituent, the structure of which is shown below: -Z1-Z2, wherein Z1 contains 0-10 amino acid residues independently selected from Gly, Glu, γGlu, and OEG, and Z2 is selected from C 12-32 The fatty acids. In some embodiments, Z1 comprises (or has) the following structure: -(OEG) a -(γGlu) b -; where a is any integer between 0 and 4, and b is any integer between 1 and 2. In some implementations, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, where c is any integer between 10 and 30.

[0366] In some embodiments, the structure of the substituent is as follows:

[0367] {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0368] Where a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific implementations, a is 1, 2, or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific implementations, a is 2 or 3, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16 or 18. In some specific implementations, a is 2, b is 1, and c is 16 or 18.

[0369] In some embodiments, Y1 is a Lys residue with a side-chain-linked substituent, said substituent being covalently linked to the ε-amino group of said Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2). 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0370] In some embodiments, the group has the structure shown below:

[0371] In some implementation schemes, X 16 X 17 and X 21 The amino acid at at least one position is Y1. In some embodiments, X 16 Y1.

[0372] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt thereof represented by formula (Ia):

[0373] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X 20 -Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40-R2(SEQ ID NO: 151)

[0374] (Ia);

[0375] Wherein, R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0376] X1 is selected from amino acid residues of Tyr or His.

[0377] X2 represents an amino acid residue of Aib;

[0378] X3 is selected from amino acid residues of Gln or His.

[0379] X 10 Amino acid residues selected from Leu or Tyr;

[0380] X 12 Amino acid residues selected from Lys, alpha-methyl-Lys, or Ile;

[0381] X 13 Amino acid residues selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr, or alpha-methyl-Leu;

[0382] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu;

[0383] X 17 Amino acid residues selected from Glu, Arg, homoArg, Ile, Lys, Gln, or alpha-methyl-Lys;

[0384] X 18 Amino acid residues selected from Ala or Aib;

[0385] X 19 Amino acid residues selected from Ala or Gln;

[0386] X 20 The amino acid residues selected from Gln, Aib, isovaleine, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0387] X 27 Amino acid residues selected from Ile or Leu;

[0388] X 28 Amino acid residues selected from Ala or Glu;

[0389] X 29 Amino acid residues selected from Gly or D-Glu;

[0390] X 40 Amino acid residues selected from Lys or absent;

[0391] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149);

[0392] Y1 is a Lys, Orn, Dap, Dab, or Cys residue with a side chain connecting to a substituent, the structure of which is shown below: -Z1-Z2, wherein Z1 contains 0-10 amino acid residues independently selected from Gly, Glu, γGlu, OEG ([2-(2-amino-ethoxy)-ethoxy]-acetyl), and Z2 is selected from C 12-32 The fatty acids. In some embodiments, Z1 comprises (or has) the following structure: -(OEG) a -(γGlu) b -; where a is any integer between 0 and 4, and b is any integer between 1 and 2. In some implementations, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, where c is any integer between 10 and 30.

[0393] In some embodiments, the structure of the substituent is as follows:

[0394] {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0395] Where a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific implementations, a is 1, 2, or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific implementations, a is 2 or 3, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16 or 18. In some specific implementations, a is 2, b is 1, and c is 16 or 18.

[0396] In some embodiments, Y1 is a Lys residue with a side-chain-linked substituent, said substituent being covalently linked to the ε-amino group of said Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2). 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0397] In some implementations, Y1 has the following structure:

[0398] In some implementations, R1 is hydrogen.

[0399] In some implementations, R2 is -NH2 or -OH.

[0400] In some implementations, R2 is -NH2.

[0401] In some implementations, Z stands for Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146).

[0402] In some implementation schemes, X 40 It does not exist.

[0403] In some implementations, Y1 is a Lys residue of the side-chain linker.

[0404] In some embodiments, this disclosure provides a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

[0405] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12-X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X 20 -Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150)

[0406] (Ib);

[0407] Where R1 is hydrogen,

[0408] R2 is -NH2 or -OH;

[0409] X1 is selected from amino acid residues of Tyr or His.

[0410] X2 represents an amino acid residue of Aib;

[0411] X3 is selected from amino acid residues of Gln or His.

[0412] X 10 Amino acid residues selected from Leu or Tyr;

[0413] X 12 Amino acid residues selected from Lys, alpha-methyl-Lys, or Ile;

[0414] X 13 Amino acid residues selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr, or alpha-methyl-Leu;

[0415] X 14 Amino acid residues selected from Leu or alpha-methyl-Leu;

[0416] X 17 Amino acid residues selected from Ile, Lys, Gln, or alpha-methyl-Lys;

[0417] X 18 Amino acid residues selected from Ala or Aib;

[0418] X 19 Amino acid residues selected from Ala or Gln;

[0419] X 20The amino acid residues selected from Gln, Aib, isovaleine, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0420] X 27 Amino acid residues selected from Ile or Leu;

[0421] X 28 Amino acid residues selected from Ala or Glu;

[0422] X 29 Amino acid residues selected from Gly or D-Glu;

[0423] Y1 is a Lys residue with a side chain connecting to a substituent, the structure of which is shown below: -Z1-Z2, wherein Z1 contains 0-10 amino acid residues independently selected from Gly, Glu, γGlu, and OEG, and Z2 is selected from C 12-32 The fatty acids. In some embodiments, Z1 comprises (or has) the following structure: -(OEG) a -(γGlu) b -; where a is any integer between 0 and 4, and b is any integer between 1 and 2. In some implementations, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, where c is any integer between 10 and 30.

[0424] In some embodiments, the structure of the substituent is as follows:

[0425] {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0426] Where a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30.

[0427] In some specific implementations, a is 1, 2, or 3, b is 1 or 2, and c is any integer from 16 to 20 (e.g., 16, 17, 18, 19, 20). In some specific implementations, a is 2 or 3, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16 or 18. In some specific implementations, a is 2, b is 1, and c is 16 or 18.

[0428] In some embodiments, the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2). 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0429] In some implementations, Y1 has the following structure:

[0430] In some embodiments, Y1, as shown in any of the foregoing embodiments, has the following structure:

[0431] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X1, X2, and X3 are selected from any of the following:

[0432] X1 is His, X2 is Aib, and X3 is His;

[0433] X1 is Tyr, X2 is Aib, and X3 is Gln; or

[0434] X1 is His, X2 is Aib, and X3 is Gln.

[0435] In some embodiments, in compounds with the structure shown in any of the foregoing embodiments, X1, X2, and X3 are selected from:

[0436] X1 is His, X2 is Aib, and X3 is His; or

[0437] X1 is His, X2 is Aib, and X3 is Gln.

[0438] In some embodiments, the compounds with the structures shown in any of the foregoing examples have X1, X2, and X3 as His, Aib, and His, respectively.

[0439] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 17 It is a Lys residue.

[0440] In some implementation schemes, X 17 X 18 X 19 and X 20 Choose from any of the following:

[0441] X 17 For Lys, X18 For Ala, X 19 For Ala and X 20 For Gln;

[0442] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 It is alpha-methyl-Ser;

[0443] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 It is isovalerine;

[0444] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 It is 1-aminocyclopropane-1-carboxylic acid;

[0445] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 It is 1-aminocyclobutane-1-carboxylic acid;

[0446] X 17 For Lys, X 18 For Ala, X 19 For Ala and X 20 For Aib;

[0447] X 17 For Lys, X 18 For Aib, X 19 For Ala and X 20 For Gln; and

[0448] X 17 For Lys, X 18 For Ala, X 19 For Gln, and X 20 It is Gln.

[0449] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 17 For Gln residues. In some embodiments, X 17 X 18 X 19 and X 20 Choose from any of the following:

[0450] X 17 For Gln, X18 For Ala, X 19 For Ala and X 20 For Gln;

[0451] X 17 For Gln, X 18 For Ala, X 19 For Ala and X 20 It is isovalerine;

[0452] X 17 For Gln, X 18 For Ala, X 19 For Ala and X 20 It is 1-aminocyclopropane-1-carboxylic acid; and

[0453] X 17 For Gln, X 18 For Ala, X 19 For Ala and X 20 It is 1-aminocyclobutane-1-carboxylic acid.

[0454] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 17 It is alpha-methyl-Lys.

[0455] In some implementation schemes, X 17 X 18 X 19 and X 20 They are alpha-methyl-Lys, Ala, Ala and Gln, respectively.

[0456] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 17 For Ile. In some implementations, X 17 X 18 X 19 and X 20 They are Ile, Ala, Ala, and Gln, respectively.

[0457] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, X 12 It is an Ile residue.

[0458] In some implementation schemes, X 12 X 13 and X 14 Choose from any of the following:

[0459] X 12 For Ile, X 13 For Leu, and X 14 For Leu; or

[0460] X 12 For Ile, X 13 For alpha-methyl-Leu, and X 14 For Leu.

[0461] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 12 It is a Lys residue.

[0462] In some implementation schemes, X 12 X 13 and X 14 Choose from any of the following:

[0463] X 12 For Lys, X 13 For alpha-methyl-Tyr, and X 14 For Leu;

[0464] X 12 For Lys, X 13 For Aib and X 14 For Leu;

[0465] X 12 For Lys, X 13 For Tyr, and X 14 For alpha-methyl-Leu; and

[0466] X 12 For Lys, X 13 For Tyr, and X 14 For Leu.

[0467] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X 12 It is an alpha-methyl-Lys residue.

[0468] In some implementation schemes, X 12 X 13 and X 14 Choose from any of the following:

[0469] X 12 alpha-methyl-Lys, X 13 For Tyr, and X 14 For Leu;

[0470] X 12 alpha-methyl-Lys, X 13 For Leu, and X 14 For Leu; or

[0471] X 12 alpha-methyl-Lys, X13 For Ile, and X 14 For Leu.

[0472] In some embodiments, compounds with the structure shown in any of the foregoing embodiments, wherein X1 to X 29 The amino acid combination is selected from any of the above (i) to (xi).

[0473] In some embodiments, Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148), or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149). In some embodiments, Z is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146). In some embodiments, X 40 The amino acid residues selected from Lys may be absent. In some embodiments, X 40 It does not exist. In some embodiments, R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pGlu, and R2 is -NH2 or -OH. In some embodiments, R1 is hydrogen, and R2 is -NH2 or -OH. In some embodiments, Y1 is a Lys, Orn, Dap, Dab, or Cys residue with a side chain connecting the substituent, the structure of which is shown below:

[0474] {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0475] Where a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific implementations, a is 1, 2, or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific implementations, a is 2 or 3, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16 or 18. In some specific implementations, a is 2, b is 1, and c is 16 or 18.

[0476] In some embodiments, the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2). 16 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 18 Y1 has the following structure: (-COOH)

[0477] In some embodiments, the compound comprises (or is) a structure shown in any of the following:

[0478] Table 2. Examples of compound sequence structures

[0479] In Table 2, αK is alpha-methyl-Lys, αY is alpha-methyl-Tyr, αL is alpha-methyl-Leu, Iva is isovaleine, e is D-Glu, Aib is α-aminoisobutyric acid, Ac3c is 1-aminocyclopropane-1-carboxylic acid, and Ac4c is 1-aminocyclobutane-1-carboxylic acid.

[0480] Y1 is a Lys, Orn, Dap, Dab, or Cys residue with a side chain connecting to a substituent, the structure of which is shown below: -Z1-Z2, wherein Z1 contains 0-10 amino acid residues independently selected from Gly, Glu, γGlu, and OEG, and Z2 is selected from C 12-32 The fatty acids. In some embodiments, Z1 comprises (or has) the following structure: -(OEG) a -(γGlu) b -; where a is any integer between 0 and 4, and b is any integer between 1 and 2. In some implementations, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, where c is any integer between 10 and 30.

[0481] In some embodiments, the structure of the substituent is as follows:

[0482] {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0483] Where a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific implementations, a is 1, 2, or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific implementations, a is 2 or 3, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16, 18, or 20. In some specific implementations, a is 2, b is 1 or 2, and c is 16 or 18. In some specific implementations, a is 2, b is 1, and c is 16 or 18.

[0484] In some embodiments, the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2). 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0485] In some implementations, Y1 has the following structure:

[0486] In some more specific implementations, the structure of Y1 is as follows:

[0487] As mentioned earlier, αK, also known as alpha-methyl-Lys, refers to α-methyl-substituted Lys. αY, also known as alpha-methyl-Tyr, refers to α-methyl-substituted Tyr. αL, also known as alpha-methyl-Leu, refers to α-methyl-substituted Leu. Iva is isovaline. e is D-Glu, a D-type Glu. Aib is α-aminoisobutyric acid. Ac3c is 1-aminocyclopropane-1-carboxylic acid, and Ac4c is 1-aminocyclobutane-1-carboxylic acid.

[0488] In some embodiments, the compound comprises (or is) any of the following structures:

[0489] Table 3

[0490] In Table 3, αK is alpha-methyl-Lys, αY is alpha-methyl-Tyr, αL is alpha-methyl-Leu, Iva is isovaleine, e is D-Glu, Aib is α-aminoisobutyric acid, Ac3c is 1-aminocyclopropane-1-carboxylic acid, Ac4c is 1-aminocyclobutane-1-carboxylic acid, and OEG is [2-(2-amino-ethoxy)-ethoxy]-acetyl.

[0491] An example structural formula is as follows:

[0492] Compound 16

[0493] Compound 17

[0494] In some embodiments, the polypeptide or its pharmaceutically acceptable salt is not...

[0495] H-Aib-HGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGPGPSSGAPPPS-NH2 (SEQ ID NO: 112);

[0496] Aib is α-aminoisobutyric acid, and OEG is [2-(2-amino-ethoxy)-ethoxy]-acetyl.

[0497] In some embodiments, the polypeptide or its pharmaceutically acceptable salt is not...

[0498] Compound 16

[0499] This disclosure also provides a pharmaceutical composition comprising a polypeptide or a pharmaceutically acceptable salt thereof and a buffer.

[0500] The buffer is selected from one or more of phosphate buffers, histidine buffers, tris(hydroxymethyl)aminomethane buffers (Tris), and 4-hydroxyethylpiperazine ethanesulfonic acid buffers (HEPES).

[0501] The polypeptide or its pharmaceutically acceptable salt comprises the following structure:

[0502] H-Aib-HGTFTSDYSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGPGPSSGAPPPS-NH2 (SEQ ID NO: 113);

[0503] Where αL is alpha-methyl-Leu, Aib is α-aminoisobutyric acid, and OEG is [2-(2-amino-ethoxy)-ethoxy]-acetyl.

[0504] In some embodiments, the polypeptide or its pharmaceutically acceptable salt containing K(-OEG-OEG-γGlu-C(O)-(CH2)18-COOH) has the structure shown below:

[0505] In some embodiments, the polypeptide or its pharmaceutically acceptable salt comprises the following structure:

[0506] In some embodiments, the buffer is selected from one or more of phosphate buffers, histidine buffers, and Tris buffers.

[0507] In some embodiments, the buffer is selected from one or more of phosphate buffers and Tris buffers.

[0508] In some embodiments, the buffer is a phosphate buffer, such as disodium hydrogen phosphate.

[0509] In some implementations, the buffer is a Tris buffer.

[0510] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt is 0.1 mg / mL to 500 mg / mL, for example, 0.5 mg / mL to 200 mg / mL, 0.5 mg / mL to 150 mg / mL, 0.5 mg / mL to 100 mg / mL, 0.5 mg / mL to 50 mg / mL, 0.5 mg / mL to 25 mg / mL, 1 mg / mL to 200 mg / mL, 1 mg / mL to 100 mg / mL, 1 mg / mL to 90 mg / mL, 1 mg / mL -80mg / mL, 1mg / mL-70mg / mL, 1mg / mL-60mg / mL, 1mg / mL-50mg / mL, 1mg / mL-40mg / mL, 1mg / mL-30mg / mL, 1mg / mL-2 0mg / mL, 2mg / mL-200mg / mL, 2mg / mL-100mg / mL, 2mg / mL-90mg / mL, 2mg / mL-80mg / mL, 2mg / mL-70mg / mL, 2mg / mL-60 mg / mL, 2mg / mL-50mg / mL, 2mg / mL-40mg / mL, 2mg / mL-30mg / mL, 2mg / mL-20mg / mL, 5mg / mL-200mg / mL, 5mg / mL-100 mg / mL, 5mg / mL-90mg / mL, 5mg / mL-80mg / mL, 5mg / mL-70mg / mL, 5mg / mL-60mg / mL, 5mg / mL-50mg / mL, 5mg / mL-40mg / mL, 5mg / mL-30mg / mL, 5mg / mL-20mg / mL, 6mg / mL-200mg / mL, 6mg / mL-100mg / mL, 6mg / mL-90mg / mL, 6mg / mL-80mg / mL, 6mg / mL-70mg / mL, 6mg / mL-60mg / mL, 6mg / mL-50mg / mL, 6mg / mL-40mg / mL, 6mg / mL-30mg / mL or 6mg / mL-20mg / mL.

[0511] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt is 5 mg / mL to 30 mg / mL, for example 5 mg / mL to 25 mg / mL, 5 mg / mL to 20 mg / mL, 10 mg / mL to 25 mg / mL, or 10 mg / mL to 20 mg / mL.

[0512] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt is 5 mg / mL to 20 mg / mL.

[0513] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt is 10 mg / mL to 20 mg / mL.

[0514] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt in the pharmaceutical composition is about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, or about 20 mg / mL.

[0515] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt in the pharmaceutical composition is about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, or about 30 mg / mL.

[0516] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.5 mg / mL to 200 mg / mL.

[0517] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt in the pharmaceutical composition is 1 mg / mL to 100 mg / mL.

[0518] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt in the pharmaceutical composition is 1 mg / mL to 50 mg / mL.

[0519] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt in the pharmaceutical composition is about 1 mg / mL, about 2 mg / mL, about 4 mg / mL, about 6 mg / mL, about 8 mg / mL, about 10 mg / mL, or about 12 mg / mL.

[0520] In some embodiments, the concentration of the polypeptide or its pharmaceutically acceptable salt in the pharmaceutical composition is about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 18 mg / mL, or about 20 mg / mL.

[0521] In some embodiments, the pharmaceutical formulation comprises about 5 mg / mL to about 30 mg / mL of the polypeptide or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical formulation comprises about 10 mg / mL to about 20 mg / mL of the polypeptide or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical formulation comprises about 10 mg / mL of the polypeptide or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical formulation comprises about 20 mg / mL of the polypeptide or a pharmaceutically acceptable form thereof.

[0522] In some embodiments, the buffer concentration is 0.1 mM-50 mM, for example 0.1 mM-40 mM, 0.1 mM-30 mM, 0.1 mM-20 mM, 0.1 mM-10 mM, 0.5 mM-40 mM, 0.5 mM-30 mM, 0.5 mM-20 mM, 0.5 mM-10 mM, 1 mM-40 mM, 1 mM-35 mM, 1 mM-30 mM, 1 mM-25 mM. 1mM-20mM, 1mM-15mM, 1mM-10mM, 2mM-40mM, 2mM-35mM, 2mM-30mM, 2mM-25mM, 2mM-20mM, 2mM-15mM, 2mM-10mM, 5mM-40mM, 5mM-35mM, 5mM-30mM, 5mM-25mM, 5mM-20mM, 5mM-15mM, or 5mM-10mM.

[0523] In some embodiments, the concentration of the buffer in the pharmaceutical composition is about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, or about 15 mM.

[0524] In some embodiments, the concentration of the buffer in the pharmaceutical composition is 0.5 mM to 40 mM.

[0525] In some embodiments, the concentration of the buffer in the pharmaceutical composition is 1 mM-20 mM.

[0526] In some embodiments, the concentration of the buffer in the pharmaceutical composition is 1 mM-15 mM.

[0527] In some embodiments, the concentration of the buffer in the pharmaceutical composition is about 10 mM.

[0528] In some embodiments, the pharmaceutical composition also includes a pH adjuster, such as sodium hydroxide and / or hydrochloric acid.

[0529] In some embodiments, the pH of the pharmaceutical composition is 6-9, for example 6.6-8.5, 6.7-8.5, 6.8-8.5, 6.9-8.5, 7-8.5, 7.1-8.5, 7.2-8.5, 7.3-8.5, 7.4-8.5, 7.5-8.5, 7.6-8.5, 7.7-8.5, 7.8-8.5, 7.9-8.5, 7-8, 7.1-8, 7.2-8, 7.3-8, 7.4-8, 7.5-8, 7-7.8, 7.1-7.8, 7.2-7.8, 7.3-7.8, or 7.4-7.8.

[0530] In some embodiments, the pH of the pharmaceutical composition is about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, or about 8.5.

[0531] In some embodiments, the pH of the pharmaceutical composition is 6.5-8.5.

[0532] In some embodiments, the pH of the pharmaceutical composition is 7-8.

[0533] In some embodiments, the pH of the pharmaceutical composition is 7-7.8, for example about 7.5 or about 7.4.

[0534] In some embodiments, the pharmaceutical composition also contains metal ions.

[0535] In some embodiments, the pharmaceutical composition also contains divalent metal ions.

[0536] In some embodiments, the metal ion is selected from divalent zinc ions, divalent calcium ions, divalent magnesium ions, and divalent iron ions.

[0537] In some embodiments, the metal ion is selected from divalent zinc ions, divalent calcium ions, and divalent magnesium ions.

[0538] In some implementations, the metal ion is selected from divalent zinc ions.

[0539] In some embodiments, the metal ion is selected from zinc acetate or zinc chloride.

[0540] In some embodiments, the metal ion is selected from zinc acetate.

[0541] In some embodiments, the pharmaceutical composition comprises a polypeptide or a pharmaceutically acceptable salt thereof and divalent zinc ions.

[0542] In some embodiments, the pharmaceutical composition comprises a polypeptide or a pharmaceutically acceptable salt thereof and zinc acetate or zinc chloride.

[0543] In some embodiments, the zinc acetate in the pharmaceutical composition of this disclosure may also be in hydrate form, such as dihydrate. In some embodiments, the zinc acetate is zinc acetate dihydrate. In some embodiments, the zinc acetate dihydrate is also described as zinc acetate dihydrate.

[0544] In some implementations, the divalent metal ion is not selected from divalent iron ions.

[0545] In some embodiments, the concentration of the zinc acetate dihydrate is 0.001 mg / ml to 20 mg / ml, for example 0.005 mg / ml to 15 mg / ml, 0.005 mg / ml to 10 mg / ml, 0.005 mg / ml to 5 mg / ml, 0.005 mg / ml to 2 mg / ml, 0.01 mg / ml to 15 mg / ml, 0.01 mg / ml to 10 mg / ml, 0.01 mg / ml to 5 mg / ml, 0.01 mg / ml to 2 mg / ml, 0.02 mg / ml to 15 mg / ml, 0.02 mg / ml to 10 mg / ml, 0.02 mg / ml to 5 mg / ml, 0.02 mg / ml to 2 mg / ml.

[0546] In some embodiments, the concentration of the zinc acetate dihydrate is 0.005 mg / ml to 15 mg / ml.

[0547] In some embodiments, the concentration of the zinc acetate dihydrate is 0.005 mg / ml to 10 mg / ml.

[0548] In some embodiments, the concentration of the zinc acetate dihydrate is 0.01 mg / ml to 5 mg / ml.

[0549] In some embodiments, the concentration of the zinc acetate dihydrate is 0.01 mg / ml to 2 mg / ml.

[0550] In some embodiments, the concentration of the zinc acetate dihydrate is about 0.042 mg / ml, about 0.1 mg / ml, about 0.2 mg / ml, about 0.25 mg / ml, about 0.3 mg / ml, about 0.45 mg / ml, about 0.5 mg / ml, about 0.6 mg / ml, about 0.675 mg / ml, about 0.7 mg / ml, about 0.75 mg / ml, about 0.8 mg / ml, or about 0.9 mg / ml.

[0551] In some embodiments, the concentration of the zinc acetate dihydrate is about 0.042 mg / ml, about 0.5 mg / ml, about 0.45 mg / ml, about 0.675 mg / ml, or about 0.9 mg / ml.

[0552] In some embodiments, the zinc acetate in the pharmaceutical composition disclosed herein may also be in other hydrate forms (including anhydrous forms) besides dihydrate, and without limitation, the concentration of said zinc acetate or hydrate is equivalent to the concentration of zinc acetate dihydrate described above by an equivalent molar amount of divalent zinc ions.

[0553] In some embodiments, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to the divalent metal ion in the pharmaceutical composition is 1:5-5:1, for example, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to the divalent metal ion is 1:4-4:1; for example, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to the divalent metal ion is 1:3-3:1; for example, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to the divalent metal ion is 1:2-2:1; for example, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to the divalent metal ion is about 1:1, about 1:2, about 2:3, or about 2:1.

[0554] In some embodiments, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to divalent zinc ions in the pharmaceutical composition described herein is 1:5-5:1; for example, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to divalent zinc ions is 1:4-4:1; for example, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to divalent zinc ions is 1:3-3:1; for example, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to divalent zinc ions is 1:2-2:1; for example, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to divalent zinc ions is about 1:1, about 1:2, about 2:3, or about 2:1.

[0555] In some embodiments, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to divalent zinc ions in the pharmaceutical composition described herein is 1:2 to 4:3.

[0556] In some embodiments, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to divalent zinc ions in the pharmaceutical composition described herein is about 1:1, about 1:2, about 2:1, about 2:3, or about 4:3.

[0557] In some embodiments, the molar ratio of divalent zinc ions to polypeptides or their pharmaceutically acceptable salts in the pharmaceutical composition described herein is 1:1.

[0558] In some embodiments, the molar ratio of divalent zinc ions to polypeptides or their pharmaceutically acceptable salts in the pharmaceutical composition described herein is at least about 1:2.

[0559] In some embodiments, the molar ratio of divalent zinc ions to polypeptides or their pharmaceutically acceptable salts in the pharmaceutical composition described herein is about 3:2.

[0560] In some embodiments, the molar ratio of divalent zinc ions to polypeptides or their pharmaceutically acceptable salts in the pharmaceutical composition described herein is at least about 3:4.

[0561] In some embodiments, the pharmaceutical composition also includes an osmotic pressure regulator.

[0562] In some embodiments, the osmotic pressure regulator is selected from one or more of mannitol, glycerol, and sodium chloride.

[0563] In some embodiments, the osmotic pressure regulator is selected from one or more of mannitol and glycerol.

[0564] In some implementations, the osmotic pressure regulator is not sodium chloride.

[0565] In some embodiments, the concentration of the osmotic pressure regulator is 0.1 mg / mL to 80 mg / mL, for example 0.1 mg / mL to 70 mg / mL, 0.1 mg / mL to 60 mg / mL, 0.1 mg / mL to 50 mg / mL, 0.1 mg / mL to 40 mg / mL, 0.1 mg / mL to 30 mg / mL, 0.1 mg / mL to 20 mg / mL, 0.5 mg / mL to 70 mg / mL, 0.5 mg / mL -60mg / mL, 0.5mg / mL-50mg / mL, 0.5mg / mL-40mg / mL, 0.5mg / mL-30mg / mL, 0.5mg / mL-20mg / mL, 1mg / mL -70mg / mL, 1mg / mL-60mg / mL, 1mg / mL-50mg / mL, 1mg / mL-40mg / mL, 1mg / mL-30mg / mL, 1mg / mL-20mg / mL.

[0566] In some embodiments, the concentration of the osmotic pressure regulator is 0.5 mg / mL to 70 mg / mL.

[0567] In some embodiments, the concentration of the osmotic pressure regulator is 1 mg / mL to 60 mg / mL.

[0568] In some embodiments, the concentration of the osmotic pressure regulator is 1 mg / mL to 50 mg / mL.

[0569] In some embodiments, the concentration of sodium chloride in the pharmaceutical composition is 0.1 mg / mL to 30 mg / mL, for example 0.5 mg / mL to 25 mg / mL, 0.5 mg / mL to 20 mg / mL, 0.5 mg / mL to 15 mg / mL, 0.5 mg / mL to 10 mg / mL, 1 mg / mL to 20 mg / mL, 1 mg / mL to 15 mg / mL, 1 mg / mL to 10 mg / mL, 5 mg / mL to 15 mg / mL, or 5 mg / mL to 10 mg / mL.

[0570] In some embodiments, the concentration of sodium chloride in the pharmaceutical composition is 0.5 mg / mL to 25 mg / mL.

[0571] In some embodiments, the concentration of sodium chloride in the pharmaceutical composition is 1 mg / mL to 20 mg / mL.

[0572] In some embodiments, the concentration of sodium chloride in the pharmaceutical composition is 5 mg / mL to 10 mg / mL.

[0573] In some embodiments, the concentration of sodium chloride in the pharmaceutical composition is about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 8.25 mg / mL, about 8.5 mg / mL, about 8.75 mg / mL, about 9 mg / mL, or about 10 mg / mL.

[0574] In some embodiments, the concentration of mannitol in the pharmaceutical composition is 1 mg / mL to 80 mg / mL, for example 1 mg / mL to 70 mg / mL, 1 mg / mL to 65 mg / mL, 1 mg / mL to 60 mg / mL, 1 mg / mL to 55 mg / mL, 1 mg / mL to 50 mg / mL, 1 mg / mL to 45 mg / mL, 1 mg / mL to 40 mg / mL, 10 mg / mL to 70 mg / mL, 10 mg / mL to 65 mg / mL, 10 mg / mL to 60 mg / mL, 10 mg / mL to 55 mg / mL, 10 mg / mL to 50 mg / mL, 10 mg / mL to 45 mg / mL, 10 mg / mL to 40 mg / mL, 20 mg / mL to 70 mg / mL, 20 mg / mL -65mg / mL, 20mg / mL-60mg / mL, 20mg / mL-55mg / mL, 20mg / mL-50mg / mL, 20mg / mL-45mg / mL, 20mg / mL-40mg / mL, 30mg / mL-70mg / mL, 30mg / mL-65mg / mL, 30mg / mL-60mg / mL, 30m g / mL-55mg / mL, 30mg / mL-50mg / mL, 30mg / mL-45mg / mL, 30mg / mL-40mg / mL, 35mg / mL-60mg / mL, 35mg / mL-55mg / mL, 35mg / mL-50mg / mL, 35mg / mL-45mg / mL or 35mg / mL-40mg / mL.

[0575] In some embodiments, the concentration of mannitol in the pharmaceutical composition is 1 mg / mL to 70 mg / mL.

[0576] In some embodiments, the concentration of mannitol in the pharmaceutical composition is 10 mg / mL to 60 mg / mL.

[0577] In some embodiments, the concentration of mannitol in the pharmaceutical composition is 30 mg / mL to 55 mg / mL.

[0578] In some embodiments, the concentration of mannitol in the pharmaceutical composition is 35 mg / mL to 50 mg / mL.

[0579] In some embodiments, the concentration of mannitol in the pharmaceutical composition is 30 mg / mL to 45 mg / mL.

[0580] In some embodiments, the concentration of mannitol in the pharmaceutical composition is 30 mg / ml, 31 mg / ml, 32 mg / ml, 33 mg / ml, 34 mg / ml, 35 mg / ml, 36 mg / ml, 37 mg / ml, 38 mg / ml, 39 mg / ml, 40 mg / ml, 41 mg / ml, 42 mg / ml, 43 mg / ml, 44 mg / ml, 45 mg / ml, 46 mg / ml, 47 mg / ml, 48 mg / ml, 49 mg / ml, or 50 mg / ml.

[0581] In some embodiments, the concentration of mannitol in the pharmaceutical composition is 36 mg / ml to 39 mg / ml.

[0582] In some embodiments, the concentration of mannitol in the pharmaceutical composition is about 39 mg / ml or about 36 mg / ml.

[0583] In some embodiments, the concentration of glycerol in the pharmaceutical composition is 1 mg / mL to 60 mg / mL, for example 1 mg / mL to 55 mg / mL, 1 mg / mL to 50 mg / mL, 1 mg / mL to 45 mg / mL, 1 mg / mL to 40 mg / mL, 1 mg / mL to 35 mg / mL, 1 mg / mL to 30 mg / mL, 1 mg / mL to 25 mg / mL, 1 mg / mL to 20 mg / mL, 5 mg / mL to 55 mg / mL, 5 mg / mL to 50 mg / mL, 5 mg / mL to 45 mg / mL. 5mg / mL-40mg / mL, 5mg / mL-35mg / mL, 5mg / mL-30mg / mL, 5mg / mL-25mg / mL, 5mg / mL-20mg / mL, 10mg / mL-55mg / mL, 10mg / mL-50 mg / mL, 10mg / mL-45mg / mL, 10mg / mL-40mg / mL, 10mg / mL-35mg / mL, 10mg / mL-30mg / mL, 10mg / mL-25mg / mL or 10mg / mL-20mg / mL.

[0584] In some embodiments, the concentration of glycerol in the pharmaceutical composition is 1 mg / mL to 50 mg / mL.

[0585] In some embodiments, the concentration of glycerol in the pharmaceutical composition is 5 mg / mL to 40 mg / mL.

[0586] In some embodiments, the concentration of glycerol in the pharmaceutical composition is 10 mg / mL to 30 mg / mL.

[0587] In some embodiments, the concentration of glycerol in the pharmaceutical composition is 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 21 mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 26 mg / ml, 27 mg / ml, 28 mg / ml, 29 mg / ml, or 30 mg / ml.

[0588] In some embodiments, the concentration of glycerol in the pharmaceutical composition is about 20 mg / ml.

[0589] In some embodiments, the pharmaceutical composition also includes an antibacterial agent.

[0590] In some embodiments, the antibacterial agent is selected from one or more of benzyl alcohol, phenol, and m-cresol.

[0591] In some implementation schemes, phenol is a pharmaceutically acceptable antibacterial agent.

[0592] In some embodiments, the concentration of the antibacterial agent in the pharmaceutical composition is 0.1 mg / mL-20 mg / mL, for example 0.5 mg / mL-20 mg / mL, 0.5 mg / mL-18 mg / mL, 0.5 mg / mL-16 mg / mL, 0.5 mg / mL-15 mg / mL, 0.5 mg / mL-14 mg / mL, 0.5 mg / mL-12 mg / mL, 0.5 mg / mL-10 mg / mL, 1 mg / mL-20 mg / mL, 1 mg / mL-18 mg / mL, 1 mg / mL-16 mg / mL, 1 mg / mL-15 mg / mL, 1 mg / mL-14 mg / mL. mg / mL, 1mg / mL-12mg / mL, 1mg / mL-10mg / mL, 2mg / mL-20mg / mL, 2mg / mL-18mg / mL, 2mg / mL-16mg / mL, 2mg / mL-15mg / mL, 2mg / mL-14mg / mL, 2mg / mL-12mg / mL, 2mg / mL-10mg / mL, 4mg / mL-15mg / mL, 4mg / mL-14mg / mL, 4mg / mL-12mg / mL, 4mg / mL-10mg / mL, 4mg / mL-8mg / mL, 4mg / mL-7mg / mL.

[0593] In some implementations, the concentration of the antibacterial agent is 0.5 mg / mL to 15 mg / mL.

[0594] In some implementations, the concentration of the antibacterial agent is 1 mg / mL to 12 mg / mL.

[0595] In some implementations, the concentration of the antibacterial agent is 1 mg / mL to 10 mg / mL.

[0596] In some embodiments, the concentration of the antibacterial agent is about 4 mg / mL, about 4.1 mg / mL, about 4.2 mg / mL, about 4.3 mg / mL, about 4.4 mg / mL, about 4.5 mg / mL, about 4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5 mg / mL, about 5.1 mg / mL, about 5.2 mg / mL, about 5.3 mg / mL, about 5.4 mg / mL, about 5.5 mg / mL, about 5.6 mg / mL, about 5.7 mg / mL, about 5.8 mg / mL, about 5.9 mg / mL, or about 6 mg / mL.

[0597] In some implementations, the concentration of the antibacterial agent is about 5.5 mg / mL or about 5.7 mg / mL.

[0598] In some embodiments, the concentration of phenol in the pharmaceutical composition is 0.1 mg / mL to 20 mg / mL, for example 0.5 mg / mL to 20 mg / mL, 0.5 mg / mL to 18 mg / mL, 0.5 mg / mL to 16 mg / mL, 0.5 mg / mL to 15 mg / mL, 0.5 mg / mL to 14 mg / mL, 0.5 mg / mL to 12 mg / mL, 0.5 mg / mL to 10 mg / mL, 1 mg / mL to 20 mg / mL, 1 mg / mL to 18 mg / mL, 1 mg / mL to 16 mg / mL, 1 mg / mL to 15 mg / mL, 1 mg / mL to 14 mg / mL. mg / mL, 1mg / mL-12mg / mL, 1mg / mL-10mg / mL, 2mg / mL-20mg / mL, 2mg / mL-18mg / mL, 2mg / mL-16mg / mL, 2mg / mL-15mg / mL, 2mg / mL-14mg / mL, 2mg / mL-12mg / mL, 2mg / mL-10mg / mL, 4mg / mL-15mg / mL, 4mg / mL-14mg / mL, 4mg / mL-12mg / mL, 4mg / mL-10mg / mL, 4mg / mL-8mg / mL, 4mg / mL-7mg / mL.

[0599] In some implementations, the phenol concentration is 0.5 mg / mL to 15 mg / mL.

[0600] In some implementations, the phenol concentration is 1 mg / mL to 12 mg / mL.

[0601] In some implementations, the phenol concentration is 1 mg / mL to 10 mg / mL.

[0602] In some embodiments, the phenol concentration is about 4 mg / mL, about 4.1 mg / mL, about 4.2 mg / mL, about 4.3 mg / mL, about 4.4 mg / mL, about 4.5 mg / mL, about 4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5 mg / mL, about 5.1 mg / mL, about 5.2 mg / mL, about 5.3 mg / mL, about 5.4 mg / mL, about 5.5 mg / mL, about 5.6 mg / mL, about 5.7 mg / mL, about 5.8 mg / mL, about 5.9 mg / mL, or about 6 mg / mL.

[0603] In some implementations, the phenol concentration is about 5.5 mg / mL or about 5.7 mg / mL.

[0604] In some embodiments, the concentration of intercalocresol in the pharmaceutical composition is 0.1 mg / mL to 15 mg / mL, for example 0.5 mg / mL to 15 mg / mL, 0.5 mg / mL to 10 mg / mL, 0.5 mg / mL to 5 mg / mL, 1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL.

[0605] In some implementations, the concentration of m-cresol is 0.5 mg / mL to 15 mg / mL.

[0606] In some implementations, the concentration of m-cresol is 1 mg / mL to 10 mg / mL.

[0607] In some implementations, the concentration of m-cresol is 1 mg / mL to 5 mg / mL.

[0608] In some embodiments, the m-cresol concentration is about 1 mg / mL, about 2 mg / mL, about 2.2 mg / mL, about 2.4 mg / mL, about 2.6 mg / mL, about 2.8 mg / mL, about 3 mg / mL, about 3.15 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 g / mL, or about 4 mg / mL.

[0609] In some implementations, the m-cresol concentration is 2 mg / mL, about 2.2 mg / mL, or about 3.15 mg / mL.

[0610] In some embodiments, this disclosure provides a pharmaceutical composition comprising any of the aforementioned polypeptides or pharmaceutically acceptable salts thereof (e.g., the structure shown in the amino acid sequence of SEQ ID NO: 113 or the structure shown in compound 17), comprising any group of the following 1)-5):

[0611] 1) Polypeptides or their medicinal salts;

[0612] Buffer, selected from phosphate buffers or Tris buffers, for example, phosphate buffers;

[0613] Divalent metal ions, such as divalent zinc ions, and zinc acetate, for example;

[0614] Osmotic pressure regulators, such as mannitol or glycerin;

[0615] Optionally, the composition further comprises an antibacterial agent, such as phenol;

[0616] 2) Polypeptides or their medicinal salts;

[0617] Buffers, for example, selected from phosphate buffers or Tris buffers, and more specifically, phosphate buffers;

[0618] Divalent zinc ions, such as zinc acetate;

[0619] Osmotic pressure regulators, such as those selected from mannitol or glycerol;

[0620] Optionally, the composition further comprises an antibacterial agent, such as phenol.

[0621] 3) Polypeptides or their medicinal salts;

[0622] Buffers, such as those selected from phosphate buffers or Tris buffers, for example, phosphate buffers;

[0623] Divalent metal ions, such as divalent zinc ions, and zinc acetate, for example;

[0624] Mannitol or glycerol;

[0625] Optionally, the composition further comprises an antibacterial agent, such as phenol;

[0626] 4) Polypeptides or their medicinally usable salts;

[0627] Buffer, selected from phosphate buffers or Tris buffers, for example, a phosphate buffer;

[0628] The pH of the pharmaceutical composition is 6-9, for example 6.5-8.5, 7-8 or 7-7.8, for example about 7.4;

[0629] 5) is a pharmaceutical composition of any one of groups 1-4), wherein the buffer is disodium hydrogen phosphate;

[0630] 6) A pharmaceutical composition of any group of 1-5) further comprising a pH adjuster, such as sodium hydroxide and / or hydrochloric acid.

[0631] In some embodiments, this disclosure provides a pharmaceutical composition comprising (or having) the structure shown in the amino acid sequence of SEQ ID NO: 113 or that of compound 17, comprising any one of the following:

[0632] 1) Polypeptides or their medicinal salts;

[0633] Divalent zinc ions, such as zinc acetate;

[0634] 2) Polypeptides or their medicinal salts;

[0635] Phosphate buffer;

[0636] Divalent zinc ions, such as zinc acetate.

[0637] In some embodiments, zinc ions (such as zinc acetate) and / or phosphate buffers (disodium hydrogen phosphate) provide excellent formulation stability for the pharmaceutical compositions described herein, especially under high temperature conditions (such as 40°C) or during use of the pharmaceutical compositions.

[0638] In some embodiments, this disclosure provides a pharmaceutical formulation comprising compound 17 or a pharmaceutically acceptable salt thereof, a phosphate buffer, zinc acetate dihydrate, mannitol, and phenol.

[0639] In some embodiments, this disclosure provides a pharmaceutical formulation comprising compound 17 or a pharmaceutically acceptable salt thereof, a phosphate buffer, zinc acetate dihydrate, mannitol, and phenol, wherein the pH of said pharmaceutical formulation is about 7 to about 8.

[0640] In some embodiments, this disclosure provides a pharmaceutical formulation comprising compound 17 or a pharmaceutically acceptable salt thereof, a phosphate buffer, zinc acetate dihydrate, phenol, and an osmotic regulator.

[0641] In some embodiments, this disclosure provides a pharmaceutical formulation comprising compound 17 or a pharmaceutically acceptable salt thereof and zinc acetate dihydrate in a molar ratio of about 1:1.

[0642] In some embodiments, this disclosure provides a pharmaceutical formulation comprising compound 17 or a pharmaceutically acceptable salt thereof, a phosphate buffer, zinc acetate dihydrate, mannitol, and phenol, wherein the molar ratio of compound 17 or a pharmaceutically acceptable salt thereof to zinc acetate dihydrate is about 1:1.

[0643] In some embodiments, this disclosure provides a pharmaceutical formulation comprising compound 17 or a pharmaceutically acceptable salt thereof and divalent zinc ions in a molar ratio of about 1:1.

[0644] In some embodiments, this disclosure provides a pharmaceutical formulation comprising compound 17 or a pharmaceutically acceptable salt thereof in a molar ratio of about 1:1 and divalent zinc ions, a phosphate buffer, mannitol, and phenol.

[0645] In some embodiments, this disclosure provides a pharmaceutical formulation comprising compound 17 or a pharmaceutically acceptable salt thereof, a phosphate buffer (sodium dihydrogen phosphate), and divalent zinc ions. In some embodiments, this disclosure provides a pharmaceutical formulation comprising compound 17 or a pharmaceutically acceptable salt thereof, a phosphate buffer, and divalent zinc ions, wherein the molar ratio of compound 17 or a pharmaceutically acceptable salt thereof to divalent zinc ions is 1:1, for example, the divalent zinc ions being zinc acetate dihydrate.

[0646] In some embodiments, this disclosure provides a pharmaceutical composition comprising any of the foregoing polypeptides or their pharmaceutically acceptable salts (e.g., the structure shown in the amino acid sequence of SEQ ID NO: 113 or the structure shown in compound 17), comprising any group of the following 1)-6):

[0647] 1) 0.1 mg / mL - 500 mg / mL polypeptides or their pharmaceutically acceptable salts;

[0648] 0.1mM-50mM phosphate buffer or Tris buffer, for example, phosphate buffer;

[0649] Divalent zinc ions, such as zinc acetate;

[0650] 0.1 mg / mL - 80 mg / mL mannitol or glycerol;

[0651] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:5-5:1.

[0652] Furthermore, the pH of the pharmaceutical composition is 6-9;

[0653] Optionally, the composition further comprises 0.1 mg / mL to 20 mg / mL phenol;

[0654] 2) 0.1 mg / mL-200 mg / mL polypeptides or their pharmaceutically acceptable salts;

[0655] 0.5mM-40mM phosphate buffer or Tris buffer, for example, phosphate buffer;

[0656] Divalent zinc ions, such as zinc acetate;

[0657] 0.5 mg / mL - 70 mg / mL mannitol or glycerol;

[0658] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:4-4:1.

[0659] Furthermore, the pH of the pharmaceutical composition is 6.5-8.5;

[0660] Optionally, the composition further comprises 0.5 mg / mL to 15 mg / mL phenol;

[0661] 3) 1 mg / mL-100 mg / mL polypeptides or their pharmaceutically acceptable salts;

[0662] 1mM-20mM phosphate buffer or Tris buffer, for example, phosphate buffer;

[0663] Divalent zinc ions, such as zinc acetate;

[0664] 1 mg / mL - 60 mg / mL mannitol or glycerol;

[0665] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:3-3:1;

[0666] Furthermore, the pH of the pharmaceutical composition is 7-8;

[0667] Optionally, the composition further comprises 1 mg / mL to 12 mg / mL phenol;

[0668] 4) 1 mg / mL-50 mg / mL polypeptides or their pharmaceutically acceptable salts;

[0669] 1mM-15mM phosphate buffer or Tris buffer, for example, phosphate buffer;

[0670] Divalent zinc ions, such as zinc acetate;

[0671] 1 mg / mL - 50 mg / mL mannitol or glycerol;

[0672] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1;

[0673] Furthermore, the pH of the pharmaceutical composition is 7-7.8;

[0674] Optionally, the composition further comprises 1 mg / mL to 10 mg / mL phenol.

[0675] 5) is a pharmaceutical composition of any one of groups 1-4), wherein the buffer is disodium hydrogen phosphate;

[0676] 6) A pharmaceutical composition of any group of 1-5) further comprising a pH adjuster, such as sodium hydroxide and / or hydrochloric acid.

[0677] In some embodiments, this disclosure provides a pharmaceutical composition comprising any of the foregoing polypeptides or their pharmaceutically acceptable salts (e.g., the structure shown in the amino acid sequence of SEQ ID NO: 113 or the structure shown in compound 17), comprising any group of the following 1)-7):

[0678] 1) 0.1 mg / mL - 500 mg / mL polypeptides or their pharmaceutically acceptable salts;

[0679] 0.1mM-50mM phosphate buffer, for example, a phosphate buffer;

[0680] Divalent zinc ions, such as zinc acetate;

[0681] 1 mg / mL - 70 mg / mL mannitol;

[0682] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:5-5:1.

[0683] Furthermore, the pH of the pharmaceutical composition is 6-9;

[0684] Optionally, the composition further comprises 0.1 mg / mL to 20 mg / mL phenol;

[0685] 2) 0.1 mg / mL-200 mg / mL polypeptides or their pharmaceutically acceptable salts;

[0686] 0.5mM-40mM phosphate buffer, for example, a phosphate buffer;

[0687] Divalent zinc ions, such as zinc acetate;

[0688] 10 mg / mL - 60 mg / mL mannitol;

[0689] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:4-4:1.

[0690] Furthermore, the pH of the pharmaceutical composition is 6.5-8.5;

[0691] Optionally, the composition further comprises 0.5 mg / mL to 15 mg / mL phenol;

[0692] 3) 1 mg / mL-100 mg / mL polypeptides or their pharmaceutically acceptable salts;

[0693] 1mM-20mM phosphate buffer, for example, phosphate buffer;

[0694] Divalent zinc ions, such as zinc acetate;

[0695] 30 mg / mL - 55 mg / mL mannitol;

[0696] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:3-3:1;

[0697] Furthermore, the pH of the pharmaceutical composition is 7-8;

[0698] Optionally, the composition further comprises 1 mg / mL to 12 mg / mL phenol;

[0699] 4) 1 mg / mL-50 mg / mL polypeptides or their pharmaceutically acceptable salts;

[0700] 1mM-15mM phosphate buffer, for example, phosphate buffer;

[0701] Divalent zinc ions, such as zinc acetate;

[0702] 35 mg / mL - 50 mg / mL mannitol;

[0703] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1;

[0704] Furthermore, the pH of the pharmaceutical composition is 7-7.8;

[0705] Optionally, the composition further comprises 1 mg / mL to 10 mg / mL phenol;

[0706] 5) is a pharmaceutical composition of any one of groups 1-4), wherein the buffer is disodium hydrogen phosphate;

[0707] 6) is a pharmaceutical composition of any one of groups 1-5), wherein the buffer zinc acetate is zinc acetate dihydrate;

[0708] 7) A pharmaceutical composition of any group of 1-6) further comprising a pH adjuster, such as sodium hydroxide and / or hydrochloric acid.

[0709] In some embodiments, this disclosure provides a pharmaceutical composition comprising any of the foregoing polypeptides or their pharmaceutically acceptable salts (e.g., the structure shown in the amino acid sequence of SEQ ID NO: 113 or the structure shown in compound 17), comprising any group of the following 1)-6):

[0710] 1) 1 mg / mL-50 mg / mL of polypeptide or pharmaceutically acceptable salt thereof, for example, about 1 mg / mL, about 2 mg / mL, about 4 mg / mL, about 6 mg / mL, about 8 mg / mL, about 10 mg / mL or about 12 mg / mL;

[0711] Approximately 10 mM phosphate buffer;

[0712] Zinc acetate;

[0713] Mannitol, for example, 36 mg / mL-49 mg / mL mannitol;

[0714] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1;

[0715] The pH of the pharmaceutical composition is 7-7.8, for example, about 7.4;

[0716] Optionally, the composition further comprises about 5.5 mg / mL or about 5.7 mg / mL of phenol;

[0717] 2) 1 mg / mL to 50 mg / mL of polypeptide or its pharmaceutically acceptable salt, for example, about 1 mg / mL, about 2 mg / mL, about 4 mg / mL, about 6 mg / mL, about 8 mg / mL, about 10 mg / mL or about 12 mg / mL;

[0718] Approximately 10 mM phosphate buffer;

[0719] Zinc acetate;

[0720] Glycerin, for example, at approximately 20 mg / mL;

[0721] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1;

[0722] The pH of the pharmaceutical composition is 7-7.8, for example, about 7.4;

[0723] Optionally, the composition further comprises about 5.5 mg / mL or about 5.7 mg / mL of phenol;

[0724] 3) is a drug composition of any one of groups 1-2), wherein the buffer is disodium hydrogen phosphate;

[0725] 4) A pharmaceutical composition of any group from 1 to 3) further comprising a pH adjuster, such as sodium hydroxide and / or hydrochloric acid;

[0726] 5) is a pharmaceutical composition of any one of groups 1-4), wherein the zinc acetate is zinc acetate dihydrate;

[0727] 6) is a drug composition of any one of groups 1-5), wherein the concentration of phenol is approximately 5.7 mg / mL;

[0728] In some embodiments, this disclosure provides a pharmaceutical composition comprising any of the aforementioned polypeptides or pharmaceutically acceptable salts thereof (e.g., the structure shown in the amino acid sequence of SEQ ID NO: 113 or the structure shown in compound 17), comprising any group of the following 1)-9):

[0729] 1) Approximately 14 mg / mL, approximately 15 mg / mL, approximately 16 mg / mL, approximately 18 mg / mL, or approximately 20 mg / mL of polypeptides or their pharmaceutically acceptable salts;

[0730] Approximately 10 mM phosphate buffer;

[0731] Zinc acetate;

[0732] Mannitol, for example, 36 mg / mL-49 mg / mL mannitol;

[0733] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1;

[0734] The pH of the pharmaceutical composition is 7-7.8, for example, about 7.4;

[0735] Optionally, the composition further comprises about 5.5 mg / mL or about 5.7 mg / mL of phenol;

[0736] 2) Approximately 14 mg / mL, approximately 15 mg / mL, approximately 16 mg / mL, approximately 18 mg / mL, or approximately 20 mg / mL of polypeptides or their pharmaceutically acceptable salts;

[0737] Approximately 10 mM phosphate buffer;

[0738] Zinc acetate;

[0739] Glycerin, for example, at approximately 20 mg / mL;

[0740] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1;

[0741] The pH of the pharmaceutical composition is 7-7.8, for example, about 7.4;

[0742] Optionally, the composition further comprises about 5.5 mg / mL or about 5.7 mg / mL of phenol;

[0743] 3) Approximately 10 mg / mL or approximately 20 mg / mL of polypeptide or its pharmaceutically acceptable salt;

[0744] Approximately 10 mM phosphate buffer;

[0745] Zinc acetate;

[0746] Approximately 36 mg / mL mannitol;

[0747] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is approximately 1:1.

[0748] The pH of the pharmaceutical composition is approximately 7.4;

[0749] Optionally, the composition further comprises about 5.7 mg / mL phenol;

[0750] 4) Approximately 10 mg / mL of polypeptide or its pharmaceutically acceptable salt;

[0751] Approximately 10 mM phosphate buffer;

[0752] Approximately 0.45 mg / ml of zinc acetate;

[0753] Approximately 36 mg / mL mannitol;

[0754] The pH of the pharmaceutical composition is approximately 7.4;

[0755] Optionally, the composition further comprises about 5.7 mg / mL phenol;

[0756] 5) Approximately 20 mg / mL of polypeptide or its pharmaceutically acceptable salt;

[0757] Approximately 10 mM phosphate buffer;

[0758] Approximately 0.9 mg / ml of zinc acetate;

[0759] Approximately 36 mg / mL mannitol;

[0760] The pH of the pharmaceutical composition is approximately 7.4;

[0761] Optionally, the composition further comprises about 5.7 mg / mL phenol;

[0762] 6) is a pharmaceutical composition from any one of groups 1-5), wherein the concentration of phenol is approximately 5.7 mg / mL;

[0763] 7) is a pharmaceutical composition of any one of groups 1-6), wherein the buffer is disodium hydrogen phosphate;

[0764] 8) A pharmaceutical composition of any group from 1 to 7) further comprising a pH adjuster, such as selected from sodium hydroxide and / or hydrochloric acid;

[0765] 9) is a pharmaceutical composition of any one of groups 1-8), wherein the zinc acetate is zinc acetate dihydrate.

[0766] In some implementations, the pharmaceutical formulation comprises:

[0767] Approximately 0.05 w / v% to approximately 2 w / v% of a polypeptide or its pharmaceutically acceptable salt;

[0768] Approximately 0.1 w / v% or approximately 0.2 w / v% of buffer;

[0769] Approximately 0.03 w / v% to approximately 0.1 w / v% of excipients containing divalent metal ions.

[0770] In some implementations, the pharmaceutical formulation further comprises:

[0771] Antimicrobial agents of approximately 0.4 w / v% to approximately 0.6 w / v%; and

[0772] Osmotic pressure regulator: approximately 3 w / v% to approximately 5 w / v%.

[0773] In some implementations, the pharmaceutical formulation comprises:

[0774] Approximately 0.05 w / v% to approximately 2 w / v% of a polypeptide or its pharmaceutically acceptable salt;

[0775] Approximately 0.1 w / v% or approximately 0.2 w / v% of buffer;

[0776] Approximately 0.03 w / v% to approximately 0.1 w / v% of excipients containing divalent metal ions;

[0777] Antimicrobial agents of approximately 0.4 w / v% to approximately 0.6 w / v%; and

[0778] Osmotic pressure regulator: approximately 3 w / v% to approximately 5 w / v%.

[0779] In some implementations, the pharmaceutical formulation comprises:

[0780] About 0.05 w / v% to about 0.15 w / v% of peptides or pharmaceutically acceptable salts thereof;

[0781] Approximately 0.1 w / v% to approximately 0.2 w / v% buffer;

[0782] Approximately 0.03 w / v% to approximately 0.05 w / v% of excipients containing divalent metal ions;

[0783] In some implementations, the pharmaceutical formulation further comprises:

[0784] Antimicrobial agents of approximately 0.4 w / v% to approximately 0.6 w / v%;

[0785] Osmotic pressure regulator: approximately 3 w / v% to approximately 5 w / v%.

[0786] In some implementations, the pharmaceutical formulation comprises:

[0787] About 0.05 w / v% to about 0.15 w / v% of peptides or pharmaceutically acceptable salts thereof;

[0788] Approximately 0.1 w / v% to approximately 0.2 w / v% buffer;

[0789] Approximately 0.03 w / v% to approximately 0.05 w / v% of excipients containing divalent metal ions;

[0790] Antimicrobial agents of approximately 0.4 w / v% to approximately 0.6 w / v%;

[0791] Osmotic pressure regulator: approximately 3 w / v% to approximately 5 w / v%.

[0792] In some implementations, the pharmaceutical formulation comprises:

[0793] Approximately 0.8 w / v% to approximately 1.5 w / v% of peptides or pharmaceutically acceptable salts thereof;

[0794] Approximately 0.1 w / v% to approximately 0.2 w / v% buffer;

[0795] Approximately 0.06 w / v% to approximately 0.1 w / v% of excipients containing divalent metal ions;

[0796] In some implementations, the pharmaceutical formulation further comprises:

[0797] Antimicrobial agents of approximately 0.4 w / v% to approximately 0.6 w / v%;

[0798] Osmotic pressure regulator: approximately 3 w / v% to approximately 5 w / v%.

[0799] In some implementations, the pharmaceutical formulation comprises:

[0800] Approximately 0.8 w / v% to approximately 1.5 w / v% of peptides or pharmaceutically acceptable salts thereof;

[0801] Approximately 0.1 w / v% to approximately 0.2 w / v% buffer;

[0802] Approximately 0.06 w / v% to approximately 0.1 w / v% of excipients containing divalent metal ions;

[0803] Antimicrobial agents of approximately 0.4 w / v% to approximately 0.6 w / v%;

[0804] Osmotic pressure regulator: approximately 3 w / v% to approximately 5 w / v%.

[0805] In some implementations, the pharmaceutical formulation comprises:

[0806] About 0.05 w / v% to about 2 w / v% of compound 17 or a pharmaceutically acceptable salt thereof;

[0807] Approximately 0.1 w / v% and approximately 0.2 w / v% of disodium hydrogen phosphate;

[0808] Approximately 0.03 w / v% to approximately 0.1 w / v% zinc acetate dihydrate;

[0809] In some implementations, the pharmaceutical formulation further comprises:

[0810] Phenol: approximately 0.4 w / v% to approximately 0.6 w / v%; and

[0811] Mannitol, approximately 3 w / v% to approximately 5 w / v%.

[0812] In some implementations, the pharmaceutical formulation comprises:

[0813] About 0.05 w / v% to about 2 w / v% of compound 17 or a pharmaceutically acceptable salt thereof;

[0814] Approximately 0.1 w / v% and approximately 0.2 w / v% of disodium hydrogen phosphate;

[0815] Approximately 0.03 w / v% to approximately 0.1 w / v% zinc acetate dihydrate;

[0816] Phenol: approximately 0.4 w / v% to approximately 0.6 w / v%; and

[0817] Mannitol, approximately 3 w / v% to approximately 5 w / v%.

[0818] In some implementations, the pharmaceutical formulation comprises:

[0819] About 0.05 w / v% to about 0.15 w / v% of compound 17 or a pharmaceutically acceptable salt thereof;

[0820] Approximately 0.1 w / v% to approximately 0.2 w / v% of disodium hydrogen phosphate;

[0821] Zinc acetate dihydrate, approximately 0.03 w / v% to approximately 0.05 w / v%.

[0822] In some implementations, the pharmaceutical formulation further comprises:

[0823] Phenol: approximately 0.4 w / v% to approximately 0.6 w / v%.

[0824] Mannitol, approximately 3 w / v% to approximately 5 w / v%.

[0825] In some implementations, the pharmaceutical formulation comprises:

[0826] About 0.05 w / v% to about 0.15 w / v% of compound 17 or a pharmaceutically acceptable salt thereof;

[0827] Approximately 0.1 w / v% to approximately 0.2 w / v% of disodium hydrogen phosphate;

[0828] Approximately 0.03 w / v% to approximately 0.05 w / v% zinc acetate dihydrate;

[0829] Phenol: approximately 0.4 w / v% to approximately 0.6 w / v%.

[0830] Mannitol, approximately 3 w / v% to approximately 5 w / v%.

[0831] In some implementations, the pharmaceutical formulation comprises:

[0832] About 0.8 w / v% to about 1.5 w / v% of compound 17 or its pharmaceutically acceptable salt;

[0833] Approximately 0.1 w / v% to approximately 0.2 w / v% of disodium hydrogen phosphate;

[0834] Zinc acetate dihydrate, approximately 0.06 w / v% to approximately 0.1 w / v%.

[0835] In some implementations, the pharmaceutical formulation further comprises:

[0836] Phenol: approximately 0.4 w / v% to approximately 0.6 w / v%.

[0837] Mannitol, approximately 3 w / v% to approximately 5 w / v%.

[0838] In some implementations, the pharmaceutical formulation comprises:

[0839] About 0.8 w / v% to about 1.5 w / v% of compound 17 or its pharmaceutically acceptable salt;

[0840] Approximately 0.1 w / v% to approximately 0.2 w / v% of disodium hydrogen phosphate;

[0841] Approximately 0.06 w / v% to approximately 0.1 w / v% zinc acetate dihydrate;

[0842] Phenol: approximately 0.4 w / v% to approximately 0.6 w / v%.

[0843] Mannitol, approximately 3 w / v% to approximately 5 w / v%.

[0844] In some embodiments, this disclosure provides a pharmaceutical composition comprising any group of the following 1)-8):

[0845] 1) 1 mg / mL to 50 mg / mL of compound 17 or its pharmaceutically acceptable salt, for example, about 1 mg / mL, about 2 mg / mL, about 4 mg / mL, about 6 mg / mL, about 8 mg / mL, about 10 mg / mL, about 12 mg / mL, about 14 mg / mL, about 16 mg / mL, about 18 mg / mL or about 20 mg / mL;

[0846] Approximately 10 mM phosphate buffer;

[0847] Zinc acetate;

[0848] Mannitol, for example, 36 mg / mL-49 mg / mL mannitol;

[0849] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1;

[0850] The pH of the pharmaceutical composition is 7-7.8, for example, about 7.4;

[0851] Optionally, the composition further comprises about 5.5 mg / mL or about 5.7 mg / mL of phenol;

[0852] 2) 1 mg / mL to 50 mg / mL of compound 17 or its pharmaceutically acceptable salt, for example, about 1 mg / mL, about 2 mg / mL, about 4 mg / mL, about 6 mg / mL, about 8 mg / mL, about 10 mg / mL, about 12 mg / mL, about 14 mg / mL, about 16 mg / mL, about 18 mg / mL or about 20 mg / mL;

[0853] Approximately 10 mM phosphate buffer;

[0854] Zinc acetate;

[0855] Glycerin, for example, at approximately 20 mg / mL;

[0856] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1;

[0857] The pH of the pharmaceutical composition is 7-7.8, for example, about 7.4;

[0858] Optionally, the composition further comprises about 5.5 mg / mL or about 5.7 mg / mL of phenol;

[0859] 3) Approximately 10 mg / mL or approximately 20 mg / mL of compound 17 or its pharmaceutically acceptable salt;

[0860] Approximately 10 mM phosphate buffer;

[0861] Zinc acetate;

[0862] Approximately 36 mg / mL mannitol;

[0863] The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is approximately 1:1.

[0864] The pH of the pharmaceutical composition is approximately 7.4;

[0865] Optionally, the composition further comprises about 5.7 mg / mL phenol;

[0866] 4) Approximately 10 mg / mL of compound 17 or its pharmaceutically acceptable salt;

[0867] Approximately 10 mM phosphate buffer;

[0868] Approximately 0.45 mg / ml of zinc acetate;

[0869] Approximately 36 mg / mL mannitol;

[0870] The pH of the pharmaceutical composition is approximately 7.4;

[0871] Optionally, the composition further comprises about 5.7 mg / mL phenol;

[0872] 5) Approximately 20 mg / mL of compound 17 or its pharmaceutically acceptable salt;

[0873] Approximately 10 mM phosphate buffer;

[0874] Approximately 0.9 mg / ml of zinc acetate;

[0875] Approximately 36 mg / mL mannitol;

[0876] The pH of the pharmaceutical composition is approximately 7.4;

[0877] Optionally, the composition further comprises about 5.7 mg / mL phenol;

[0878] 6) is a pharmaceutical composition from any one of groups 1-5), wherein the concentration of phenol is approximately 5.7 mg / mL;

[0879] 7) is a pharmaceutical composition of any one of groups 1-6), wherein the buffer is disodium hydrogen phosphate;

[0880] 8) A pharmaceutical composition of any group from 1 to 7) further comprising a pH adjuster, such as selected from sodium hydroxide and / or hydrochloric acid;

[0881] 9) is a pharmaceutical composition of any one of groups 1-8), wherein the zinc acetate is zinc acetate dihydrate.

[0882] The pharmaceutical composition disclosed herein is stable and can be stored stably for a long period of time.

[0883] In some embodiments, a pharmaceutical preparation is considered "stable" or exhibits "stability" when no visible precipitate forms after being stored under environmental or accelerated conditions for a period of time (e.g., 1 to 30 days). In some embodiments, the provided pharmaceutical preparation remains stable under accelerated conditions (e.g., placed at 40°C for 10 or 30 days).

[0884] In some embodiments, zinc ions in the pharmaceutical composition of this disclosure reduce or inhibit the generation of hydrolytic impurities in polypeptide compounds, for example, by reducing or inhibiting the generation of hydrolytic impurities in polypeptide compounds under high-temperature conditions.

[0885] In some embodiments, the phosphate buffer or Tris buffer in the pharmaceutical composition of this disclosure reduces or inhibits the generation of hydrolytic impurities of peptide compounds, for example, by reducing or inhibiting the generation of hydrolytic impurities and polymers of peptide compounds under high temperature conditions.

[0886] In some embodiments, the phosphate buffer in the pharmaceutical composition of this disclosure reduces or inhibits the generation of hydrolytic impurities and polymers in the polypeptide compound, for example, by reducing or inhibiting the generation of hydrolytic impurities and polymers in the polypeptide compound under high temperature conditions.

[0887] In some embodiments, the hydrolytic impurities of the polypeptide compound are hydrolytic impurities generated by the N-terminal His-Aib cleavage of the polypeptide compound.

[0888] In some embodiments, the hydrolytic impurity of the polypeptide compound is an impurity with a relative retention time of 1.09. In some embodiments, the impurity with a relative retention time of 1.09 is compound 17 with an N-terminal His-Aib cleavage, namely Des-[His1-Aib2]- compound 17.

[0889] In some embodiments, the pharmaceutical composition described herein, when placed under high temperature conditions for 10 days, has a hydrolysis impurity content of no more than 2%, for example, no more than 3%, for example, no more than 2%, for example, no more than 1%, for example, no more than 0.6%.

[0890] In some embodiments, the pharmaceutical composition of this disclosure, when placed under high temperature conditions for 10 days, has a content of hydrolytic impurities generated by the N-terminal His-Aib cleavage not exceeding 5%, for example not exceeding 3%, for example not exceeding 2%, for example not exceeding 1%, for example not exceeding 0.6%.

[0891] In some embodiments, the pharmaceutical composition of this disclosure, after being placed at high temperature for 10 days, has an impurity content of no more than 5%, for example no more than 3%, for example no more than 2%, for example no more than 1%, for example no more than 0.6%, and for example the impurity with a relative retention time of 1.09 is compound 17 with an N-terminal His-Aib cleavage, namely Des-[His1-Aib2]- compound 17.

[0892] In some embodiments, the high temperature conditions described in this disclosure are 25°C, 30°C, or 40°C; preferably, the high temperature conditions are 30°C or 40°C.

[0893] This disclosure provides a method for preparing the aforementioned pharmaceutical composition, comprising the step of dissolving the aforementioned polypeptide or its pharmaceutically acceptable salt.

[0894] In some embodiments, this disclosure provides a method for preparing the aforementioned pharmaceutical composition, comprising the following steps:

[0895] a) Dissolve the buffer, osmotic pressure regulator, and antibacterial agent in water;

[0896] b) Add the aforementioned polypeptide or its pharmaceutically acceptable salt to the solution obtained in step a);

[0897] c) Then add the metal ion solution.

[0898] In some embodiments, the preparation method further includes filtration and / or filling steps.

[0899] In some implementations, the water in step a) is water for injection.

[0900] To facilitate drug transportation, the drug composition disclosed herein can be further formulated into a lyophilized preparation.

[0901] This disclosure also provides a lyophilized formulation, characterized in that the lyophilized formulation, after reconstitution, can form a pharmaceutical composition as described in any of the preceding claims.

[0902] This disclosure also provides a lyophilized formulation obtained by freeze-drying a pharmaceutical composition as described in any of the preceding claims.

[0903] This disclosure provides a reconstituted solution prepared by reconstituted the aforementioned lyophilized formulation. In some embodiments, the reconstituted solution is selected from, but not limited to, water for injection, physiological saline, or glucose solution.

[0904] This disclosure also provides an article of manufacture comprising a container containing a pharmaceutical composition as described above, a lyophilized formulation as described above, or a reconstituted solution as described above. In some embodiments, the container is a neutral borosilicate glass vial for injection. In some embodiments, the article of manufacture includes a pharmaceutical instruction leaflet.

[0905] Suitable packaging for the compositions according to this disclosure is, for example, a syringe or glass tube with a suitable locking mechanism from which an individual therapeutically effective dose can be drawn when needed. Also suitable are injection pens for administering the dose; such pens include a container (e.g., a tube) containing the pharmaceutical composition according to this disclosure.

[0906] This disclosure also provides pharmaceutical compositions or lyophilized formulations or reconstituted solutions of lyophilized formulations for the treatment or relief of diseases or conditions.

[0907] In some embodiments, this disclosure provides pharmaceutically acceptable salts or solvates of any of the aforementioned compounds. In some embodiments, the compounds of any structure in this disclosure are amphoteric compounds, which can be reacted with by those skilled in the art using known techniques to form salts with acidic or basic compounds, or to form solvates using techniques known in the art. For example, a solvate is a stoichiometric complex formed between a compound, a pharmaceutically acceptable salt, and a solvent (including, but not limited to, water).

[0908] Medical uses and treatment methods

[0909] This disclosure provides the pharmaceutical use of the aforementioned pharmaceutical composition or lyophilized preparation or reconstituted solution of lyophilized preparation in the preparation of a medicament for the prevention, treatment or relief of the aforementioned diseases or symptoms.

[0910] In some embodiments, this disclosure provides the use of the aforementioned pharmaceutical composition or lyophilized formulation or reconstituted solution of lyophilized formulation in the preparation of a medicament for the prevention and / or treatment of metabolic disorder-related diseases or conditions.

[0911] In some implementations, the metabolic disorder-related diseases or conditions include diabetes, diabetes-related conditions, obesity, obesity-related conditions, weight control, and metabolic dysfunction-associated steatotic liver disease (MASLD).

[0912] In some embodiments, this disclosure provides the use of the aforementioned pharmaceutical compositions, lyophilized formulations, or reconstituted solutions of lyophilized formulations in the preparation of medicaments for the prevention and / or treatment of type 2 diabetes.

[0913] In some embodiments, this disclosure provides the use of the aforementioned pharmaceutical compositions, lyophilized formulations, or reconstituted solutions of lyophilized formulations in the preparation of medicaments for the prevention and / or treatment of obesity.

[0914] In some embodiments, this disclosure provides the use of the aforementioned pharmaceutical compositions, lyophilized formulations, or reconstituted solutions of lyophilized formulations in the preparation of medicaments for the prevention and / or treatment of obesity and type 2 diabetes.

[0915] In some embodiments, this disclosure provides methods for preventing or treating a disease, including administering the aforementioned pharmaceutical composition or lyophilized formulation or a reconstituted solution of a lyophilized formulation to a subject in need.

[0916] In some embodiments, this disclosure also provides a method for preventing and / or treating metabolic disorder-related diseases or conditions, comprising administering the aforementioned pharmaceutical composition or lyophilized formulation or a reconstituted solution of a lyophilized formulation to a subject in need.

[0917] In some implementations, the metabolic disorder-related diseases or conditions include diabetes, diabetes-related conditions, obesity, obesity-related conditions, weight control, and fatty liver disease associated with metabolic dysfunction.

[0918] In addition to being non-limiting, this disclosure also provides another exemplary implementation:

[0919] Implementation Scheme 1: A method for treating overweight or obesity, comprising administering any of the above-described pharmaceutical compositions to a subject in need.

[0920] Implementation Scheme 2: A method for treating overweight or obesity, comprising administering to a subject in need a pharmaceutical composition comprising any of the above-described compounds 17 or a pharmaceutically acceptable salt thereof:

[0921] Implementation Scheme 3: A method for reducing the weight of a subject, comprising administering any of the above-described pharmaceutical compositions to a subject in need.

[0922] Implementation Scheme 4: A method for reducing the weight of a subject, comprising administering to a subject in need a pharmaceutical composition comprising any of the above-described compounds 17 or a pharmaceutically acceptable salt thereof:

[0923] Implementation Scheme 5: A method for reducing excess weight in a subject, comprising administering any of the above-described pharmaceutical compositions to a subject in need.

[0924] Implementation Scheme 6: A method for reducing excess weight in a subject, comprising administering to a subject in need a pharmaceutical composition comprising any of the above-described compounds 17 or a pharmaceutically acceptable salt thereof:

[0925] Implementation Scheme 7: A method for reducing the BMI of a subject, comprising administering any of the above-described pharmaceutical compositions to a subject in need.

[0926] Implementation Scheme 8: A method for reducing the BMI of a subject, comprising administering to a subject in need a pharmaceutical composition comprising any of the above-described compounds 17 or a pharmaceutically acceptable salt thereof:

[0927] Implementation Scheme 9: A method for reducing waist circumference in a subject, comprising administering any of the above-described pharmaceutical compositions to a subject in need.

[0928] Implementation Scheme 10: A method for reducing waist circumference in a subject, comprising administering to a subject in need a pharmaceutical composition comprising any of the above-described compounds 17 or a pharmaceutically acceptable salt thereof:

[0929] Implementation Scheme 11: The method according to any one of Implementation Schemes 1-10, wherein the subject is obese.

[0930] Implementation Scheme 12: The method according to any one of Implementation Schemes 1-11, wherein the subject is overweight.

[0931] Implementation Scheme 13: The method according to any one of Implementation Schemes 1-10, wherein the subject suffers from at least one weight-related complication.

[0932] Implementation Scheme 14: The method according to Implementation Scheme 13, wherein the weight-related complications are selected from prediabetes, dyslipidemia, and fatty liver disease associated with metabolic dysfunction.

[0933] Implementation Scheme 15: The method according to any one of Implementation Schemes 1-14, wherein the subject has diabetes.

[0934] Implementation Scheme 16: The method according to any one of Implementation Schemes 1-15, wherein the subject has type 2 diabetes.

[0935] Implementation Scheme 17: The method according to any one of Implementation Schemes 1-16, wherein the subject does not have diabetes.

[0936] Implementation Scheme 18: A method of treating type 2 diabetes, comprising administering any of the above-described pharmaceutical compositions to a subject in need.

[0937] Implementation Scheme 19: A method of treating type 2 diabetes, comprising administering to a subject in need a pharmaceutical composition comprising any of the above-described compounds 17 or a pharmaceutically acceptable salt thereof:

[0938] Implementation Scheme 20: A method for improving glycemic control, comprising administering any of the above-described pharmaceutical compositions to a subject in need.

[0939] Implementation Scheme 21: A method for improving glycemic control, comprising administering to a subject in need a pharmaceutical composition comprising any of the above-described compounds 17 or a pharmaceutically acceptable salt thereof:

[0940] Implementation Scheme 22: A method for reducing HbA1c, comprising administering any of the above-described pharmaceutical compositions to a subject in need.

[0941] Implementation Scheme 23: A method for lowering HbA1c, comprising administering to a subject in need a pharmaceutical composition comprising any of the above-described compounds 17 or a pharmaceutically acceptable salt thereof:

[0942] Implementation Scheme 24: The method according to any one of Implementation Schemes 18-23, wherein the subject has diabetes.

[0943] Implementation Scheme 25: The method according to Implementation Scheme 24, wherein the subject has type 2 diabetes.

[0944] Implementation Scheme 26: The method according to any one of Implementation Schemes 18-25, wherein the method further comprises a dietary therapy (such as a calorie diet).

[0945] Implementation Scheme 27: The method according to any one of Implementation Schemes 18-26, wherein the method further comprises exercise therapy (e.g., increasing physical activity). Attached Figure Description

[0946] Figure 1 shows the changes in body weight (g) over time in diet-induced obese (DIO) rats after subcutaneous injection of the compound.

[0947] Figure 2 shows the weight change (%) at different time points (days) in diet-induced obese (DIO) rats after subcutaneous injection of the compound.

[0948] Figure 3 shows a graph illustrating the change in daily food intake over time in diet-induced obese (DIO) rats after subcutaneous injection of the compound.

[0949] Figure 4 shows a graph illustrating the cumulative food intake over time in diet-induced obese (DIO) rats after subcutaneous injection of the compound.

[0950] Detailed description of the invention

[0951] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0952] In the context of this disclosure, Greek letters may be represented by their symbols or corresponding written names, for example: α = alpha; β = beta; ε = epsilon; γ = gamma; ω = omega; etc.

[0953] This document uses the term "compound" to refer to a molecular entity; therefore, a "compound" may have different structural elements in addition to having the minimum elements defined for each compound or group of compounds. Thus, a compound may be a peptide or a derivative thereof, provided that the compound contains the defined structural and / or functional elements.

[0954] The term "polypeptide" refers to a sequence of two or more amino acids. A "polypeptide" can also include amino acid elongations at the N-terminus and / or C-terminus, and / or truncations at the N-terminus and / or C-terminus. Typically, amino acid residues are represented by their full name, their one-letter code, and / or their three-letter code. These three methods are completely equivalent.

[0955] In the context of this disclosure, the terms "peptide," "compound," and "peptide compound" are used interchangeably.

[0956] Amino acids are molecules that contain amino and carboxylic acid groups and optionally one or more additional groups, often referred to as side chains.

[0957] The term "amino acid" includes proteinogenic (or naturally occurring) amino acids (of which 20 are standard amino acids) and non-proteinogenic (or non-natural) amino acids. Proteinogenic amino acids are those naturally incorporated into proteins. Standard amino acids are those encoded by the genetic code. Non-proteinogenic amino acids either do not exist in proteins or are not produced through standard cellular mechanisms (e.g., they may have undergone post-translational modifications). Non-limiting examples of non-proteinogenic amino acids are Aib (α-aminoisobutyric acid or 2-aminoisobutyric acid), leucine (Nle), valine, and the D-isomers of proteinogenic amino acids. D-Ala is D-alanine, -αL- is alpha-methylated leucine, αS is alpha-methylated serine, αK is alpha-methylated lysine, etc.

[0958] "Natural amino acids" refers to 20 common amino acids (i.e., 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).

[0959] "Non-natural amino acids" refer to amino acids that are not naturally encoded or found in the genetic code of any organism. They can be, for example, purely synthetic compounds. Examples of non-natural amino acids include, but are not limited to, hydroxyproline, γ-carboxyglutamic acid, O-phosphoserine, azacyclobutanecarboxylic acid, 2-aminohexanoic acid, 3-aminohexanoic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic 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- Ethyl asparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, n-valine, n-leucine, ornithine, D-ornithine, D-arginine, p-aminophenylalanine, pentylglycine, pipecolic acid, and thioproline. Additionally, it includes natural or non-natural amino acids whose C-terminal carboxyl group, N-terminal amino group, and / or their side chain functional groups are chemically modified.

[0960] The term “agonist” is defined as a substance that activates the type of receptor in question. For example, in the context of this disclosure, the term GLP-1 / GIP / GCG triagonal agonist refers to a substance or ligand that can simultaneously activate the GLP-1 receptor, the GIP receptor, and the GCG receptor.

[0961] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 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, 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 their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0962] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0963] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0964] In this disclosure, when the N-terminus of an amino acid structure is represented by "HH-...", unless otherwise specified, the first "H" refers to hydrogen, and the second "H" refers to a histidine (His) residue. That is, the sequence "HH..." indicates a structure where the N-terminus is a hydrogen atom linked to a histidine residue. For example, the following structural formulas represent the same polypeptide:

[0965] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0966] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0967] "Giving," "applying," and "treatment," when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid, such as in therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cell. "Giving," "applying," and "treatment" also mean treatment, such as of cells, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo. When applied to humans, veterinary, or research subjects, it refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0968] "Treatment" means administering an oral or topical therapeutic agent, such as a pharmaceutical composition comprising any of the binding proteins of this disclosure or thereof, to a subject who has, is suspected of having, or is predisposed to having one or more metabolic-related diseases or their symptoms, and for whom the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in a treated subject or population in an amount that effectively relieves symptoms of one or more diseases, whether by inducing the regression of such symptoms or inhibiting their progression to any clinically measurable degree. The amount of therapeutic agent that effectively relieves any specific disease symptom (also referred to as the "therapeuticly effective amount") can vary depending on a variety of factors, such as the subject's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the subject. Whether the disease symptoms have been relieved can be evaluated using any clinical test that a physician or other healthcare professional typically uses to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating the symptoms of the target disease in a particular subject, they should reduce the symptoms of the target disease in a statistically significant number of subjects, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test.

[0969] "Effective amount" includes an amount sufficient to improve or prevent the symptoms or condition of a medical condition. Effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount used on a subject may vary depending on factors such as the condition to be treated, the subject's overall health, the route and dosage of administration, and the severity of side effects. Effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Subjects in this disclosure may be animal or human subjects.

[0970] "Optional" or "optionally" means that the event or circumstance described below may, but does not necessarily, occur, and the description includes the possibility that the event or circumstance may or may not occur. "And / or" should be interpreted as specifically disclosing that each of the two specified features or components has or does not have the other. Therefore, the term "and / or" as used in phrases such as "A and / or B" in this disclosure includes "A and B," "A or B," "A" (alone), and "B" (alone). Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc., should be understood to have an inclusive meaning rather than an exclusive or exhaustive meaning; that is, the meaning of "including but not limited to."

[0971] The “subject” or “patient” in this disclosure can be a mammal, including humans or non-human mammals such as non-human primates (e.g., apes, Old World monkeys, or New World monkeys), livestock (e.g., cattle or pigs), companion animals (e.g., dogs or cats), or laboratory animals such as rodents (e.g., mice or rats).

[0972] "Buffer" refers to a buffer that is resistant to pH changes through the action of its acid-base conjugate components. Examples of buffers that maintain pH within an appropriate range include acetates, succinates, citrates, phosphates, gluconates, histidines, oxalates, lactates, phosphates, citrates, tartrates, fumarates, glycylglycine, and other organic acid buffers.

[0973] "Histidine buffers" are buffers containing histidine ions. Examples of histidine buffers include histidine-hydrochloride, histidine-acetate, histidine-phosphate, and histidine-sulfate buffers, such as histidine-acetate buffers or histidine-hydrochloride buffers. Histidine-acetate buffers are prepared by reacting histidine with acetic acid, while histidine buffers are prepared by reacting histidine with hydrochloric acid.

[0974] A "phosphate buffer" is a buffer that contains phosphate ions. Examples of phosphate buffers include disodium hydrogen phosphate-sodium dihydrogen phosphate, disodium hydrogen phosphate-potassium dihydrogen phosphate, and disodium hydrogen phosphate-citric acid. A phosphate buffer can be disodium hydrogen phosphate-sodium dihydrogen phosphate.

[0975] The terms “about” and “approximately” mean that a numerical value is within the acceptable error range of a specific value as determined by a person skilled in the art, the numerical value depending in part on how it is measured or determined (i.e., the limits of the measurement system). For example, “about” may mean within or above 1 standard deviation. Alternatively, “about” or “substantially includes” may mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, or between 0.5% and 1%. In this disclosure, each instance of a number or range of values ​​preceded by the term “about” also includes embodiments of a given number. Unless otherwise stated, when a specific value appears in this application and claims, the meaning of “about” or “substantially includes” should be assumed to be within the acceptable error range of that specific value.

[0976] "Pharmaceutical composition" refers to a mixture containing one or more antibodies described herein, along with other chemical components, such as physiological / pharmaceutical-grade carriers and excipients. The purpose of a pharmaceutical composition is to maintain the stability of the active ingredient, facilitate administration to the organism, and enhance the absorption of the active ingredient to exert its biological activity.

[0977] In this disclosure, "pharmaceutical composition" and "formulation" are not mutually exclusive.

[0978] Unless otherwise specified, the solvent in the solution form of the pharmaceutical compositions described in this disclosure is water.

[0979] "Lyophilized formulation" refers to a pharmaceutical composition or formulation obtained by a vacuum freeze-drying step after the liquid or solution form has been processed. Detailed Implementation

[0980] To illustrate the present invention in more detail, the following specific embodiments are provided in this specification, but the embodiments of the present invention are not limited thereto.

[0981] Example

[0982] The preparation and purification methods of the GLP-1 / GIP / GCG receptor triagonal agonist in this application have been described in the patent application document No. WO2025016303, and the entire contents of the aforementioned application document can be incorporated into this disclosure.

[0983] Example 1. Preparation of the target compound

[0984] Experimental reagents

[0985] Table 1

[0986] 2. Experimental apparatus

[0987] Table 2

[0988] 3.1 Chemical synthesis of compound 0125 (compound 17)

[0989] Compound 0125 was chemically synthesized using the fluorenylmethoxycarbonyl (Fmoc) / tert-butyl (t-Bu) synthesis method on a Prelude-X fully automated peptide synthesizer. The resin used was Rink-amide MBHA resin with a substitution degree of 0.54 mmol / g. The amino acid residues used for fatty acid modification were Fmoc-L-Lys(Mtt)-OH, and the N-terminal amino acid was Boc-L-His(Trt)-OH. Before the amino acid condensation step, the Fmoc group was removed using a DMF solution containing 20% ​​4-methylpiperidine (reaction twice, 8 minutes each). All standard amino acid condensations used equimolar ratios of Fmoc amino acids, HATU, and 2 equivalents of 4-methylmorpholine, condensed at room temperature for 25 minutes at a dose exceeding the theoretical peptide loading by 10 equivalents. Exceptions were made for coupling to Cα-methylated amino acids, requiring two or three condensations, each lasting 60 minutes, to ensure complete condensation. After completing the above peptide-resin extension, the resin peptide was washed with dichloromethane and then a hexafluoroisopropanol / dichloromethane mixture (30% hexafluoroisopropanol, 10 mL) was added. The mixture was shaken at room temperature for 45 minutes, then removed. Another hexafluoroisopropanol / dichloromethane mixture (30%, 10 mL) was added, and the mixture was shaken at room temperature for 45 minutes, then removed. After the reaction, the resin was washed three times with DMF. Additional coupling / deprotection cycles to extend the lysine side chain using the Fmoc / tBu solid-phase synthesis strategy on the same peptide synthesizer involved Fmoc-AEEA-OH (twice), Fmoc-L-Glu-OtBu (once), and eicosanoic acid monotert-butyl ester (once). Condensation was performed using equimolar ratios of Fmoc amino acids, HATU, and 2 equivalents of 4-methylmorpholine at room temperature for 25 minutes at 10 equivalents above the theoretical peptide loading. The exception is the coupling of eicosanoic acid monotert-butyl ester, which requires condensation at room temperature for at least 3 hours to ensure complete condensation.

[0990] After synthesis, the obtained resin peptide was washed three times with DMF and DCM, then vacuum dried. 10 mL of freshly prepared lysis buffer (trifluoroacetic acid: triisopropylsilane: water = 90:5:5, v:v:v) was added, and the mixture was shaken at room temperature for 3-4 hours. After the reaction, the mixture was filtered, and the resin was washed twice with trifluoroacetic acid. The filtrates were combined, and a large amount of methyl tert-butyl ether was added to precipitate the crude peptide solid. After centrifugation to remove the supernatant, the crude peptide with compound number 0125 was obtained. The crude peptide was dissolved in a mixed solvent containing 20% ​​acetic acid / water, filtered through a 0.22 μm membrane, and separated using a WATERS Prep150 LC reversed-phase high-performance liquid chromatography system. The mobile phases were A (0.1% trifluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). The chromatographic column used was an X-SELECT OBD C-18 (WATERS) reversed-phase column. During purification, the detection wavelength was set to 220 nm, and the flow rate was 15-20 mL / min. The relevant fractions of the product were collected and lyophilized to obtain the pure peptide, compound number 0125. The purity and compound identity of the pure peptide were determined by analytical ultra-high performance liquid chromatography (UHPLC) and liquid chromatography / mass spectrometry (LC / MS), with a purity of 95.58% and a determined molecular weight of 4868.7.

[0991] Compound 17 (number 0125)

[0992] Example 2. Detection of the agonist activity of the compound on human glucagon-like peptide-1 receptor (GLP-1R), human glucose-dependent insulinotropic peptide receptor (GIPR), and human glucagon receptor (GCGR).

[0993] The purpose of this embodiment is to detect the agonist activity of the test compound in human glucagon-like peptide-1 receptor, human glucose-dependent insulinotropic peptide receptor, and human glucagon receptor.

[0994] 2.1 Experimental Methods:

[0995] Functional activity was assessed in CHO-K1 clonal cell lines expressing GIPR, GLP-1R, and GCGR. The peptides were diluted 10-fold (8–10 spots) in DMEM / F12 1:1 (HyClone, SH30023.01) supplemented with 5% FBS (fetal bovine serum, Gibco, 10099141), 0.1% Casein (Sigma, C4765), and 0.25 mM IBMX (Selleck, S5836) in 10 μL assay volume. Recipient cells (5000 cells / well) were added to SV 96-well plates (Cisbio, 66PL96025) and incubated with the prepared peptides at 37°C for 30 minutes. The increase in intracellular cAMP was quantified using a cAMP-GS dynamic HTRF assay kit (Cisbio, 62AM4PEJ). In short, intracellular cAMP levels were detected by adding a cAMP-d2 conjugate to cell lysis buffer, followed by the addition of an antibody-anti-cAMP-Eu cavitation compound (also in cell lysis buffer). The resulting competitive assay was incubated at room temperature for at least 60 minutes and then detected using a Tecan Infinite F Plex instrument with excitation at 320 nm and emission at 665 nm and 620 nm. The measured data (emission at 665 nm / 620 nm * 10000) were inversely proportional to the amount of cAMP present and converted to the cAMP content per well using a cAMP standard curve.

[0996] The amount of cAMP generated in each well was converted into the percentage of the maximum response observed with human GLP-1 (7-36)-NH2, human GCG (1-29), or human GIP (1-42)-NH2 (purchased from Sigma). The percentage of maximum response versus the added peptide concentration was used to derive the relative EC using nonlinear regression analysis. 50 The values ​​are fitted to a four-parameter logarithmic equation. Specific data are shown in Table 3 below. For the LY3437943 molecule, see Example 12 of WO2019 / 125938. The aforementioned patent is incorporated herein by reference in its entirety.

[0997] Table 3

[0998] The results above show that the polypeptide molecules provided in this disclosure have good agonistic activity against GLP-1R, GIPR and GCGR.

[0999] Example 3. Evaluation of the in vivo efficacy of the compound in a diet-induced obesity (DIO) rat model.

[1000] 3.1. Experimental Objective

[1001] This experiment used a DIO rat model established by a 45% high-fat diet (HFD) to evaluate the effects of compounds on obesity-related indicators in DIO rats.

[1002] 3.2 Experimental Methods

[1003] After one week of acclimatization, all rats were randomly divided into two groups: a normal group and a model group. The rats in the model group were then fed 45% HFD (Medison: MD12032), while the rats in the normal group were fed normal food. The rats' body weight was measured weekly to monitor the modeling process.

[1004] DIO rats fed a high-fat diet for 37 weeks were weighed, and 75 DIO rats (approximately 1100g) and 8 rats on a normal diet (approximately 800g) were selected and housed individually. Each cage was given approximately 100g of feed, which was changed every 48 hours. A preliminary sham dose experiment was then conducted. Subcutaneous injections were made in the neck at 4 PM daily for 9 days. Before each injection, the rats' weight was measured, and the effect of the sham dose on their weight was observed. A curve showing the change in weight over time was plotted. Once the weight stabilized, the formal drug administration experiment began.

[1005] Six Chow diet rats (approximately 800g in weight) and 30 HFD rats (approximately 1100g in weight) were selected through a preliminary sham dose experiment for subsequent drug administration experiments. The six Chow diet rats served as the control group (Naive group), while the remaining HFD rats were randomly divided into six groups based on body weight: Model group, LY3437943 group, 0120 low-dose group, 0120 high-dose group, 0125 low-dose group, and 0125 high-dose group, with five rats in each group. All rats were housed individually throughout the experiment. The compound was dissolved in PBS solution at pH 7.4. On the first day of grouping (Day 1), rats in each group were administered the drug via subcutaneous injection in the neck, once daily (QD), as detailed in Table 4. Starting on day 15 (D15), the dosage of the LY3437943 group was adjusted from 1 nmol / kg to 10 nmol / kg, and the dosage of the 0120 low-dose group and the 0125 low-dose group was adjusted from 0.3 nmol / kg to 3 nmol / kg. Body weight was measured daily at 15:00 or before administration, and a graph showing the change in body weight over time was plotted. Food intake: Days 1-7, measured daily at 15:00 or before administration; Days 8-40, measured every three days at 15:00 or before administration. A graph showing the change in daily food intake / cumulative food intake over time was plotted.

[1006] Table 4. Experimental Group Dosing Information Table

[1007] 3.3 Test Results

[1008] The rat body weight results are shown in Figures 1 and 2. Before adjusting the dosage, the body weight of rats in the model group (Naive group) was significantly increased compared with the control group (Naive group). Compared with the model group (Naive group), the body weight of rats in the compound 16 (1 nmol / kg) group and the compound 17 (1 nmol / kg) group showed a decreasing trend. After adjusting the dosage of LY3437943 from 1 nmol / kg to 10 nmol / kg, the dosage of compound 16 from 0.3 nmol / kg to 3 nmol / kg, and the dosage of compound 17 from 0.3 nmol / kg to 3 nmol / kg, the body weight of rats in each group began to decrease rapidly. Specifically, the weight loss at the end of the experiment was 29.4% in the LY3437943 (10 nmol / kg) group, 30.2% in the compound 16 (3 nmol / kg) group, and 33.2% in the compound 17 (3 nmol / kg) group. Compound 16 is another polypeptide provided in this application.

[1009] As shown in Figures 3 and 4, before dose adjustment, the 24-hour food intake and cumulative food intake of each treatment group were basically equivalent to those of the model group. After dose adjustment, compared with the model group, the 24-hour food intake and cumulative food intake of rats in the LY3437943 (10 nmol / kg), compound 16 (3 nmol / kg), and compound 17 (3 nmol / kg) groups were significantly reduced. Furthermore, the 24-hour food intake gradually decreased with the extension of the administration time. Throughout the entire administration period (before and after dose adjustment), the cumulative food intake of each treatment group was as follows: LY3437943 (10 nmol / kg) group: 273.8 ± 15.0 g, with a body weight reduction of 29.4%; Compound 16 (3 nmol / kg) group: 258.8 ± 23.5 g, with a body weight reduction of 30.2%; Compound 17 (3 nmol / kg) group: 224.5 ± 25.8 g, with a body weight reduction of 33.2%. Compound 16 is another polypeptide provided in this application.

[1010] The active ingredient used in the following examples is a GLP-1 / GIP / GCG receptor triagonal agonist, namely the aforementioned compound number 0125 (i.e., compound 17), H-Aib-HGTFTSDYSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2)). 18 -COOH)-KAAQEFVEWLLAGPGPSSGAPPPS-NH2.

[1011] Exemplary pharmaceutical composition preparation process

[1012] The pharmaceutical composition disclosed herein can be prepared according to the following process:

[1013] Preparation of the stock solution: Take an appropriate amount of water for injection, add an appropriate amount of buffer salt solution, weigh out the prescribed amount of antibacterial agent and osmotic pressure regulator, add them to the above solution, and stir until dissolved. Weigh out the prescribed amount of GLP-1 / GIP / GCG receptor tri-agonist, add it to the above solution, stir until dissolved, and add an appropriate amount of water for injection.

[1014] Preparation of the formulation: Take an appropriate amount of mother liquor, add the prescribed amount of metal ion solution as needed, adjust the pH with 1M NaOH solution or 0.5M HCl solution, and add water for injection to make up the volume.

[1015] Filtration and filling: Filter the prescription through a 0.22μm PVDF filter membrane into 2mL vials, 1mL / vial.

[1016] Alternatively, the pharmaceutical composition disclosed herein can be prepared according to the following process:

[1017] Preparation: Take an appropriate amount of water for injection, add the prescribed amounts of buffer, antibacterial agent, and osmotic pressure regulator, and stir until dissolved. Weigh the prescribed amount of GLP-1 / GIP / GCG receptor triagonal agonist and add it to the above solution, stirring until dissolved. Add the prescribed amount of metal ion solution as needed, adjust the pH with NaOH or HCl solution, add water for injection to make up to volume, filter for sterilization, and fill into inner packaging materials.

[1018] Example 4: Investigation of the formulation buffer system

[1019] Different formulations were prepared using four different buffer systems: phosphate buffer, HEPES, Tris, and histidine. The formulation formulations are shown in Table 5. The physical and chemical stability of the formulations at high temperature (40℃) was investigated. Evaluation methods included visual inspection of appearance, HPLC detection of related substances, and SEC determination of polymer content.

[1020] Table 5. Formulation Information Note: Phosphate is disodium hydrogen phosphate; zinc acetate* is zinc acetate dihydrate.

[1021] Table 6. Results of the appearance stability of the formulation

[1022] Table 7. Chemical stability results of the formulation Note: RRT stands for Relative Retention Time.

[1023] The values ​​in parentheses represent the changes relative to the initial value.

[1024] Experimental results: Under high temperature conditions, formulations containing the HEPES buffer system showed abnormal appearance after being stored at high temperature for a certain period of time. Formulations containing histidine, Tris, or phosphate buffer systems did not show any abnormal appearance. In terms of chemical stability, the phosphate buffer system was superior to the Tris system and superior to the histidine system.

[1025] Example 5: pH Study of the Formulation

[1026] Prepare a buffer system containing 12 mg / ml API 0125, 10 mM phosphate buffer (disodium hydrogen phosphate), and 0.5 mg / ml zinc acetate dihydrate (Zn). 2+ A formulation of 36 mg / ml mannitol and 5.5 mg / ml phenol (API = 1:1) was prepared, and formulations P6-P10 with target pH values ​​of 7.0, 7.2, 7.5, 7.8, and 8.0 were prepared respectively. The formulation information is shown in Table 8. High temperature test at 40℃ was conducted (after 10 days and 30 days). The screening was carried out using visible foreign matter, pH, related substances, polymers, and content as indicators.

[1027] Table 8: Physicochemical Indicators Results

[1028] Table 9: Results of Liquid Phase Investigation Note: Content (%) refers to the percentage of the actual detected concentration of the active ingredient relative to the labeled amount. The labeled amount is the target amount specified in the prescription. For P6-P10, the labeled amount is 12 mg / ml.

[1029] Experimental results showed that there were no significant differences in the physicochemical properties of the formulation under different pH conditions during high-temperature storage. Liquid chromatography analysis showed that within the pH range of 7.0-7.8, there were no significant differences in the increase of related substances and polymers in the formulation; however, when the solution pH was 8.0, the related substances and polymers showed a slight increase.

[1030] Example 6: Investigation of Osmotic Pressure Regulators in Formulation

[1031] Three different osmotic pressure regulators—glycerol, mannitol, and sodium chloride—were selected to prepare formulations P11-P14 as shown in Table 10. The formulations underwent high-temperature testing at 40°C (for 10 and 30 days), and were screened based on indicators such as appearance, visible foreign matter, pH, insoluble particles, related substances, polymers, and content.

[1032] Table 10. Formulation Information Note: Phosphate is disodium hydrogen phosphate; zinc acetate* is zinc acetate dihydrate.

[1033] Table 11. Physicochemical Indicators

[1034] Table 12. Results of Liquid Phase Investigation Note: Content (%) refers to the percentage of the actual detected concentration of the active ingredient relative to the labeled amount. The labeled amount is the target amount specified in the prescription. For P11-P14, the labeled amount is 12 mg / ml.

[1035] Experimental results showed that API 0125 could not dissolve in excipient solutions containing sodium chloride. Formulation solutions containing glycerol or mannitol showed no significant difference in stability after being placed under high-temperature conditions, and formulations containing different concentrations of mannitol also showed no significant effect on stability.

[1036] Example 7: Investigation of the antibacterial agent in the formulation

[1037] Formulations were prepared using phenol, m-cresol, and a combination of phenol and m-cresol. Except for the antibacterial agent, all other components of each composition were identical, consisting of a 10 mM phosphate buffer system (disodium hydrogen phosphate), mannitol, and zinc acetate (Zn). 2+ (API = 1:1), the formulation information is shown in Table 13. All samples prepared in Table 13 were subjected to a high temperature test at 40℃ (stored for 10 days and 30 days). The screening was conducted using visible foreign matter, pH, related substances, polymers, and content as indicators.

[1038] Table 13. Formulation Information Note: Zinc acetate* refers to zinc acetate dihydrate.

[1039] Table 14. Results of Physicochemical Indicators

[1040] Table 15. Results of Liquid Phase Investigation Note: Content (%) refers to the percentage of the actual detected concentration of the active ingredient relative to the labeled amount. The labeled amount is the target amount specified in the prescription. The labeled amount is 12 mg / ml for P15-P18 and 12 mg / ml for P19-P22.

[1041] Experimental results show that, under high temperature conditions, the polymer growth rate in formulations containing m-cresol is faster than that in formulations containing only phenol.

[1042] Example 8: Investigation of Zinc Ion Concentration in the Formulation

[1043] Zinc ions with molar ratios of 1:2, 1:1, or 3:2 were selected for formulation preparation. Except for zinc ions, all other components of each composition were identical, consisting of a 10 mM phosphate buffer system (disodium hydrogen phosphate) and 5.5 mg / ml phenol. Formulation information is shown in Table 16. All samples underwent a 40°C high-temperature test (10 days and 30 days of storage), and screening was conducted using visible foreign matter, pH, related substances, polymers, and their content as indicators.

[1044] Table 16. Formulation Prescription Information Table Note: Zinc acetate* refers to zinc acetate dihydrate.

[1045] Table 17. Results of Physicochemical Indicators

[1046] Table 18. Results of Liquid Phase Investigation Note: Content (%) refers to the percentage of the actual detected concentration of the active ingredient relative to the labeled amount. The labeled amount is the target amount specified in the prescription. For P23, 19 and 24, the labeled amount is 12 mg / ml.

[1047] The results showed that increasing the amount of zinc ions helped reduce the rise of related substances and polymers, which was beneficial to stability.

[1048] Example 9: Investigation of different concentrations of GLP-1 / GIP / GCG receptor triagonists

[1049] Formulations with different API concentrations were prepared and subjected to high-temperature tests at 40°C (for 10 and 30 days). The results were evaluated based on properties, visible foreign matter, pH value, related substances, and polymers.

[1050] Table 19. Formulation Prescription Information Table Note: Phosphate is disodium hydrogen phosphate; zinc acetate* is zinc acetate dihydrate.

[1051] Table 20. Results of Physicochemical Indicators

[1052] Table 21. Results of Liquid Phase Investigation

[1053] The results showed that formulations with API concentrations of 10 mg / ml to 20 mg / ml exhibited good stability.

Claims

1. A pharmaceutical composition comprising a polypeptide or a pharmaceutically acceptable salt thereof and a buffer. in, The buffer is selected from one or more of phosphate buffers, histidine buffers, tris(hydroxymethyl)aminomethane buffer (Tris), and 4-hydroxyethylpiperazine ethanesulfonic acid buffer (HEPES). Preferably, the buffer is selected from one or more of phosphate buffers, histidine buffers, and Tris buffers. More preferably, one or more selected from phosphate buffers and Tris buffers, Phosphate buffers are also preferred; The polypeptide or its pharmaceutically acceptable salt comprises the following structure: H-Aib-HGTFTSDYSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:113); Where αL is alpha-methyl-Leu, Aib is α-aminoisobutyric acid, and OEG is [2-(2-amino-ethoxy)-ethoxy]-acetyl.

2. The pharmaceutical composition according to claim 1, wherein the concentration of the polypeptide or its pharmaceutically acceptable salt is 0.1 mg / mL to 500 mg / mL; Preferably, the concentration is 0.5 mg / mL to 200 mg / mL; More preferably 1 mg / mL-100 mg / mL; It is also preferred to use 1 mg / mL-50 mg / mL.

3. The pharmaceutical composition according to claim 1 or 2, wherein the concentration of the buffer is 0.1 mM-50 mM; The preferred concentration is 0.5 mM-40 mM; More preferably, it is 1mM-20mM; It is also preferred to use 1mM-15mM.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the pH of the pharmaceutical composition is 6-9. The preferred value is 6.5-8.

5. More preferably 7-8, It is also preferred to be 7-7.

8.

5. The pharmaceutical composition according to any one of claims 1-4, further comprising a divalent metal ion. Preferably, the divalent metal ion is selected from one or more of divalent zinc ions, divalent calcium ions, divalent magnesium ions, and divalent iron ions; More preferably, the divalent metal ion is selected from divalent zinc ions; Alternatively, the divalent metal ion is selected from one or more of zinc acetate and zinc chloride; Preferably, the divalent metal ion is zinc acetate.

6. The pharmaceutical composition according to claim 5, wherein, The molar ratio of the polypeptide or its pharmaceutically acceptable salt to the divalent metal ion is 1:5-5:1; Preferably, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to the divalent metal ion is 1:4-4:1; More preferably, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to the divalent metal ion is 1:3-3:1; Preferably, the molar ratio of the polypeptide or its pharmaceutically acceptable salt to the divalent metal ion is 1:2-2:

1.

7. The pharmaceutical composition according to any one of claims 1-6, further comprising an osmotic pressure regulator; Preferably, the osmotic pressure regulator is selected from one or more of mannitol, glycerol, and sodium chloride; More preferably, the osmotic regulator is selected from one or more of mannitol and glycerol.

8. The pharmaceutical composition according to claim 7, wherein the concentration of the osmotic pressure regulator is 0.1 mg / mL to 80 mg / mL. The preferred concentration is 0.5 mg / mL to 70 mg / mL. More preferably, 1 mg / mL-60 mg / mL; It is also preferred to use 1 mg / mL-50 mg / mL.

9. The pharmaceutical composition according to any one of claims 1-8, further comprising an antibacterial agent; Preferably, the antibacterial agent is selected from one or more of benzyl alcohol, phenol, and m-cresol; More preferably, the antibacterial agent is phenol.

10. The pharmaceutical composition according to claim 9, wherein the concentration of the antibacterial agent is 0.1 mg / mL to 20 mg / mL; Preferred concentration: 0.5 mg / mL - 15 mg / mL; More preferably, 1 mg / mL-12 mg / mL; It is also preferred to use 1 mg / mL-10 mg / mL.

11. The pharmaceutical composition according to any one of claims 1-10, wherein the polypeptide or its pharmaceutically acceptable salt contains K(-OEG-OEG-γGlu-C(O)-(CH2)18-COOH) having the following structure:

12. The pharmaceutical composition according to any one of claims 1-11, wherein the polypeptide or a pharmaceutically acceptable salt thereof comprises the structure shown below:

13. A pharmaceutical composition comprising any one of the following: 1) The polypeptide or its pharmaceutically acceptable salt as described in any one of claims 1, 11-12; The buffer is selected from phosphate buffers or Tris buffers, preferably phosphate buffers; Divalent metal ions, preferably divalent zinc ions, and more preferably zinc acetate; Osmotic pressure regulator, preferably mannitol or glycerol; Optionally, the pharmaceutical composition further comprises an antibacterial agent, preferably phenol; 2) The polypeptide or its pharmaceutically acceptable salt as described in any one of claims 1, 11-12; The buffer is preferably a phosphate buffer or a Tris buffer, more preferably a phosphate buffer; Divalent zinc ions, preferably zinc acetate; Osmotic pressure regulator, preferably mannitol or glycerol; Optionally, the pharmaceutical composition further comprises an antibacterial agent, preferably phenol. 3) The polypeptide or its pharmaceutically acceptable salt as described in any one of claims 1, 11-12; The buffer is preferably a phosphate buffer or a Tris buffer, more preferably a phosphate buffer; Divalent metal ions, preferably divalent zinc ions, and more preferably zinc acetate; Mannitol or glycerol; Optionally, the composition further comprises an antibacterial agent, preferably phenol.

14. A pharmaceutical composition comprising any group of 1)-4) below: 1) 0.1 mg / mL to 500 mg / mL of the polypeptide or a pharmaceutically acceptable salt thereof as described in any one of claims 1, 11-12; 0.1mM-50mM phosphate buffer or Tris buffer, preferably phosphate buffer; Divalent zinc ions, preferably zinc acetate; 0.1 mg / mL - 80 mg / mL mannitol or glycerol; in, The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:5-5:1; Furthermore, the pH of the pharmaceutical composition is 6-9; Optionally, the composition further comprises 0.1 mg / mL to 20 mg / mL phenol; 2) 0.1 mg / mL to 200 mg / mL of the polypeptide or its pharmaceutically acceptable salt as described in any one of claims 1, 11-12; 0.5mM-40mM phosphate buffer or Tris buffer, preferably phosphate buffer; Divalent zinc ions, preferably zinc acetate; 0.5 mg / mL - 70 mg / mL mannitol or glycerol; The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:4-4:

1. Furthermore, the pH of the pharmaceutical composition is 6.5-8.5; Optionally, the composition further comprises 0.5 mg / mL to 15 mg / mL phenol; 3) 1 mg / mL to 100 mg / mL of the polypeptide or its pharmaceutically acceptable salt as described in any one of claims 1, 11-12; 1mM-20mM phosphate buffer or Tris buffer, preferably phosphate buffer; Divalent zinc ions, preferably zinc acetate; 1 mg / mL - 60 mg / mL mannitol or glycerol; The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:3-3:1; Furthermore, the pH of the pharmaceutical composition is 7-8; Optionally, the composition further comprises 1 mg / mL to 12 mg / mL phenol; 4) 1 mg / mL-50 mg / mL of the polypeptide or its pharmaceutically acceptable salt as described in any one of claims 1, 11-12; 1mM-15mM phosphate buffer or Tris buffer, preferably phosphate buffer; Divalent zinc ions, preferably zinc acetate; 1 mg / mL - 50 mg / mL mannitol or glycerol; The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1; Furthermore, the pH of the pharmaceutical composition is 7-7.8; Optionally, the composition further comprises 1 mg / mL to 10 mg / mL phenol.

15. A pharmaceutical composition comprising any one of the following: 1) 1 mg / mL to 50 mg / mL of the polypeptide or pharmaceutically acceptable salt thereof as described in any one of claims 1, 11-12, preferably about 1 mg / mL, about 2 mg / mL, about 4 mg / mL, about 6 mg / mL, about 8 mg / mL, about 10 mg / mL or about 12 mg / mL; Approximately 10 mM phosphate buffer; Zinc acetate; Mannitol, preferably 36 mg / mL-49 mg / mL; in, The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1; Furthermore, the pH of the pharmaceutical composition is 7-7.8, preferably about 7.4; Optionally, the composition further comprises about 5.7 mg / mL phenol; 2) 1 mg / mL to 50 mg / mL of the polypeptide or pharmaceutically acceptable salt thereof as described in any one of claims 1, 11-12, preferably about 1 mg / mL, about 2 mg / mL, about 4 mg / mL, about 6 mg / mL, about 8 mg / mL, about 10 mg / mL or about 12 mg / mL; Approximately 10 mM phosphate buffer; Zinc acetate; Glycerin, preferably about 20 mg / mL; The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1; Furthermore, the pH of the pharmaceutical composition is 7-7.8, preferably about 7.4; Optionally, the composition further comprises about 5.7 mg / mL of phenol.

16. A pharmaceutical composition comprising any one of the following: 1) A polypeptide or a pharmaceutically acceptable salt thereof at a concentration of about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 18 mg / mL or about 20 mg / mL as described in any one of claims 1, 11-12; Approximately 10 mM phosphate buffer; Zinc acetate; Mannitol, preferably 36 mg / mL-49 mg / mL; in, The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1; Furthermore, the pH of the pharmaceutical composition is 7-7.8, preferably about 7.4; Optionally, the composition further comprises about 5.7 mg / mL phenol; 2) A polypeptide or a pharmaceutically acceptable salt thereof at a concentration of about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 18 mg / mL or about 20 mg / mL as described in any one of claims 1, 11-12; Approximately 10 mM phosphate buffer; Zinc acetate; Glycerin, preferably about 20 mg / mL; The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1; Furthermore, the pH of the pharmaceutical composition is 7-7.8, preferably about 7.4; Optionally, the composition further comprises about 5.7 mg / mL of phenol.

17. A pharmaceutical composition comprising any one of the following: 1) Polypeptides or their pharmaceutically acceptable salts at concentrations of 1 mg / mL to 50 mg / mL. The polypeptide or its pharmaceutically acceptable salt comprises the following structure: Approximately 10 mM phosphate buffer; Zinc acetate; Mannitol; in, The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1; Furthermore, the pH of the pharmaceutical composition is 7-7.8; Optionally, the composition further comprises about 5.7 mg / mL phenol; 2) A polypeptide or its pharmaceutically acceptable salt at concentrations of approximately 1 mg / mL, 2 mg / mL, 4 mg / mL, 6 mg / mL, 8 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 18 mg / mL, or 20 mg / mL. The polypeptide or its pharmaceutically acceptable salt comprises the following structure: Approximately 10 mM phosphate buffer; Zinc acetate; 36 mg / mL - 49 mg / mL mannitol; The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1; The pH of the pharmaceutical composition is approximately 7.4; Optionally, the composition further comprises about 5.7 mg / mL phenol; 3) Approximately 10 mg / mL or approximately 20 mg / mL of polypeptides or their pharmaceutically acceptable salts. The polypeptide or its pharmaceutically acceptable salt comprises the following structure: Approximately 10 mM phosphate buffer; Zinc acetate; Approximately 36 mg / mL mannitol; The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is approximately 1:

1. The pH of the pharmaceutical composition is approximately 7.4; Optionally, the composition further comprises about 5.7 mg / mL phenol; 4) Polypeptides or their pharmaceutically acceptable salts at concentrations of 1 mg / mL to 50 mg / mL; The polypeptide or its pharmaceutically acceptable salt comprises the following structure: Approximately 10 mM phosphate buffer; Zinc acetate; glycerin; The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1; Furthermore, the pH of the pharmaceutical composition is 7-7.8; Optionally, the composition further comprises about 5.7 mg / mL phenol; 5) Polypeptides or pharmaceutically acceptable salts thereof at concentrations of approximately 1 mg / mL, 2 mg / mL, 4 mg / mL, 6 mg / mL, 8 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 18 mg / mL, or 20 mg / mL. The polypeptide or its pharmaceutically acceptable salt comprises the following structure: Approximately 10 mM phosphate buffer; Zinc acetate; Approximately 20 mg / mL glycerol; The molar ratio of the polypeptide or its pharmaceutically acceptable salt to zinc ions is 1:2-2:1; The pH of the pharmaceutical composition is approximately 7.4; Optionally, the composition further comprises about 5.7 mg / mL of phenol.

18. A lyophilized formulation, wherein the lyophilized formulation, upon reconstitution, can form a pharmaceutical composition according to any one of claims 1 to 17, or the lyophilized formulation is obtained by freeze-drying a pharmaceutical composition according to any one of claims 1 to 17.

19. A reconstituted solution, wherein the reconstituted solution is prepared by reconstituted reconstituted lyophilized formulation of claim 18.

20. An article comprising a container containing a pharmaceutical composition as claimed in any one of claims 1 to 17, a lyophilized formulation as claimed in claim 18, or a reconstituted solution as claimed in claim 19.

21. The use of the pharmaceutical composition according to any one of claims 1-17, the lyophilized formulation according to claim 18, or the reconstituted solution according to claim 19, in the preparation of a medicament for the prevention or treatment of metabolic disorder-related diseases or conditions; Preferably, the metabolic disorder-related disease or condition is selected from diabetes or diabetes-related conditions, obesity or obesity-related conditions, and fatty liver disease related to metabolic dysfunction.

22. Use of the pharmaceutical composition according to any one of claims 1-17, the lyophilized formulation of claim 18, or the reconstituted solution of claim 19 in the preparation of a medicament for the prevention or treatment of type 2 diabetes.

23. Use of the pharmaceutical composition according to any one of claims 1-17, the lyophilized formulation of claim 18, or the reconstituted solution of claim 19 in the preparation of a medicament for the prevention or treatment of obesity.

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