Drug delivery composition

Abstract

A pharmaceutical composition for delivering a polypeptide, a preparation method therefor, and a use thereof. The composition has excellent bioavailability.

Description

Drug delivery composition Technical Field

[0001] This disclosure relates to the field of pharmaceutical formulations, and more particularly to pharmaceutical compositions for delivering peptides and their pharmaceutical uses. Background Technology

[0002] GLP-1 receptor agonists have become one of the effective treatments for type 2 diabetes or obesity. Currently marketed GLP-1 receptor agonists, such as liraglutide, semaglutide, and telpoxetine, are mostly complex polypeptide macromolecules. Because polypeptide and protein drugs are easily inactivated by gastric acid and digestive enzymes, they have difficulty passing through the gastrointestinal mucosa, resulting in low overall bioavailability. Therefore, they are mostly administered by injection, with oral administration being rare.

[0003] Novo Nordisk has launched the first oral tablet of the GLP-1 agonist semaglutide. However, the bioavailability of oral peptide formulations remains low, necessitating the development of peptide formulations with higher bioavailability. Summary of the Invention

[0004] This disclosure provides a pharmaceutical composition containing a polypeptide drug, which has excellent oral bioavailability and stability.

[0005] Pharmaceutical Composition

[0006] This disclosure provides a pharmaceutical composition comprising:

[0007] (a) polypeptide;

[0008] (b) The compound represented by formula (A) or its pharmaceutically acceptable salt: RCOOH(A), wherein R is an aliphatic group;

[0009] (c) The compound represented by formula (B) or its pharmaceutically acceptable salt:

[0010] Where n is selected from integers between 0 and 4;

[0011] G 1 Independently selected from OH, NH2, NH(C) 1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), halogen, C 1-4 Alkyl or C 1-4 alkoxy groups; and

[0012] L 1 For C2-C 16 Alkylene or C2-C 16 imidene group; and

[0013] (d) Polymers containing basic groups, such as sodium carboxymethyl starch.

[0014] This disclosure also provides a pharmaceutical composition comprising any one of the following:

[0015] Group 1:

[0016] peptides, and

[0017] Sodium carboxymethyl starch;

[0018] Group 2:

[0019] polypeptide;

[0020] The compound represented by formula (A) or its pharmaceutically acceptable salt: RCOOH(A), wherein R is an aliphatic group, and

[0021] Sodium carboxymethyl starch;

[0022] Group 3:

[0023] polypeptide,

[0024] The compound represented by formula (A) or its pharmaceutically acceptable salt: RCOOH(A), wherein R is an aliphatic group, and

[0025] The compound represented by formula (B) or its pharmaceutically acceptable salt:

[0026] Where n is selected from integers between 0 and 4;

[0027] G 1 Independently selected from OH, NH2, NH(C) 1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), halogen, C 1-4 Alkyl or C 1-4 alkoxy groups; and

[0028] L 1 For C2-C 16 Alkylene or C2-C 16 alkenyl;

[0029] Group 4:

[0030] Polypeptides (such as the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt),

[0031] The compound represented by formula (B) or its pharmaceutically acceptable salt:

[0032] Where n is selected from integers between 0 and 4;

[0033] G 1 Independently selected from OH, NH2, NH(C)1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), halogen, C 1-4 Alkyl or C 1-4 alkoxy groups; and

[0034] L 1 For C2-C 16 Alkylene or C2-C 16 imidene group, and

[0035] Sodium carboxymethyl starch.

[0036] In some embodiments, n is selected from 0, 1, 2, 3, or 4. In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0037] In some embodiments, R in the compound of formula (A) is an alkyl group with 1-30 carbon atoms. In some embodiments, R in the compound of formula (A) is an alkyl group with 3-20 carbon atoms. In some embodiments, R in the compound of formula (A) is an alkyl group with 5-16 carbon atoms, for example, an alkyl group with 7, 9, or 11 carbon atoms. In some embodiments, R in the compound of formula (A) is a straight-chain or branched alkyl group. In some embodiments, R in the compound of formula (A) is a straight-chain alkyl group with 7, 9, or 11 carbon atoms.

[0038] In some embodiments, the compound represented by formula (A) is a straight-chain fatty acid with 5-16 carbon atoms, such as a straight-chain fatty acid. In some embodiments, the compound represented by formula (A) is caprylic acid, capric acid, or lauric acid. In some embodiments, the compound represented by formula (A) is caprylic acid. In some embodiments, the pharmaceutical composition comprises caprylate. In some embodiments, the pharmaceutical composition comprises sodium caprylate.

[0039] In some embodiments, n is 0 in the compound represented by formula (B). In some embodiments, n is 1 in the compound represented by formula (B), G 1 Halogen, C 1-4 Alkyl or C 1-4 Alkyl group. In some embodiments, n is 1 in the compound represented by formula (B), and G... 1 It is Cl or -OCH3.

[0040] In some embodiments, L in the compound represented by formula (B) 1 C 2-16Alkylene. In some embodiments, L in the compound shown in formula (B) 1 C 3-15 Alkylene. In some embodiments, L in the compound shown in formula (B) 1 C 5-13 Alkylene. In some embodiments, L in the compound shown in formula (B) 1 C 5-9 Alkylene.

[0041] In some embodiments, the compound represented by formula (B) is the compound represented by formula (C):

[0042] Its chemical name is 8-(2-hydroxybenzamido)octanoic acid. In some embodiments, the pharmaceutical compositions disclosed herein comprise a salt of 8-(2-hydroxybenzamido)octanoic acid. In some embodiments, the 8-(2-hydroxybenzamido)octanoic acid salt comprises one monovalent cation, two monovalent cations, or one divalent cation. In some embodiments, the 8-(2-hydroxybenzamido)octanoic acid salt is selected from the sodium, potassium, and calcium salts of N-(8-(2-hydroxybenzoyl)amino)octanoic acid. The 8-(2-hydroxybenzamido)octanoic acid salt can be crystalline and / or amorphous. In some embodiments, the 8-(2-hydroxybenzamido)octanoic acid salt is selected from anhydrous, monohydrate, dihydrate, trihydrate, solvate, or one-third hydrate forms, and combinations thereof.

[0043] In some embodiments, the 8-(2-hydroxybenzamido)octanoate is sodium 8-(2-hydroxybenzamido)octanoate (also referred to as “SNAC” in this disclosure), and is also known as sodium 8-(salicylamido)octanoate.

[0044] In some embodiments, the compound represented by formula (B) is a compound with any of the following structures:

[0045] or

[0046] In some embodiments, the pharmaceutical compositions disclosed herein comprise:

[0047] (a) polypeptide;

[0048] (b) Caprylic acid or its medicinal salts.

[0049] (c) The compound of formula (C) or its pharmaceutically acceptable salt (e.g., sodium salt),

[0050] and

[0051] (d) Sodium carboxymethyl starch.

[0052] In some embodiments, the pharmaceutical compositions disclosed herein comprise:

[0053] (a) polypeptide;

[0054] (b) Sodium octanoate, and

[0055] (c)SNAC, and

[0056] (d) Sodium carboxymethyl starch.

[0057] In some embodiments, the pharmaceutical compositions provided in this disclosure comprise any one of the following groups:

[0058] Group 1:

[0059] Polypeptides (such as the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt), and

[0060] Sodium carboxymethyl starch;

[0061] Group 2:

[0062] Polypeptides (e.g., compounds shown in Figure 1# 18 or their pharmaceutically acceptable salts);

[0063] Sodium octanoate, and

[0064] Sodium carboxymethyl starch;

[0065] Group 3:

[0066] Polypeptides (such as the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt),

[0067] Sodium octanoate, and

[0068] The compound of formula (C) or its pharmaceutically acceptable salt (e.g., sodium salt, such as SNAC),

[0069] Group 4:

[0070] Polypeptides (such as the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt),

[0071] The compound of formula (C) or its pharmaceutically acceptable salt (e.g., sodium salt, such as SNAC),

[0072] and

[0073] Sodium carboxymethyl starch.

[0074] In some embodiments, the content ratio of the compound of formula (A) or its pharmaceutically acceptable salt, the compound of formula (B) or its pharmaceutically acceptable salt, and sodium carboxymethyl starch is 0.1-20:0.1-20:0.01-10, by weight, for example 0.5-15:0.5-15:0.1-5, 1-10:1-10:0.5-3, 3-8:3-6:0.5-2.5. In some embodiments, the content ratio of the compound of formula (A) or its pharmaceutically acceptable salt, the compound of formula (B) or its pharmaceutically acceptable salt, and sodium carboxymethyl starch is about 6:5:1, about 5:4:1, about 5.5:4.5:1, about 5.6:4.7:1, about 5.7:4.5:1, about 4.6:5.7:1, or about 6.5:4.1:1.

[0075] In some embodiments, the sum of the contents of the compound represented by formula (A) or its pharmaceutically acceptable salt and the compound represented by formula (B) or its pharmaceutically acceptable salt is 50% w / w to 98% w / w, and the content of sodium carboxymethyl starch is 0.5% w / w to 20% w / w. In some embodiments, the sum of the contents of the compound represented by formula (A) or its pharmaceutically acceptable salt and the compound represented by formula (B) or its pharmaceutically acceptable salt is 65% w / w to 95% w / w, and the content of sodium carboxymethyl starch is 1% w / w to 15% w / w. In some embodiments, the sum of the contents of the compound represented by formula (A) or its pharmaceutically acceptable salt and the compound represented by formula (B) or its pharmaceutically acceptable salt is 70% w / w to 90% w / w, and the content of sodium carboxymethyl starch is 2% w / w to 10%. In some embodiments, the sum of the contents of the compound represented by formula (A) or its pharmaceutically acceptable salt and the compound represented by formula (B) or its pharmaceutically acceptable salt is 70% w / w to 95% w / w, and the content of sodium carboxymethyl starch is 2% w / w to 10%.

[0076] In some embodiments, the sum of the contents of the compound represented by formula (A) or its pharmaceutically acceptable salt, the compound represented by formula (B) or its pharmaceutically acceptable salt, and sodium carboxymethyl starch is at least 70% w / w, for example at least 75% w / w, at least 80% w / w, or at least 90% w / w.

[0077] In some embodiments, the content of the compound represented by formula (A) or its pharmaceutically acceptable salt is 5% w / w to 70% w / w, calculated as a percentage of the total mass of the composition, for example 10% w / w to 65% w / w, 10% w / w to 60% w / w, 10% w / w to 55% w / w, 10% w / w to 50% w / w, 10% w / w to 45% w / w, 15% w / w to 65% w / w, 15% w / w to 60% w / w, 15% w / w to 55% w / w, 15% w / w to 50% w / w, 15% w / w to 45% w / w, 20% w / w -65%w / w, 20%w / w-60%w / w, 20%w / w-55%w / w, 20%w / w-50%w / w, 20%w / w-45%w / w, 25%w / w-65%w / w, 25%w / w-60%w / w, 25%w / w-55% w / w, 25% w / w-50% w / w, 25% w / w-45% w / w, 30% w / w-65% w / w, 30% w / w-60% w / w, 30% w / w-55% w / w, 30% w / w-50% w / w, 30% w / w-45% w / w. In some embodiments, the content of the compound represented by the aforementioned formula (A) or its pharmaceutically acceptable salt is 15% w / w to 65% w / w, calculated as a percentage of the total mass of the composition, for example 25% w / w to 60% w / w, 30% w / w to 60% w / w. In some embodiments, the content of the compound represented by formula (A) above or its pharmaceutically acceptable salt is about 30% w / w, about 31% w / w, about 32% w / w, about 33% w / w, about 34% w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 39% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, about 54% w / w, or about 55% w / w. In some embodiments, the content of the compound represented by formula (A) or its pharmaceutically acceptable salt is about 33% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 42% w / w, about 45% w / w, about 46% w / w, about 48% w / w, about 51% w / w, about 52% w / w, or about 53% w / w. In some embodiments, the content of the compound represented by formula (A) or its pharmaceutically acceptable salt is about 37% w / w, about 38% w / w, or about 52% w / w.

[0078] In some embodiments, the content of the compound represented by the foregoing formula (B) or its pharmaceutically acceptable salt is 10% w / w - 90% w / w, calculated based on the total mass of the composition, for example 10% w / w - 80% w / w, 10% w / w - 75% w / w, 10% w / w - 70% w / w, 10% w / w - 65% w / w, 10% w / w - 60% w / w, 10% w / w - 55% w / w, 10% w / w - 50% w / w, 10% w / w - 45% w / w, 10% w / w - 40% w / w, 10% w / w - 35% w / w, 15% w / w - 80% w / w, 15% w / w - 75% w / w, 15% w / w - 70% w / w, 15% w / w - 65% w / w, 15% w / w - 60% w / w, 15% w / w - 55% w / w, 15% w / w - 50% w / w, 15% w / w - 45% w / w, 15% w / w - 40% w / w, 15% w / w - 35% w / w, 20% w / w - 80% w / w, 20% w / w - 75% w / w, 20% w / w - 70% w / w, 20% w / w - 65% w / w, 20% w / w - 60% w / w, 20% w / w - 55% w / w, 20% w / w - 50% w / w, 20% w / w - 45% w / w, 20% w / w - 40% w / w, 20% w / w - 35% w / w, 25% w / w - 75% w / w, 25% w / w - 70% w / w, 25% w / w - 65% w / w, 25% w / w - 6, 25% w / w - 55% w / w, 25% w / w - 50% w / w, 25% w / w - 45% w / w, 25% w / w - 40% w / w, 25% w / w - 35% w / w, 30% w / w - 75% w / w, 30% w / w - 70% w / w, 30% w / w - 65% w / w, 30% w / w - 60% w / w, 30% w / w - 55% w / w, 30% w / w - 50% w / w, 30% w / w - 45% w / w, 30% w / w - 40% w / w, 30% w / w - 35% w / w, 35% w / w - 75% w / w, 35% w / w - 70% w / w, 35% w / w - 65% w / w, 35% w / w - 60% w / w, 35% w / w - 55% w / w, |5% w / w - 50% w / w, 35% w / w - 45% w / w. In some embodiments, the content of the compound represented by the foregoing formula (B) or its pharmaceutically acceptable salt is 15% w / w - 75% w / w, calculated based on the total mass of the composition, for example 20% w / w - 65% w / w, 25% w / w - |5% w / w.In some embodiments, the content of the compound represented by formula (B) above or its pharmaceutically acceptable salt is about 30% w / w, about 31% w / w, about 32% w / w, about 33% w / w, about 34% w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 39% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, or about 50% w / w. In some embodiments, the content of the compound represented by formula (B) or its pharmaceutically acceptable salt is about 30% w / w, about 32% w / w, about 33% w / w, about 35% w / w, about 37% w / w, about 38% w / w, about 40% w / w, about 41% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, or about 48% w / w. In some embodiments, the content of the compound represented by formula (B) or its pharmaceutically acceptable salt is about 33% w / w, about 46% w / w, or about 47% w / w.

[0079] In some embodiments, the sodium carboxymethyl starch content is 0.1% w / w to 30% w / w, calculated as a percentage of the total mass of the composition, for example, 0.5% w / w to 20% w / w, 1% w / w to 15% w / w, 2% w / w to 10% w / w, or 2% w / w to 9% w / w. In some embodiments, the sodium carboxymethyl starch content is <10% w / w, such as <9% w / w. In some embodiments, the sodium carboxymethyl starch content is about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, or about 10% w / w. In some embodiments, the sodium carboxymethyl starch content is about 7% w / w or about 8% w / w.

[0080] In some embodiments, the peptide content is 0.1% w / w to 30% w / w, calculated as a percentage of the total mass of the composition, for example 0.1% w / w to 25% w / w, 0.1% w / w to 20% w / w, 0.1% w / w to 15% w / w, 0.1% w / w to 10% w / w, 0.1% w / w to 5% w / w, 0.5% w / w to 25% w / w, 0.5% w / w to 20% w / w, 0.5% w / w to 15% w / w, 0.5% w / w to 10% w / w, 0.5% w / w to 5% w / w, 1% w / w to 20% w / w, 1% w / w to 15% w / w, 1% w / w to 10% w / w, 1% w / w to 5% w / w. In some embodiments, the peptide content is about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, and about 2%. 4% w / w, approximately 2.5% w / w, approximately 2.6% w / w, approximately 2.7% w / w, approximately 2.8% w / w, approximately 2.9% w / w, approximately 3% w / w, approximately 3.1% w / w, approximately 3.2% w / w, approximately 3.3% w / w, approximately 3.4% w / w, approximately 3.5% w / w, approximately 3.6% w / w, approximately 3.7% w / w, approximately 3.8% w / w, approximately 3.9% w / w, approximately 4% w / w, approximately 4.1% w / w, approximately 4.2% w / w, approximately 4.3% w / w, approximately 4.4% w / w, approximately 4.5% w / w / w, approximately 4.6% w / w, approximately 4.7% w / w, approximately 4.8% w / w, approximately 4.9% w / w, approximately 5% w / w, approximately 5.1% w / w, approximately 5.2% w / w, approximately 5.3% w / w, approximately 5.4% w / w, approximately 5.5% w / w, approximately 5.6% w / w, approximately 5.7% w / w, approximately 5.8% w / w, approximately 5.9% w / w, approximately 6% w / w, approximately 6.1% w / w, approximately 6.2% w / w, approximately 6.3% w / w, approximately 6.4% w / w, approximately 6.5% w / w, approximately 6.6% w / w, Approximately 6.7% w / w, approximately 6.8% w / w, approximately 6.9% w / w, approximately 7% w / w, approximately 7.1% w / w, approximately 7.2% w / w, approximately 7.3% w / w, approximately 7.4% w / w, approximately 7.5% w / w, approximately 7.6% w / w, approximately 7.7% w / w, approximately 7.8% w / w, approximately 7.9% w / w, approximately 8% w / w, approximately 8.1% w / w, approximately 8.2% w / w, approximately 8.3% w / w, approximately 8.4% w / w, approximately 8.5% w / w, approximately 8.6% w / w, approximately 8.7% w / w, approximately 8.8% w / w, approximately 8.9% w / w, approximately 9% w / w, approximately 9.1% w / w, approximately 9.2% w / w, approximately 9.3% w / w, approximately 9.4% w / w, approximately 9.5% w / w, approximately 9.6% w / w, approximately 9.7% w / w, approximately 9.8% w / w, approximately 9.9% w / w, approximately 10% w / w, approximately 10.1% w / w, approximately 10.2% w / w, approximately 10.3% w / w, approximately 10.4% w / w, approximately 10 0.5% w / w, approximately 10.6% w / w, approximately 10.7% w / w, approximately 10.8% w / w, approximately 10.9% w / w, approximately 11% w / w, approximately 13.1% w / w, approximately 13.2% w / w, approximately 13.3% w / w, approximately 13.4% w / w, approximately 13.5% w / w, approximately 13.6% w / w, approximately 13.7% w / w, approximately 13.8% w / w, approximately 13.9% w / w, approximately 14% w / w. In some embodiments, the peptide content is about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.3% w / w, about 1.6% w / w, about 1.9% w / w, about 2.6% w / w, about 3% w / w, about 3.1% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4.5% w / w, about 5.1% w / w, about 5.4% w / w, about 5.9% w / w, about 7.1% w / w, about 9.7% w / w, or about 13.3% w / w.

[0081] In some embodiments, the molar ratio of the compound of formula (A) or its pharmaceutically acceptable salt to the polypeptide is >70:1, for example, greater than 140:1, greater than 148:1, greater than 150:1, greater than 200:1, or greater than 250:1. In some embodiments, the molar ratio of the compound of formula (A) or its pharmaceutically acceptable salt to the polypeptide is greater than 148:1.

[0082] In some embodiments, the sum of the contents of the compound of formula (A) or its pharmaceutically acceptable salt and the compound of formula (B) or its pharmaceutically acceptable salt is 50% w / w to 98% w / w, the sodium carboxymethyl starch content is 0.5% w / w to 20% w / w, and the molar ratio of the compound of formula (A) or its pharmaceutically acceptable salt to the polypeptide is greater than 148:1. In some embodiments, the sum of the contents of the compound of formula (A) or its pharmaceutically acceptable salt and the compound of formula (B) or its pharmaceutically acceptable salt is 65% w / w to 95% w / w, the sodium carboxymethyl starch content is 1% w / w to 15% w / w, and the molar ratio of the compound of formula (A) or its pharmaceutically acceptable salt to the polypeptide is greater than 148:1. In some embodiments, the sum of the contents of the compound of formula (A) or its pharmaceutically acceptable salt and the compound of formula (B) or its pharmaceutically acceptable salt is 70% w / w to 95% w / w, and the content of sodium carboxymethyl starch is 2% w / w to 10%, and the molar ratio of the compound of formula (A) or its pharmaceutically acceptable salt to the polypeptide is greater than 148:1.

[0083] In some embodiments, the sum of the contents of the compound of formula (A) or its pharmaceutically acceptable salt, the compound of formula (B) or its pharmaceutically acceptable salt, and sodium carboxymethyl starch is at least 70% w / w, for example at least 75% w / w, at least 80% w / w, at least 90% w / w, and the molar ratio of the compound of formula (A) or its pharmaceutically acceptable salt to the polypeptide is greater than 1:148.

[0084] In some embodiments, the sum of the contents of the compound represented by formula (A) or its pharmaceutically acceptable salt and the compound represented by formula (B) or its pharmaceutically acceptable salt is 50% w / w to 98% w / w.

[0085] The sodium carboxymethyl starch content is 0.5-20% w / w.

[0086] The molar ratio of the compound shown in formula (A) or its pharmaceutically usable salt to the compound shown in formula (B) or its pharmaceutically usable salt is 1-5:0.1-1, for example 1:0.1-1, 1:0.1-0.8, 1:0.1-0.65, 1:0.1-0.5.

[0087] In some embodiments, the sum of the contents of the compound represented by formula (A) or a pharmaceutically acceptable salt thereof and the compound represented by formula (B) or a pharmaceutically acceptable salt thereof is 65% w / w to 95% w / w.

[0088] The sodium carboxymethyl starch content is 1% w / w-15% w / w.

[0089] The molar ratio of the compound shown in formula (A) or its pharmaceutically usable salt to the compound shown in formula (B) or its pharmaceutically usable salt is 1-5:0.1-1, for example 1:0.1-1, 1:0.1-0.8, 1:0.1-0.65, 1:0.1-0.5.

[0090] In some embodiments, the sum of the contents of the compound represented by formula (A) or a pharmaceutically acceptable salt thereof and the compound represented by formula (B) or a pharmaceutically acceptable salt thereof is 70% w / w to 95% w / w.

[0091] The sodium carboxymethyl starch content is 2% w / w-10%.

[0092] The molar ratio of the compound shown in formula (A) or its pharmaceutically usable salt to the compound shown in formula (B) or its pharmaceutically usable salt is 1-5:0.1-1, for example 1:0.1-1, 1:0.1-0.8, 1:0.1-0.65, 1:0.1-0.5.

[0093] In some implementation schemes,

[0094] The molar ratio of the polypeptide to the compound of formula (A) or its pharmaceutically acceptable salt is ≥1:148.

[0095] The sum of the contents of the compound represented by formula (A) or its pharmaceutically acceptable salt and the compound represented by formula (B) or its pharmaceutically acceptable salt is 70% w / w to 95% w / w.

[0096] The sodium carboxymethyl starch content is 2% w / w-10%.

[0097] The molar ratio of the compound shown in formula (A) or its pharmaceutically usable salt to the compound shown in formula (B) or its pharmaceutically usable salt is 1-5:0.1-1, for example 1:0.1-1, 1:0.1-0.8, 1:0.1-0.65, 1:0.1-0.5.

[0098] In some embodiments, the sum of the contents of the compound of formula (A) or its pharmaceutically acceptable salt, the compound of formula (B) or its pharmaceutically acceptable salt, and sodium carboxymethyl starch is at least 70% w / w, for example at least 75% w / w, at least 80% w / w, or at least 90% w / w, and the molar ratio of the compound of formula (A) or its pharmaceutically acceptable salt to the compound of formula (B) or its pharmaceutically acceptable salt is 1-5:0.1-1, for example 1:0.1-1, 1:0.1-0.8, 1:0.1-0.65, or 1:0.1-0.5.

[0099] In some embodiments, the aforementioned pharmaceutical composition further comprises one or more of a filler, a lubricant, and a flow aid. In some embodiments, the filler is sorbitol. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the flow aid is colloidal silica or gelled silica. In some embodiments, the flow aid is colloidal silica. In some embodiments, the flow aid is gelled silica. In some embodiments, the aforementioned pharmaceutical composition further comprises sorbitol, magnesium stearate, and colloidal silica. In some embodiments, the aforementioned pharmaceutical composition further comprises sorbitol, magnesium stearate, and gelled silica.

[0100] In some embodiments, the filler does not necessarily function as a filler in the compositions disclosed herein; the lubricant does not necessarily function as a lubricant in the compositions disclosed herein; and the flow aid does not necessarily function as a flow aid in the compositions disclosed herein.

[0101] In some embodiments, the filler (e.g., sorbitol) content is 0.01% w / w to 20% w / w, for example 0.05% w / w to 15% w / w, 0.1% w / w to 10% w / w, or 0.5% w / w to 8% w / w. In some embodiments, the filler (e.g., sorbitol) content is about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, or about 2.6% w / w. w, approximately 2.7% w / w, approximately 2.8% w / w, approximately 2.9% w / w, approximately 3.0% w / w, approximately 3.2% w / w, approximately 3.4% w / w, approximately 3.6% w / w, approximately 3.8% w / w, approximately 4.0% w / w, approximately 4.2% w / w, approximately 4.6% w / w, approximately 4.8% w / w, approximately 5.0% w / w, approximately 5.5% w / w, approximately 6.0% w / w, approximately 6.5% w / w, approximately 7.0% w / w, approximately 7.5% w / w, or approximately 8% w / w.

[0102] In some embodiments, the lubricant (e.g., magnesium stearate) content is 0.01% w / w to 15% w / w, for example 0.05% w / w to 10% w / w, 0.1% w / w to 8% w / w, or 0.5% w / w to 5% w / w. In some embodiments, the lubricant (e.g., magnesium stearate) content is about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2.0% w / w, about 2... 0.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3.0% w / w, about 3.2% w / w, about 3.4% w / w, about 3.6% w / w, about 3.8% w / w, about 4.0% w / w, about 4.2% w / w, about 4.6% w / w, about 4.8% w / w, or about 5.0% w / w.

[0103] In some embodiments, the flow aid (e.g., colloidal silica or gel silica) content is 0.01% w / w to 20% w / w, for example 0.05% w / w to 15% w / w, 0.1% w / w to 10% w / w, or 0.5% w / w to 5% w / w. In some embodiments, the flow aid (e.g., colloidal silica) content is about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1.0% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, or about 1.6% w / w. %w / w, approximately 1.7%w / w, approximately 1.8%w / w, approximately 1.9%w / w, approximately 2.0%w / w, approximately 2.1%w / w, approximately 2.2%w / w, approximately 2.3%w / w, approximately 2.4%w / w, approximately 2.5%w / w, approximately 2.6%w / w, approximately 2.7%w / w, approximately 2.8%w / w, approximately 2.9%w / w, or approximately 3.0%w / w.

[0104] This disclosure provides a pharmaceutical composition comprising or being any of the following:

[0105] Group 1:

[0106] (a) Polypeptides (e.g., compounds shown in Figure 1# 18 or their pharmaceutically acceptable salts);

[0107] (b) Sodium octanoate;

[0108] (c) The compound of formula (C) or its pharmaceutically acceptable salt (e.g., sodium salt);

[0109] (d) Sodium carboxymethyl starch;

[0110] Optionally, it also includes at least one of a filler, a lubricant, and a flow aid;

[0111] Group 2:

[0112] (a) 0.1% w / w-30% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0113] (b) 5% w / w-70% w / w sodium octanoate;

[0114] (c) 10% w / w-90% w / w of the compound of formula (C) or a pharmaceutically acceptable salt (e.g., sodium salt);

[0115] (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch;

[0116] Optionally, it also includes:

[0117] (e) 0.01% w / w - 20% w / w filler;

[0118] (f) 0.01% w / w - 15% w / w lubricant;

[0119] (g) 0.01% w / w - 20% w / w gliding agent;

[0120] Group 3:

[0121] (a) 0.5% w / w-20% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0122] (b) 10% w / w-60% w / w sodium octanoate;

[0123] (c) 20% w / w to 80% w / w of the compound of formula (C) or a pharmaceutically acceptable salt (e.g., a sodium salt);

[0124] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0125] Optional, also includes

[0126] (e) 0.05% w / w - 15% w / w filler;

[0127] (f) 0.05% w / w - 10% w / w lubricant;

[0128] (g) 0.05% w / w - 15% w / w gliding agent;

[0129] Group 4:

[0130] (a) 1% w / w-10% w / w polypeptides (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0131] (b) 20% w / w-50% w / w sodium octanoate;

[0132] (c) 30% w / w-70% w / w of the compound of formula (C) or a pharmaceutically acceptable salt (e.g., sodium salt);

[0133] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0134] Optional, also includes

[0135] (e) 0.1% w / w - 10% w / w filler;

[0136] (f) 0.1% w / w - 8% w / w lubricant;

[0137] (g) 0.1% w / w-10% w / w gliding agent;

[0138] Group 5:

[0139] (a) 1% w / w-5% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0140] (b) 25% w / w-45% w / w sodium octanoate;

[0141] (c) 35% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt (e.g., sodium salt);

[0142] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0143] Optional, also includes

[0144] (e) 0.5% w / w - 8% w / w filler;

[0145] (f) 0.5% w / w - 5% w / w lubricant;

[0146] (g) 0.5% w / w - 5% w / w gliding agent;

[0147] Group 6:

[0148] (a) 0.5% w / w-25% w / w polypeptide;

[0149] (b) 15% w / w-65% w / w sodium octanoate;

[0150] (c) 15% w / w-75% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0151] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0152] Optional, also includes

[0153] (e) 0.05% w / w - 15% w / w filler;

[0154] (f) 0.05% w / w - 10% w / w lubricant;

[0155] (g) 0.05% w / w - 15% w / w gliding agent;

[0156] Group 7:

[0157] (a) 0.5% w / w-20% w / w polypeptide;

[0158] (b) 25% w / w-60% w / w sodium octanoate;

[0159] (c) 20% w / w-65% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0160] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0161] Optional, also includes

[0162] (e) 0.1% w / w - 10% w / w filler;

[0163] (f) 0.1% w / w - 8% w / w lubricant;

[0164] (g) 0.1% w / w-10% w / w gliding agent;

[0165] Group 8:

[0166] (a) 0.5% w / w-15% w / w polypeptide;

[0167] (b) 30% w / w-60% w / w sodium octanoate;

[0168] (c) 25% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0169] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0170] Optional, also includes

[0171] (e) 0.5% w / w - 8% w / w filler;

[0172] (f) 0.5% w / w - 5% w / w lubricant;

[0173] (g) 0.5% w / w - 5% w / w gliding agent

[0174] Group 9:

[0175] (a) Polypeptides (e.g., compounds shown in Figure 1# 18 or their pharmaceutically acceptable salts);

[0176] (b) Sodium octanoate;

[0177] (c)SNAC;

[0178] (d) Sodium carboxymethyl starch;

[0179] (e) Sorbitol;

[0180] (f) Magnesium stearate;

[0181] (g) Colloidal silica;

[0182] Group 10:

[0183] (a) Polypeptides (e.g., compounds shown in Figure 1# 18 or their pharmaceutically acceptable salts);

[0184] (b) Sodium octanoate;

[0185] (c)SNAC;

[0186] (d) Sodium carboxymethyl starch;

[0187] (e) Sorbitol;

[0188] (f) Magnesium stearate;

[0189] (g) Gel-coated silica;

[0190] Group 11:

[0191] (a) 0.1% w / w-30% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0192] (b) 5% w / w-70% w / w sodium octanoate;

[0193] (c) 10% w / w - 90% w / w SNAC;

[0194] (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch;

[0195] (e) 0.01% w / w - 20% w / w sorbitol;

[0196] (f) 0.01% w / w - 15% w / w magnesium stearate;

[0197] (g) 0.01% w / w - 20% w / w colloidal silica;

[0198] Group 12:

[0199] (a) 0.1% w / w-30% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0200] (b) 5% w / w-70% w / w sodium octanoate;

[0201] (c) 10% w / w - 90% w / w SNAC;

[0202] (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch;

[0203] (e) 0.01% w / w - 20% w / w sorbitol;

[0204] (f) 0.01% w / w - 15% w / w magnesium stearate;

[0205] (g) 0.01% w / w-20% w / w gelled silica;

[0206] Group 13:

[0207] (a) 0.5% w / w-20% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0208] (b) 10% w / w-60% w / w sodium octanoate;

[0209] (c) 20% w / w - 80% w / w SNAC;

[0210] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0211] (e) 0.05% w / w - 15% w / w sorbitol;

[0212] (f) 0.05% w / w - 10% w / w magnesium stearate;

[0213] (g) 0.05% w / w - 15% w / w colloidal silica;

[0214] Group 14:

[0215] (a) 0.5% w / w-20% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0216] (b) 10% w / w-60% w / w sodium octanoate;

[0217] (c) 20% w / w - 80% w / w SNAC;

[0218] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0219] (e) 0.05% w / w - 15% w / w sorbitol;

[0220] (f) 0.05% w / w - 10% w / w magnesium stearate;

[0221] (g) 0.05% w / w - 15% w / w gelled silica;

[0222] Group 15:

[0223] (a) 1% w / w-10% w / w polypeptides (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0224] (b) 20% w / w-50% w / w sodium octanoate;

[0225] (c) 30% w / w - 70% w / w SNAC;

[0226] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0227] (e) 0.1% w / w - 10% w / w sorbitol;

[0228] (f) 0.1% w / w - 8% w / w magnesium stearate;

[0229] (g) 0.1% w / w-10% w / w colloidal silica;

[0230] Group 16:

[0231] (a) 1% w / w-10% w / w polypeptides (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0232] (b) 20% w / w-50% w / w sodium octanoate;

[0233] (c) 30% w / w - 70% w / w SNAC;

[0234] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0235] (e) 0.1% w / w - 10% w / w sorbitol;

[0236] (f) 0.1% w / w - 8% w / w magnesium stearate;

[0237] (g) 0.1% w / w-10% w / w gelled silica;

[0238] Group 17:

[0239] (a) 1% w / w-5% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0240] (b) 25% w / w-45% w / w sodium octanoate;

[0241] (c) 35% w / w - 55% w / w SNAC;

[0242] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0243] (e) 0.5% w / w - 8% w / w sorbitol;

[0244] (f) 0.5% w / w - 5% w / w magnesium stearate;

[0245] (g) 0.5% w / w - 5% w / w colloidal silica;

[0246] Group 18:

[0247] (a) 1% w / w-5% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0248] (b) 25% w / w-45% w / w sodium octanoate;

[0249] (c) 35% w / w - 55% w / w SNAC;

[0250] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0251] (e) 0.5% w / w - 8% w / w sorbitol;

[0252] (f) 0.5% w / w - 5% w / w magnesium stearate;

[0253] (g) 0.5% w / w - 5% w / w gel silica;

[0254] Group 19:

[0255] (a) 0.5% w / w-25% w / w peptides (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0256] (b) 15% w / w-65% w / w sodium octanoate;

[0257] (c) 15% w / w - 75% w / w SNAC;

[0258] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0259] (e) 0.05% w / w - 15% w / w sorbitol;

[0260] (f) 0.05% w / w - 10% w / w magnesium stearate;

[0261] (g) 0.05% w / w-15% w / w colloidal silica or gel silica;

[0262] Group 20:

[0263] (a) 0.5% w / w-20% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0264] (b) 25% w / w-60% w / w sodium octanoate;

[0265] (c) 20% w / w - 65% w / w SNAC;

[0266] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0267] (e) 0.1% w / w - 10% w / w sorbitol;

[0268] (f) 0.1% w / w - 8% w / w magnesium stearate;

[0269] (g) 0.1% w / w-10% w / w colloidal silica or gel silica;

[0270] Group 21:

[0271] (a) 0.5% w / w-15% w / w peptides (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0272] (b) 30% w / w-60% w / w sodium octanoate;

[0273] (c) 25% w / w - 55% w / w SNAC;

[0274] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0275] (e) 0.5% w / w - 8% w / w sorbitol;

[0276] (f) 0.5% w / w - 5% w / w magnesium stearate;

[0277] (g) 0.5% w / w-5% w / w colloidal silica or gel silica;

[0278] Group 22:

[0279] (a) Approximately 3.8% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0280] (b) Approximately 37% w / w sodium octanoate;

[0281] (c) Approximately 46% w / w SNAC;

[0282] (d) Approximately 8% w / w sodium carboxymethyl starch;

[0283] (e) Approximately 2.7 w / w sorbitol;

[0284] (f) Approximately 1.8% w / w magnesium stearate;

[0285] (g) Approximately 0.9% w / w colloidal silica;

[0286] Group 23:

[0287] (a) Approximately 3.8% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0288] (b) Approximately 37% w / w sodium octanoate;

[0289] (c) Approximately 46% w / w SNAC;

[0290] (d) Approximately 8% w / w sodium carboxymethyl starch;

[0291] (e) Approximately 2.7 w / w sorbitol;

[0292] (f) Approximately 1.8% w / w magnesium stearate;

[0293] (g) Approximately 0.9% w / w gelled silica;

[0294] Group 24:

[0295] (a) Approximately 1.6% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0296] (b) Approximately 38% w / w sodium octanoate;

[0297] (c) Approximately 47% w / w SNAC;

[0298] (d) Approximately 8% w / w sodium carboxymethyl starch;

[0299] (e) Approximately 2.8 w / w sorbitol;

[0300] (f) Approximately 1.8% w / w magnesium stearate;

[0301] (g) Approximately 0.9% w / w colloidal silica;

[0302] Group 25:

[0303] (a) Approximately 1.6% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0304] (b) Approximately 38% w / w sodium octanoate;

[0305] (c) Approximately 47% w / w SNAC;

[0306] (d) Approximately 8% w / w sodium carboxymethyl starch;

[0307] (e) Approximately 2.8 w / w sorbitol;

[0308] (f) Approximately 1.8% w / w magnesium stearate;

[0309] (g) Approximately 0.9% w / w gelled silica;

[0310] Group 26:

[0311] (a) Approximately 1% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0312] (b) Approximately 37.9% w / w sodium octanoate;

[0313] (c) Approximately 47.3% w / w SNAC;

[0314] (d) Approximately 8.3% w / w sodium carboxymethyl starch;

[0315] (e) Approximately 2.8 w / w sorbitol;

[0316] (f) Approximately 1.9% w / w colloidal silica or gel silica;

[0317] (g) Approximately 1% w / w magnesium stearate;

[0318] Group 27:

[0319] (a) Approximately 1.9% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0320] (b) Approximately 37.5% w / w sodium octanoate;

[0321] (c) Approximately 46.9% w / w SNAC;

[0322] (d) Approximately 8.2% w / w sodium carboxymethyl starch;

[0323] (e) Approximately 2.8 w / w sorbitol;

[0324] (f) Approximately 1.9% w / w colloidal silica or gel silica;

[0325] (g) Approximately 0.9% w / w magnesium stearate;

[0326] Group 28:

[0327] (a) Approximately 3.7% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0328] (b) Approximately 36.8% w / w sodium octanoate;

[0329] (c) Approximately 46.0% w / w SNAC;

[0330] (d) Approximately 8.0% w / w sodium carboxymethyl starch;

[0331] (e) Approximately 2.7% w / w sorbitol;

[0332] (f) Approximately 1.8% w / w colloidal silica or gel silica;

[0333] (g) Approximately 0.9% w / w magnesium stearate;

[0334] Group 29:

[0335] (a) Approximately 2.6% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0336] (b) Approximately 52.2% w / w sodium octanoate;

[0337] (c) Approximately 32.6% w / w SNAC;

[0338] (d) Approximately 8.0% w / w sodium carboxymethyl starch;

[0339] (e) Approximately 1.7 w / w sorbitol;

[0340] (f) Approximately 1.7% w / w colloidal silica or gel silica;

[0341] (g) Approximately 1.1% w / w magnesium stearate;

[0342] Group 30:

[0343] 0.1% w / w–30% w / w peptides (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt), for example 0.5% w / w–20% w / w, 1% w / w–10% w / w, or 1% w / w–5% w / w, and

[0344] 0.1% w / w-30% w / w sodium carboxymethyl starch, for example 0.5% w / w-20% w / w, 1% w / w-15% w / w, or 2% w / w-10% w / w.

[0345] This disclosure provides a pharmaceutical composition, wherein a unit dosage form contains or comprises:

[0346] Group 1:

[0347] (a) 0.1% w / w-30% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0348] (b) The molar ratio of sodium octanoate to SNAC is 1:0.1-1;

[0349] (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch;

[0350] Optionally, it also includes:

[0351] (e) 0.01% w / w - 20% w / w filler;

[0352] (f) 0.01% w / w - 15% w / w lubricant;

[0353] (g) 0.01% w / w - 20% w / w gliding agent;

[0354] Group 2:

[0355] (a) 0.5% w / w-25% w / w peptides (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0356] (b) The molar ratio of sodium octanoate to SNAC is 1:0.1-0.8;

[0357] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0358] (e) 0.05% w / w - 15% w / w sorbitol;

[0359] (f) 0.05% w / w - 10% w / w magnesium stearate;

[0360] (g) 0.05% w / w-15% w / w colloidal silica or gel silica;

[0361] Group 3:

[0362] (a) 0.5% w / w-20% w / w polypeptide (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0363] (b) The molar ratio of sodium octanoate to SNAC is 1:0.1-0.65;

[0364] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0365] (e) 0.1% w / w - 10% w / w sorbitol;

[0366] (f) 0.1% w / w - 8% w / w magnesium stearate;

[0367] (g) 0.1% w / w-10% w / w colloidal silica or gel silica;

[0368] Group 4:

[0369] (a) 0.5% w / w-15% w / w peptides (e.g., the compound shown in Figure 1# 18 or its pharmaceutically acceptable salt);

[0370] (b) The molar ratio of sodium octanoate to SNAC is 1:0.1-0.5;

[0371] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0372] (e) 0.5% w / w - 8% w / w sorbitol;

[0373] (f) 0.5% w / w - 5% w / w magnesium stearate;

[0374] (g) 0.5% w / w-5% w / w colloidal silica or gel silica;

[0375] Group 5: Any of the aforementioned compositions, wherein the molar ratio of sodium octanoate to polypeptide is >70:1, for example, greater than 140:1, greater than 148:1, greater than 150:1, greater than 200:1, or greater than 250:1.

[0376] This disclosure provides a pharmaceutical composition, wherein a unit dosage form comprises or is any one of the following:

[0377] Group 1:

[0378] (a) A polypeptide ≤12 mg, approximately 12 mg, approximately 6 mg, or approximately 3 mg;

[0379] (b) 5% w / w-70% w / w sodium octanoate;

[0380] (c) 35% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0381] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0382] Optional, also includes

[0383] (e) 0.5% w / w - 8% w / w filler;

[0384] (f) 0.5% w / w - 5% w / w lubricant;

[0385] (g) 0.5% w / w - 5% w / w gliding agent;

[0386] Group 2:

[0387] (a) A polypeptide ≤12 mg, approximately 12 mg, approximately 6 mg, or approximately 3 mg;

[0388] (b) 15% w / w-65% w / w sodium octanoate;

[0389] (c) 15% w / w-75% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0390] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0391] Optional, also includes

[0392] (e) 0.05% w / w - 15% w / w filler;

[0393] (f) 0.05% w / w - 10% w / w lubricant;

[0394] (g) 0.05% w / w - 15% w / w gliding agent;

[0395] Group 3:

[0396] (a) A polypeptide ≤12 mg, approximately 12 mg, approximately 6 mg, or approximately 3 mg;

[0397] (b) 25% w / w-60% w / w sodium octanoate;

[0398] (c) 20% w / w-65% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0399] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0400] Optional, also includes

[0401] (e) 0.1% w / w - 10% w / w filler;

[0402] (f) 0.1% w / w - 8% w / w lubricant;

[0403] (g) 0.1% w / w-10% w / w gliding agent;

[0404] Group 4:

[0405] (a) Peptides ≤12 mg, such as about 12 mg, about 6 mg or about 3 mg;

[0406] (b) 30% w / w-60% w / w sodium octanoate;

[0407] (c) 25% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0408] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0409] Optional, also includes

[0410] (e) 0.5% w / w - 8% w / w filler;

[0411] (f) 0.5% w / w - 5% w / w lubricant;

[0412] (g) 0.5% w / w - 5% w / w gliding agent;

[0413] Group 5:

[0414] (a) Peptides > 12 mg, such as about 18 mg, about 24 mg or about 48 mg;

[0415] (b) 30% w / w-55% w / w sodium octanoate;

[0416] (c) 30% w / w-65% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0417] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0418] Optional, also includes

[0419] (e) 0.5% w / w - 8% w / w filler;

[0420] (f) 0.5% w / w - 5% w / w lubricant;

[0421] (g) 0.5% w / w - 5% w / w gliding agent.

[0422] This disclosure provides a pharmaceutical composition comprising or being any of the following:

[0423] Group 1:

[0424] (a) 1% w / w-30% w / w peptides;

[0425] (b) The molar ratio of sodium octanoate to polypeptide is greater than 140, for example, a molar ratio greater than 148 or a molar ratio greater than 295;

[0426] (c) 30% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0427] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0428] Optional, also includes

[0429] (e) 0.5% w / w - 8% w / w filler;

[0430] (f) 0.5% w / w - 5% w / w lubricant;

[0431] (g) 0.5% w / w - 5% w / w gliding agent;

[0432] Group 2:

[0433] (a) 0.5% w / w-25% w / w polypeptide;

[0434] (b) The molar ratio of sodium octanoate to polypeptide is greater than 140, for example, greater than 148 or greater than 295;

[0435] (c) 15% w / w-75% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0436] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0437] Optional, also includes

[0438] (e) 0.05% w / w - 15% w / w filler;

[0439] (f) 0.05% w / w - 10% w / w lubricant;

[0440] (g) 0.05% w / w - 15% w / w gliding agent;

[0441] Group 3:

[0442] (a) 1% w / w-20% w / w peptides;

[0443] (b) The molar ratio of sodium octanoate to polypeptide is greater than 140, for example, greater than 148 or greater than 295;

[0444] (c) 20% w / w-65% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0445] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0446] Optional, also includes

[0447] (e) 0.1% w / w - 10% w / w filler;

[0448] (f) 0.1% w / w - 8% w / w lubricant;

[0449] (g) 0.1% w / w-10% w / w gliding agent;

[0450] Group 4:

[0451] (a) 1% w / w-15% w / w peptides;

[0452] (b) The molar ratio of polypeptide to sodium octanoate is greater than 140, for example, greater than 148 or greater than 295;

[0453] (c) 25% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0454] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0455] Optional, also includes

[0456] (e) 0.5% w / w - 8% w / w filler;

[0457] (f) 0.5% w / w - 5% w / w lubricant;

[0458] (g) 0.5% w / w - 5% w / w gliding agent;

[0459] Group 5: Any one of Groups 1-4 above, wherein the content of the compound of formula (C) or its pharmaceutically acceptable salt is ≥200mg, for example ≥250mg or ≥300mg.

[0460] This disclosure provides a pharmaceutical composition comprising or being any of the following:

[0461] Group 1:

[0462] (a) Compound 18# or its pharmaceutically acceptable salt;

[0463] (b) Sodium octanoate;

[0464] (c) The compound of formula (C) or its pharmaceutically acceptable salt (e.g., sodium salt);

[0465] (d) Sodium carboxymethyl starch;

[0466] Optionally, it also includes at least one of a filler, a lubricant, and a flow aid;

[0467] Group 2:

[0468] (a) 0.1% w / w-30% w / w compound 18# or its pharmaceutically acceptable salt;

[0469] (b) 5% w / w-70% w / w sodium octanoate;

[0470] (c) 10% w / w-90% w / w of the compound of formula (C) or a pharmaceutically acceptable salt (e.g., sodium salt);

[0471] (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch;

[0472] Optionally, it also includes:

[0473] (e) 0.01% w / w - 20% w / w filler;

[0474] (f) 0.01% w / w - 15% w / w lubricant;

[0475] (g) 0.01% w / w - 20% w / w gliding agent;

[0476] Group 3:

[0477] (a) 0.5% w / w-20% w / w compound 18# or its pharmaceutically acceptable salt;

[0478] (b) 10% w / w-60% w / w sodium octanoate;

[0479] (c) 20% w / w to 80% w / w of the compound of formula (C) or a pharmaceutically acceptable salt (e.g., a sodium salt);

[0480] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0481] Optional, also includes

[0482] (e) 0.05% w / w - 15% w / w filler;

[0483] (f) 0.05% w / w - 10% w / w lubricant;

[0484] (g) 0.05% w / w - 15% w / w gliding agent;

[0485] Group 4:

[0486] (a) 1% w / w-10% w / w compound 18# or its pharmaceutically acceptable salt;

[0487] (b) 20% w / w-50% w / w sodium octanoate;

[0488] (c) 30% w / w-70% w / w of the compound of formula (C) or a pharmaceutically acceptable salt (e.g., sodium salt);

[0489] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0490] Optional, also includes

[0491] (e) 0.1% w / w - 10% w / w filler;

[0492] (f) 0.1% w / w - 8% w / w lubricant;

[0493] (g) 0.1% w / w-10% w / w gliding agent;

[0494] Group 5:

[0495] (a) 1% w / w-5% w / w compound 18# or its pharmaceutically acceptable salt;

[0496] (b) 25% w / w-45% w / w sodium octanoate;

[0497] (c) 35% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt (e.g., sodium salt);

[0498] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0499] Optional, also includes

[0500] (e) 0.5% w / w - 8% w / w filler;

[0501] (f) 0.5% w / w - 5% w / w lubricant;

[0502] (g) 0.5% w / w - 5% w / w gliding agent;

[0503] Group 6:

[0504] (a) 0.5% w / w to 25% w / w compound 18# or its pharmaceutically acceptable salt;

[0505] (b) 15% w / w-65% w / w sodium octanoate;

[0506] (c) 15% w / w-75% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0507] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0508] Optional, also includes

[0509] (e) 0.05% w / w - 15% w / w filler;

[0510] (f) 0.05% w / w - 10% w / w lubricant;

[0511] (g) 0.05% w / w - 15% w / w gliding agent;

[0512] Group 7:

[0513] (a) 0.5% w / w-20% w / w compound 18# or its pharmaceutically acceptable salt;

[0514] (b) 25% w / w-60% w / w sodium octanoate;

[0515] (c) 20% w / w-65% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0516] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0517] Optional, also includes

[0518] (e) 0.1% w / w - 10% w / w filler;

[0519] (f) 0.1% w / w - 8% w / w lubricant;

[0520] (g) 0.1% w / w-10% w / w gliding agent;

[0521] Group 8:

[0522] (a) 0.5% w / w to 15% w / w compound 18# or its pharmaceutically acceptable salt;

[0523] (b) 30% w / w-60% w / w sodium octanoate;

[0524] (c) 25% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0525] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0526] Optional, also includes

[0527] (e) 0.5% w / w - 8% w / w filler;

[0528] (f) 0.5% w / w - 5% w / w lubricant;

[0529] (g) 0.5% w / w - 5% w / w gliding agent

[0530] Group 9:

[0531] (a) Compound 18# or its pharmaceutically acceptable salt;

[0532] (b) Sodium octanoate;

[0533] (c)SNAC;

[0534] (d) Sodium carboxymethyl starch;

[0535] (e) Sorbitol;

[0536] (f) Magnesium stearate;

[0537] (g) Colloidal silica;

[0538] Group 10:

[0539] (a) Compound 18# or its pharmaceutically acceptable salt;

[0540] (b) Sodium octanoate;

[0541] (c)SNAC;

[0542] (d) Sodium carboxymethyl starch;

[0543] (e) Sorbitol;

[0544] (f) Magnesium stearate;

[0545] (g) Gel-coated silica;

[0546] Group 11:

[0547] (a) 0.1% w / w-30% w / w compound 18# or its pharmaceutically acceptable salt;

[0548] (b) 5% w / w-70% w / w sodium octanoate;

[0549] (c) 10% w / w - 90% w / w SNAC;

[0550] (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch;

[0551] (e) 0.01% w / w - 20% w / w sorbitol;

[0552] (f) 0.01% w / w - 15% w / w magnesium stearate;

[0553] (g) 0.01% w / w - 20% w / w colloidal silica;

[0554] Group 12:

[0555] (a) 0.1% w / w-30% w / w compound 18# or its pharmaceutically acceptable salt;

[0556] (b) 5% w / w-70% w / w sodium octanoate;

[0557] (c) 10% w / w - 90% w / w SNAC;

[0558] (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch;

[0559] (e) 0.01% w / w - 20% w / w sorbitol;

[0560] (f) 0.01% w / w - 15% w / w magnesium stearate;

[0561] (g) 0.01% w / w-20% w / w gelled silica;

[0562] Group 13:

[0563] (a) 0.5% w / w-20% w / w compound 18# or its pharmaceutically acceptable salt;

[0564] (b) 10% w / w-60% w / w sodium octanoate;

[0565] (c) 20% w / w - 80% w / w SNAC;

[0566] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0567] (e) 0.05% w / w - 15% w / w sorbitol;

[0568] (f) 0.05% w / w - 10% w / w magnesium stearate;

[0569] (g) 0.05% w / w - 15% w / w colloidal silica;

[0570] Group 14:

[0571] (a) 0.5% w / w-20% w / w compound 18# or its pharmaceutically acceptable salt;

[0572] (b) 10% w / w-60% w / w sodium octanoate;

[0573] (c) 20% w / w - 80% w / w SNAC;

[0574] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0575] (e) 0.05% w / w - 15% w / w sorbitol;

[0576] (f) 0.05% w / w - 10% w / w magnesium stearate;

[0577] (g) 0.05% w / w - 15% w / w gelled silica;

[0578] Group 15:

[0579] (a) 1% w / w-10% w / w compound 18# or its pharmaceutically acceptable salt;

[0580] (b) 20% w / w-50% w / w sodium octanoate;

[0581] (c) 30% w / w - 70% w / w SNAC;

[0582] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0583] (e) 0.1% w / w - 10% w / w sorbitol;

[0584] (f) 0.1% w / w - 8% w / w magnesium stearate;

[0585] (g) 0.1% w / w-10% w / w colloidal silica;

[0586] Group 16:

[0587] (a) 1% w / w-10% w / w compound 18# or its pharmaceutically acceptable salt;

[0588] (b) 20% w / w-50% w / w sodium octanoate;

[0589] (c) 30% w / w - 70% w / w SNAC;

[0590] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0591] (e) 0.1% w / w - 10% w / w sorbitol;

[0592] (f) 0.1% w / w - 8% w / w magnesium stearate;

[0593] (g) 0.1% w / w-10% w / w gelled silica;

[0594] Group 17:

[0595] (a) 1% w / w-5% w / w Compound 18# or its pharmaceutically acceptable salt; (b) 25% w / w-45% w / w sodium octanoate;

[0596] (c) 35% w / w - 55% w / w SNAC;

[0597] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0598] (e) 0.5% w / w - 8% w / w sorbitol;

[0599] (f) 0.5% w / w - 5% w / w magnesium stearate;

[0600] (g) 0.5% w / w - 5% w / w colloidal silica;

[0601] Group 18:

[0602] (a) 1% w / w-5% w / w compound 18# or its pharmaceutically acceptable salt;

[0603] (b) 25% w / w-45% w / w sodium octanoate;

[0604] (c) 35% w / w - 55% w / w SNAC;

[0605] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0606] (e) 0.5% w / w - 8% w / w sorbitol;

[0607] (f) 0.5% w / w - 5% w / w magnesium stearate;

[0608] (g) 0.5% w / w - 5% w / w gel silica;

[0609] Group 19:

[0610] (a) 0.5% w / w to 25% w / w compound 18# or its pharmaceutically acceptable salt;

[0611] (b) 15% w / w-65% w / w sodium octanoate;

[0612] (c) 15% w / w - 75% w / w SNAC;

[0613] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0614] (e) 0.05% w / w - 15% w / w sorbitol;

[0615] (f) 0.05% w / w - 10% w / w magnesium stearate;

[0616] (g) 0.05% w / w-15% w / w colloidal silica or gel silica;

[0617] Group 20:

[0618] (a) 0.5% w / w-20% w / w compound 18# or its pharmaceutically acceptable salt;

[0619] (b) 25% w / w-60% w / w sodium octanoate;

[0620] (c) 20% w / w - 65% w / w SNAC;

[0621] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0622] (e) 0.1% w / w - 10% w / w sorbitol;

[0623] (f) 0.1% w / w - 8% w / w magnesium stearate;

[0624] (g) 0.1% w / w-10% w / w colloidal silica or gel silica;

[0625] Group 21:

[0626] (a) 0.5% w / w to 15% w / w compound 18# or its pharmaceutically acceptable salt;

[0627] (b) 30% w / w-60% w / w sodium octanoate;

[0628] (c) 25% w / w - 55% w / w SNAC;

[0629] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0630] (e) 0.5% w / w - 8% w / w sorbitol;

[0631] (f) 0.5% w / w - 5% w / w magnesium stearate;

[0632] (g) 0.5% w / w-5% w / w colloidal silica or gel silica;

[0633] Group 22:

[0634] (a) Approximately 3.8% w / w of compound 18# or its pharmaceutically acceptable salt;

[0635] (b) Approximately 37% w / w sodium octanoate;

[0636] (c) Approximately 46% w / w SNAC;

[0637] (d) Approximately 8% w / w sodium carboxymethyl starch;

[0638] (e) Approximately 2.7 w / w sorbitol;

[0639] (f) Approximately 1.8% w / w magnesium stearate;

[0640] (g) Approximately 0.9% w / w colloidal silica;

[0641] Group 23:

[0642] (a) Approximately 3.8% w / w of compound 18# or its pharmaceutically acceptable salt;

[0643] (b) Approximately 37% w / w sodium octanoate;

[0644] (c) Approximately 46% w / w SNAC;

[0645] (d) Approximately 8% w / w sodium carboxymethyl starch;

[0646] (e) Approximately 2.7 w / w sorbitol;

[0647] (f) Approximately 1.8% w / w magnesium stearate;

[0648] (g) Approximately 0.9% w / w gelled silica;

[0649] Group 24:

[0650] (a) Approximately 1.6% w / w of compound 18# or its pharmaceutically acceptable salt;

[0651] (b) Approximately 38% w / w sodium octanoate;

[0652] (c) Approximately 47% w / w SNAC;

[0653] (d) Approximately 8% w / w sodium carboxymethyl starch;

[0654] (e) Approximately 2.8 w / w sorbitol;

[0655] (f) Approximately 1.8% w / w magnesium stearate;

[0656] (g) Approximately 0.9% w / w colloidal silica;

[0657] Group 25:

[0658] (a) Approximately 1.6% w / w of compound 18# or its pharmaceutically acceptable salt;

[0659] (b) Approximately 38% w / w sodium octanoate;

[0660] (c) Approximately 47% w / w SNAC;

[0661] (d) Approximately 8% w / w sodium carboxymethyl starch;

[0662] (e) Approximately 2.8 w / w sorbitol;

[0663] (f) Approximately 1.8% w / w magnesium stearate;

[0664] (g) Approximately 0.9% w / w gelled silica;

[0665] Group 26:

[0666] (a) Approximately 1% w / w of compound 18# or its pharmaceutically acceptable salt;

[0667] (b) Approximately 37.9% w / w sodium octanoate;

[0668] (c) Approximately 47.3% w / w SNAC;

[0669] (d) Approximately 8.3% w / w sodium carboxymethyl starch;

[0670] (e) Approximately 2.8 w / w sorbitol;

[0671] (f) Approximately 1.9% w / w colloidal silica or gel silica;

[0672] (g) Approximately 1% w / w magnesium stearate;

[0673] Group 27:

[0674] (a) Approximately 1.9% w / w of compound 18# or its pharmaceutically acceptable salt;

[0675] (b) Approximately 37.5% w / w sodium octanoate;

[0676] (c) Approximately 46.9% w / w SNAC;

[0677] (d) Approximately 8.2% w / w sodium carboxymethyl starch;

[0678] (e) Approximately 2.8 w / w sorbitol;

[0679] (f) Approximately 1.9% w / w colloidal silica or gel silica;

[0680] (g) Approximately 0.9% w / w magnesium stearate;

[0681] Group 28:

[0682] (a) Approximately 3.7% w / w of compound 18# or its pharmaceutically acceptable salt;

[0683] (b) Approximately 36.8% w / w sodium octanoate;

[0684] (c) Approximately 46.0% w / w SNAC;

[0685] (d) Approximately 8.0% w / w sodium carboxymethyl starch;

[0686] (e) Approximately 2.7% w / w sorbitol;

[0687] (f) Approximately 1.8% w / w colloidal silica or gel silica;

[0688] (g) Approximately 0.9% w / w magnesium stearate;

[0689] Group 29:

[0690] (a) Approximately 2.6% w / w of compound 18# or its pharmaceutically acceptable salt;

[0691] (b) Approximately 52.2% w / w sodium octanoate;

[0692] (c) Approximately 32.6% w / w SNAC;

[0693] (d) Approximately 8.0% w / w sodium carboxymethyl starch;

[0694] (e) Approximately 1.7 w / w sorbitol;

[0695] (f) Approximately 1.7% w / w colloidal silica or gel silica;

[0696] (g) Approximately 1.1% w / w magnesium stearate;

[0697] Group 30:

[0698] 0.1% w / w-30% w / w compound 18# or its pharmaceutically acceptable salts, for example 0.5% w / w-20% w / w, 1% w / w-10% w / w, or 1% w / w-5% w / w, and

[0699] 0.1% w / w-30% w / w sodium carboxymethyl starch, for example 0.5% w / w-20% w / w, 1% w / w-15% w / w, or 2% w / w-10% w / w.

[0700] This disclosure provides a pharmaceutical composition, wherein a unit dosage form contains or comprises:

[0701] Group 1:

[0702] (a) 0.1% w / w-30% w / w compound 18# or its pharmaceutically acceptable salt;

[0703] (b) The molar ratio of sodium octanoate to SNAC is 1:0.1-1;

[0704] (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch;

[0705] Optionally, it also includes:

[0706] (e) 0.01% w / w - 20% w / w filler;

[0707] (f) 0.01% w / w - 15% w / w lubricant;

[0708] (g) 0.01% w / w - 20% w / w gliding agent;

[0709] Group 2:

[0710] (a) 0.5% w / w to 25% w / w compound 18# or its pharmaceutically acceptable salt;

[0711] (b) The molar ratio of sodium octanoate to SNAC is 1:0.1-0.8;

[0712] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0713] (e) 0.05% w / w - 15% w / w sorbitol;

[0714] (f) 0.05% w / w - 10% w / w magnesium stearate;

[0715] (g) 0.05% w / w-15% w / w colloidal silica or gel silica;

[0716] Group 3:

[0717] (a) 0.5% w / w-20% w / w compound 18# or its pharmaceutically acceptable salt;

[0718] (b) The molar ratio of sodium octanoate to SNAC is 1:0.1-0.65;

[0719] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0720] (e) 0.1% w / w - 10% w / w sorbitol;

[0721] (f) 0.1% w / w - 8% w / w magnesium stearate;

[0722] (g) 0.1% w / w-10% w / w colloidal silica or gel silica;

[0723] Group 4:

[0724] (a) 0.5% w / w to 15% w / w compound 18# or its pharmaceutically acceptable salt;

[0725] (b) The molar ratio of sodium octanoate to SNAC is 1:0.1-0.5;

[0726] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0727] (e) 0.5% w / w - 8% w / w sorbitol;

[0728] (f) 0.5% w / w - 5% w / w magnesium stearate;

[0729] (g) 0.5% w / w-5% w / w colloidal silica or gel silica;

[0730] Group 5: Any of the aforementioned compositions, wherein the molar ratio of sodium octanoate to polypeptide is >70:1, for example, greater than 140:1, greater than 148:1, greater than 150:1, greater than 200:1, or greater than 250:1.

[0731] This disclosure provides a pharmaceutical composition, wherein a unit dosage form comprises or is any one of the following:

[0732] Group 1:

[0733] (a) ≤12 mg of compound 18# or its pharmaceutically acceptable salt, about 12 mg, about 6 mg or about 3 mg;

[0734] (b) 5% w / w-70% w / w sodium octanoate;

[0735] (c) 35% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0736] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0737] Optional, also includes

[0738] (e) 0.5% w / w - 8% w / w filler;

[0739] (f) 0.5% w / w - 5% w / w lubricant;

[0740] (g) 0.5% w / w - 5% w / w gliding agent;

[0741] Group 2:

[0742] (a) ≤12 mg of compound 18# or its pharmaceutically acceptable salt, about 12 mg, about 6 mg or about 3 mg;

[0743] (b) 15% w / w-65% w / w sodium octanoate;

[0744] (c) 15% w / w-75% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0745] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0746] Optional, also includes

[0747] (e) 0.05% w / w - 15% w / w filler;

[0748] (f) 0.05% w / w - 10% w / w lubricant;

[0749] (g) 0.05% w / w - 15% w / w gliding agent;

[0750] Group 3:

[0751] (a) ≤12 mg of compound 18# or its pharmaceutically acceptable salt, about 12 mg, about 6 mg or about 3 mg;

[0752] (b) 25% w / w-60% w / w sodium octanoate;

[0753] (c) 20% w / w-65% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0754] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0755] Optional, also includes

[0756] (e) 0.1% w / w - 10% w / w filler;

[0757] (f) 0.1% w / w - 8% w / w lubricant;

[0758] (g) 0.1% w / w-10% w / w gliding agent;

[0759] Group 4:

[0760] (a) ≤12 mg of compound 18# or its pharmaceutically acceptable salt, such as about 12 mg, about 6 mg or about 3 mg;

[0761] (b) 30% w / w-60% w / w sodium octanoate;

[0762] (c) 25% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0763] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0764] Optional, also includes

[0765] (e) 0.5% w / w - 8% w / w filler;

[0766] (f) 0.5% w / w - 5% w / w lubricant;

[0767] (g) 0.5% w / w - 5% w / w gliding agent;

[0768] Group 5:

[0769] (a) Compound 18# or its pharmaceutically acceptable salts, which are greater than 12 mg, for example, about 18 mg, about 24 mg or about 48 mg;

[0770] (b) 30% w / w-55% w / w sodium octanoate;

[0771] (c) 30% w / w-65% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0772] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0773] Optional, also includes

[0774] (e) 0.5% w / w - 8% w / w filler;

[0775] (f) 0.5% w / w - 5% w / w lubricant;

[0776] (g) 0.5% w / w - 5% w / w gliding agent.

[0777] This disclosure provides a pharmaceutical composition comprising or being any of the following:

[0778] Group 1:

[0779] (a) 1% w / w-30% w / w compound 18# or its pharmaceutically acceptable salt;

[0780] (b) The molar ratio of sodium octanoate to polypeptide is greater than 140, for example, a molar ratio greater than 148 or a molar ratio greater than 295;

[0781] (c) 30% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0782] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0783] Optional, also includes

[0784] (e) 0.5% w / w - 8% w / w filler;

[0785] (f) 0.5% w / w - 5% w / w lubricant;

[0786] (g) 0.5% w / w - 5% w / w gliding agent;

[0787] Group 2:

[0788] (a) 0.5% w / w to 25% w / w compound 18# or its pharmaceutically acceptable salt;

[0789] (b) The molar ratio of sodium octanoate to polypeptide is greater than 140, for example, greater than 148 or greater than 295;

[0790] (c) 15% w / w-75% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0791] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[0792] Optional, also includes

[0793] (e) 0.05% w / w - 15% w / w filler;

[0794] (f) 0.05% w / w - 10% w / w lubricant;

[0795] (g) 0.05% w / w - 15% w / w gliding agent;

[0796] Group 3:

[0797] (a) 1% w / w-20% w / w compound 18# or its pharmaceutically acceptable salt;

[0798] (b) The molar ratio of sodium octanoate to polypeptide is greater than 140, for example, greater than 148 or greater than 295;

[0799] (c) 20% w / w-65% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0800] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[0801] Optional, also includes

[0802] (e) 0.1% w / w - 10% w / w filler;

[0803] (f) 0.1% w / w - 8% w / w lubricant;

[0804] (g) 0.1% w / w-10% w / w gliding agent;

[0805] Group 4:

[0806] (a) 1% w / w-15% w / w compound 18# or its pharmaceutically acceptable salt;

[0807] (b) The molar ratio of polypeptide to sodium octanoate is greater than 140, for example, greater than 148 or greater than 295;

[0808] (c) 25% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[0809] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[0810] Optional, also includes

[0811] (e) 0.5% w / w - 8% w / w filler;

[0812] (f) 0.5% w / w - 5% w / w lubricant;

[0813] (g) 0.5% w / w - 5% w / w gliding agent;

[0814] Group 5: Any one of Groups 1-4 above, wherein the content of the compound of formula (C) or its pharmaceutically acceptable salt is ≥200mg, for example ≥250mg or ≥300mg.

[0815] In some embodiments, the pharmaceutical compositions of this disclosure are oral dosage forms. In some embodiments, the pharmaceutical compositions of this disclosure are oral solid dosage forms, such as tablets or capsules.

[0816] This disclosure provides a unit dosage form of any of the aforementioned pharmaceutical compositions. In some embodiments, the unit dosage form is a tablet, for example, a 13mm x 7mm tablet, or, for example, a tablet with a diameter of 2mm-10mm, such as a tablet with a diameter of 6mm or 7mm. This disclosure provides a unit dosage form of any of the aforementioned pharmaceutical compositions. In some embodiments, the unit dosage form is a tablet, for example, a 15mm x 7.5mm tablet.

[0817] In some embodiments, the tablets weigh between 50 mg and 450 mg, for example, 60 mg to 400 mg or 80 mg to 350 mg. In some embodiments, the tablets weigh about 80 mg, about 106 mg, about 108 mg, about 212 mg, or about 320 mg.

[0818] This disclosure provides a multi-unit dosage form pharmaceutical composition comprising at least two discrete unit dosage forms and bound together by a coating and / or a matrix, optionally wherein the coating and / or matrix disintegrates or dissolves in saliva and / or gastrointestinal fluids, thereby releasing the unit dosage form immediately after oral administration, for example, the coating and / or matrix disintegrates or dissolves in saliva and / or gastrointestinal fluids within no more than 5 minutes.

[0819] In some embodiments, the pharmaceutical compositions described herein have good erosion and dissolution properties.

[0820] In some embodiments, the pharmaceutical compositions of this disclosure exhibit good in vivo exposure and / or oral bioavailability. In some embodiments, compared to pharmaceutical compositions containing only any two combinations of the compounds of formula (A) (e.g., sodium caprylate), the compounds of formula (B) (e.g., SNAC), and sodium carboxymethyl starch, the pharmaceutical compositions of this disclosure containing the combination of the compounds of formula (A) (e.g., sodium caprylate), the compounds of formula (B) (e.g., SNAC), and sodium carboxymethyl starch exhibit improved in vivo exposure and / or oral bioavailability, for example, an increase in Cmax of at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500%, and / or, for example, AUClast increased by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500%.

[0821] In some embodiments, the aforementioned pharmaceutical compositions of this disclosure exhibit good stability. In some embodiments, sodium carboxymethyl starch has the effect of increasing the stability of the pharmaceutical compositions of this disclosure.

[0822] In some embodiments, the polypeptide in the aforementioned pharmaceutical composition is a polypeptide suitable for oral administration.

[0823] GLP-1 agonists

[0824] In some embodiments, the polypeptide of this disclosure is a GLP-1 receptor agonist. In some embodiments, the aforementioned polypeptide of this disclosure is a dual agonist of both the GLP-1 receptor and the GIP receptor. In some embodiments, the aforementioned polypeptide of this disclosure is semaglutide or telposide.

[0825] In some embodiments, the polypeptide described above in this disclosure is a GLP-1 analog or a pharmaceutically acceptable salt thereof as shown in (a) general formula (I), R1-X1-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -Glu-Phe-X 23 -X 24-Trp-Leu-X 27 -X 28 -X 29 -X 30 -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2(I)

[0826] in:

[0827] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, pGlu, or absent;

[0828] R2 is -NH2, -OH, or does not exist;

[0829] X1 is selected from amino acid residues of Tyr or His.

[0830] X2 is selected from amino acid residues of Aib or D-Ala;

[0831] X 10 Amino acid residues selected from Val or Tyr or Y1;

[0832] X 12 Amino acid residues selected from Ser or Ile or Y1;

[0833] X 13 Amino acid residues selected from Tyr or Ala or Y1;

[0834] X 14 Amino acid residues selected from Leu or Nle or Y1;

[0835] X 15 Amino acid residues selected from Asp or Glu;

[0836] X 16 Amino acid residues selected from Arg, Glu, Gly, Lys, or Aib, or Y1;

[0837] X 17 Amino acid residues selected from Glu, Ile, or Gln, or Y1;

[0838] X 18 Amino acid residues selected from Ala, Aib, or His;

[0839] X 19 Amino acid residues selected from Ala, Aib, or Gln;

[0840] X 20 Amino acid residues selected from Gln, Glu, and Lys;

[0841] X 23 Amino acid residues selected from Ile or Val;

[0842] X 24 Amino acid residues selected from Ala, Asn, or Gln;

[0843] X 27 Amino acid residues selected from Val, Leu, or Ile;

[0844] X 28 Amino acid residues selected from Arg or Ala;

[0845] X 29 Amino acid residues selected from Gly or Gln;

[0846] X 30 Amino acid residues selected from Gly and Lys;

[0847] Y1 is a Lys, Orn, Dap, Dab, or Cys residue containing a substituent on its side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl}. a -(γ-Glu) b -CO-(CH2) c -COOH;

[0848] a is an integer from 1 to 3 (1, 2, and 3 can be mentioned);

[0849] b is 1 or 2;

[0850] c is an integer between 10 and 30 (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 can be mentioned).

[0851] In some implementations, the GLP-1 analogue represented by the aforementioned general formula (I),

[0852] X1 is selected from amino acid residues of Tyr;

[0853] X2 is selected from amino acid residues of Aib;

[0854] X 10 Amino acid residues selected from Tyr;

[0855] X 12 Amino acid residues selected from Ile;

[0856] X 13 Amino acid residues selected from Tyr;

[0857] X 14 Selected from amino acid residues of Leu or Y1;

[0858] X15 Amino acid residues selected from Asp or Glu;

[0859] X 16 Amino acid residues selected from Arg or Lys or Y1;

[0860] X 17 Amino acid residues selected from Ile;

[0861] X 18 Amino acid residues selected from Ala;

[0862] X 19 Amino acid residues selected from Ala;

[0863] X 20 Amino acid residues selected from Gln;

[0864] X 23 Amino acid residues selected from Ile or Val;

[0865] X 24 Amino acid residues selected from Asn;

[0866] X 27 Amino acid residues selected from Leu or Ile;

[0867] X 28 Amino acid residues selected from Ala;

[0868] X 29 Amino acid residues selected from Gly;

[0869] X 30 Amino acid residues selected from Gly;

[0870] Y1 is a Lys, Orn, Dap, Dab, or Cys residue containing a substituent on its side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl}. a -(γ-Glu) b -CO-(CH2) c -COOH;

[0871] a is an integer between 1 and 3;

[0872] b is 1 or 2;

[0873] c is an integer between 10 and 30.

[0874] In some implementations, the GLP-1 analogue represented by the aforementioned general formula (I) is:

[0875] X1 is Tyr;

[0876] X2 is Aib;

[0877] X 10 For Tyr;

[0878] X 12 For Ile;

[0879] X 13 For Tyr;

[0880] X 14 Y1;

[0881] X 15 For Asp or Glu;

[0882] X 16 For Arg or Lys;

[0883] X 17 For Ile;

[0884] X 18 For Ala;

[0885] X 19 For Ala;

[0886] X 20 For Gln;

[0887] X 23 For Ile or Val;

[0888] X 24 For Asn;

[0889] X 27 For Ile or Leu;

[0890] X 28 For Ala;

[0891] X 29 For Gly;

[0892] X 30 For Gly;

[0893] Y1 is a Lys, Orn, Dap, Dab, or Cys residue containing a substituent on its side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl}. a -(γ-Glu) b -CO-(CH2) c -COOH;

[0894] a is an integer between 1 and 3;

[0895] b is 1 or 2;

[0896] c is an integer between 10 and 30.

[0897] In some implementations, the GLP-1 analogue represented by the aforementioned general formula (I),

[0898] X 16 For Lys;

[0899] X 23 For Val;

[0900] X 27 For Leu.

[0901] In some implementations, the GLP-1 analogue represented by the aforementioned general formula (I),

[0902] X1 is Tyr;

[0903] X2 is either Aib or D-Ala;

[0904] X 10 For Tyr;

[0905] X 12 For Ile;

[0906] X 13 For Tyr;

[0907] X 14 Y1;

[0908] X 15 For Glu;

[0909] X 16 For Arg or Lys;

[0910] X 17 For Ile;

[0911] X 18 For Ala;

[0912] X 19 For Ala;

[0913] X 20 For Gln or Lys;

[0914] X 23 For Ile or Val;

[0915] X 24 For Asn or Gln;

[0916] X 27 For Ile or Leu;

[0917] X 28 For Ala;

[0918] X 29For Gly;

[0919] X 30 For Gly;

[0920] Y1 is a Lys, Orn, Dap, Dab, or Cys residue containing a substituent on its side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl}. a -(γ-Glu) b -CO-(CH2) c -COOH;

[0921] a is an integer between 1 and 3;

[0922] b is 1 or 2;

[0923] c is an integer between 10 and 30.

[0924] In some implementations, the GLP-1 analogue represented by the aforementioned general formula (I),

[0925] X2 is Aib;

[0926] X 20 For Gln;

[0927] X 24 It is Asn.

[0928] In some implementations, a is 2, b is 1 or 2, and c is an integer from 16 to 20 (e.g., c is 16, 17, 18, 19, 20).

[0929] In some implementations, a is 2, b is 1 or 2, and c is 16, 18, or 20.

[0930] In some embodiments, Y1 is Lys with a substituent on its side chain, said substituent being of the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl}. a -(γ-Glu) b -CO-(CH2) c The structure is shown as -COOH; a is 2; b is 1 or 2; c is 16 or 18.

[0931] In some embodiments, the side chain amino groups of the Lys residues in Y1 are covalently linked to the substituents by forming amide bonds.

[0932] In some embodiments, Y1 is K(-OEG-OEG-γGlu-C18-OH) or K(-OEG-OEG-γGlu-C20-OH), wherein K(-OEG-OEG-γGlu-C18-OH) has the following structure:

[0933] K(-OEG-OEG-γGlu-C20-OH) has the following structure:

[0934] In some embodiments, Y1 is K(-OEG-OEG-γGlu-C18-OH) or K(-OEG-OEG-γGlu-C20-OH), wherein:

[0935] K(-OEG-OEG-γGlu-C18-OH) has the following structure:

[0936] K(-OEG-OEG-γGlu-C20-OH) has the following structure:

[0937] In some embodiments, Y1 is composed of an ε-amino group of a Lys residue covalently linked to a substituent via an amide bond, and an α-amino group of a Lys residue linked to the peptide chain.

[0938] In some embodiments of this disclosure, the GLP-1 analogue is selected from the compounds shown as numbers 1#-18# below:

[0939] In some embodiments, the GLP-1 analogues disclosed herein are selected from compounds shown as 7#, 12#, 13#, 14#, 15#, 16#, 17#, or 18#.

[0940] In some embodiments, the GLP-1 analogues of this disclosure comprise the following structures:

[0941] In some embodiments, the GLP-1 analogues of this disclosure are amphoteric compounds, and their pharmaceutically acceptable salts include salts formed by the reaction of acidic or basic compounds with them. In some embodiments, the acidic compound is selected from: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. The basic compound is selected from ammonium, hydroxides of alkali metals or alkaline earth metals, and carbonates and bicarbonates, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, and potassium carbonate.

[0942] In some embodiments, the pharmaceutically acceptable salt of the GLP-1 analogue of this disclosure may be selected from sodium salt or acetate salt. In some embodiments, the pharmaceutically acceptable salt of the GLP-1 analogue of this disclosure is sodium salt.

[0943] In some embodiments, the pharmaceutically acceptable salts of the GLP-1 analogs disclosed herein are selected from sodium salts with the following structures:

[0944] Method for preparing pharmaceutical compositions

[0945] This disclosure also provides a method for producing the aforementioned pharmaceutical composition, comprising the step of mixing the polypeptide with a compound of formula (A) or a pharmaceutically acceptable salt thereof, a compound of formula (B) or a pharmaceutically acceptable salt thereof, and / or sodium carboxymethyl starch.

[0946] In some implementations, the method includes tableting, granulation, or capsule filling steps.

[0947] In some embodiments, the method includes the steps of direct powder compression, wet granulation, dry granulation, or filling enteric-coated capsule shells.

[0948] Use of pharmaceutical compositions

[0949] This disclosure provides the use of any of the foregoing pharmaceutical compositions in the preparation of medicaments for treating non-insulin-dependent diabetes mellitus (e.g., type 2 diabetes), insulin-dependent diabetes mellitus, obesity, non-alcoholic fatty liver disease, hepatic steatosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, dyslipidemia associated with insulin resistance, and / or dyslipidemia associated with diabetes. In some embodiments, this disclosure provides the use of any of the foregoing pharmaceutical compositions in the preparation of medicaments for treating non-insulin-dependent diabetes mellitus. In some embodiments, this disclosure provides the use of any of the foregoing pharmaceutical compositions in the preparation of medicaments for treating obesity. In some embodiments, this disclosure provides the use of any of the foregoing pharmaceutical compositions in the preparation of medicaments for treating type 2 diabetes.

[0950] This disclosure provides a method for treating a disease or condition, said disease or condition being non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, obesity, non-alcoholic fatty liver disease, hepatic steatosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, dyslipidemia associated with insulin resistance, and / or dyslipidemia associated with diabetes.

[0951] This disclosure provides the use of any of the aforementioned pharmaceutical compositions in the preparation of a medicament for treating non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, obesity, non-alcoholic fatty liver disease, hepatic steatosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, dyslipidemia associated with insulin resistance, and / or dyslipidemia associated with diabetes.

[0952] In some embodiments, the treatment comprises simultaneously oral administration of at least two discrete unit dosage forms of the aforementioned formulations, and the at least two unit dosage forms are not included in a multi-unit dosage form. In some embodiments, the treatment comprises simultaneously oral administration of 2-10 unit dosage forms, for example, 2, 3, 4, 5, 6, or 8 unit dosage forms.

[0953] In some embodiments, the unit dosage form is a tablet, for example, a 13mm*7mm tablet, or a tablet with a diameter of 2mm-10mm, such as a tablet with a diameter of 6mm or 7mm. In some embodiments, the unit dosage form is a tablet, for example, a 15*7.5mm tablet. In some embodiments, the unit dosage form is a tablet, for example, a 15*7mm tablet.

[0954] This disclosure provides the use of a multi-unit dosage form of any of the foregoing pharmaceutical compositions in the treatment of non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, obesity, non-alcoholic fatty liver disease, hepatic steatosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, dyslipidemia associated with insulin resistance, and / or dyslipidemia associated with diabetes.

[0955] In some embodiments, the multi-unit dosage form of the pharmaceutical composition comprises at least two discrete unit dosage forms and is bound together by a coating and / or matrix, optionally the coating and / or matrix disintegrating or dissolving in gastric juice and / or saliva within 5 minutes, thereby releasing the unit dosage form immediately after oral administration.

[0956] In some embodiments, the pharmaceutical compositions described herein have good dissolution properties.

[0957] In some embodiments, the aforementioned pharmaceutical compositions of this disclosure exhibit good stability.

[0958] This disclosure also provides another exemplary implementation:

[0959] Implementation Scheme 1: A pharmaceutical composition comprising:

[0960] (a) polypeptide;

[0961] (b) The compound represented by formula (A) or its pharmaceutically acceptable salt: RCOOH(A), wherein R is an aliphatic group;

[0962] (c) The compound represented by formula (B) or its pharmaceutically acceptable salt:

[0963] Where n is selected from an integer between 0 and 4, preferably 0, 1, 2, 3 or 4;

[0964] G1 Independently selected from OH, NH2, NH(C) 1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), halogen, C 1-4 Alkyl or C 1-4 alkoxy groups; and

[0965] L 1 For C2-C 16 Alkylene or C2-C 16 imidene group; and

[0966] (d) Sodium carboxymethyl starch.

[0967] Implementation Scheme 2: The pharmaceutical composition according to Implementation Scheme 1, wherein R in the compound represented by formula (A) is an alkyl group with 1-30 carbon atoms, preferably an alkyl group with 3-20 carbon atoms, and more preferably an alkyl group with 5-16 carbon atoms.

[0968] Implementation Scheme 3: The pharmaceutical composition according to Implementation Scheme 1, wherein the compound represented by formula (A) is a straight-chain fatty acid with 5-16 carbon atoms, preferably caprylic acid, capric acid, or lauric acid.

[0969] Implementation Scheme 4: A pharmaceutical composition according to any one of Implementation Schemes 1-3, wherein the compound represented by formula (B) contains,

[0970] 1) n is 0; or

[0971] 2) When n is 1, G 1 Halogen, C 1-4 Alkyl or C 1-4 Alkoxy, preferably, n is 1, G 1 It is Cl or -OCH3.

[0972] Implementation Scheme 5: A pharmaceutical composition according to any one of Implementation Schemes 1-4, wherein in the compound represented by formula (B), L 1 C 2-16 Alkylene, preferably C 3-15 Alkylene, more preferably C 5-13 Alkylene, most preferably C 5-9 Alkylene.

[0973] Implementation Scheme 6: A pharmaceutical composition according to any one of Implementation Schemes 1-4, wherein the compound represented by formula (B) is selected from compounds with any of the following structures.

[0974] or

[0975] Preferably, it is a compound represented by formula (C):

[0976] Implementation Scheme 7: A pharmaceutical composition according to any one of Implementation Schemes 1-6, wherein the content ratio of the compound represented by formula (b) (A) or a pharmaceutically acceptable salt thereof, the compound represented by formula (c) (B) or a pharmaceutically acceptable salt thereof, and (d) sodium carboxymethyl starch is 0.1-20:0.1-20:0.01-10, preferably 0.5-15:0.5-15:0.1-5 by weight, more preferably 1-10:1-10:0.5-3.

[0977] Implementation Scheme 8: A pharmaceutical composition according to any one of Implementation Schemes 1-6, wherein the sum of the contents of the compound represented by formula (b) (A) or a pharmaceutically acceptable salt thereof and the compound represented by formula (c) (B) or a pharmaceutically acceptable salt thereof is 50% w / w to 98% w / w, and the content of sodium carboxymethyl starch (d) is 0.5% w / w to 20%.

[0978] Preferably, the sum of the contents of the compound represented by formula (b) (A) or its pharmaceutically acceptable salt and the compound represented by formula (c) (B) or its pharmaceutically acceptable salt is 65% w / w to 95% w / w, and the content of sodium carboxymethyl starch (d) is 1% w / w to 15% w / w;

[0979] More preferably, the sum of the contents of the compound represented by formula (b) (A) or its pharmaceutically acceptable salt and the compound represented by formula (c) (B) or its pharmaceutically acceptable salt is 70% w / w to 90% w / w, and the content of sodium carboxymethyl starch (d) is 2% w / w to 10%.

[0980] Implementation Scheme 9: The pharmaceutical composition according to any one of Implementation Schemes 1-8, comprising:

[0981] b) Caprylic acid or its medicinal salts, and

[0982] c) The compound of formula (C) or its pharmaceutically acceptable salt.

[0983] Preferably, it includes

[0984] b) Sodium octanoate, and

[0985] c) The sodium salt of the compound described in formula (C),

[0986] Implementation Scheme 10: A pharmaceutical composition according to any one of Implementation Schemes 1-9, wherein the content of the compound represented by formula (A) or its pharmaceutically acceptable salt is 5% w / w to 70% w / w, preferably 10% w / w to 60% w / w, more preferably 20% w / w to 50% w / w, and most preferably 25% w / w to 45% w / w, calculated based on the total mass of the composition.

[0987] Implementation Scheme 11: A pharmaceutical composition according to any one of Implementation Schemes 1-10, wherein the content of the compound represented by formula (B) or its pharmaceutically acceptable salt is 10% w / w to 90% w / w, preferably 20% w / w to 80% w / w or 15% w / w to 75% w / w, more preferably 30% w / w to 70% w / w, and most preferably 35% w / w to 55% w / w, calculated based on the total mass of the composition.

[0988] Implementation Scheme 12: The pharmaceutical composition according to any one of Implementation Schemes 1-11, wherein the content of sodium carboxymethyl starch is 0.1% w / w-30% w / w, preferably 0.5% w / w-20% w / w, more preferably 1% w / w-15% w / w, and most preferably 2% w / w-10% w / w, calculated based on the total mass of the composition.

[0989] Implementation Scheme 13: The pharmaceutical composition according to any one of Implementation Schemes 1-12, wherein the content of the polypeptide is 0.1% w / w-30% w / w, preferably 0.5% w / w-20% w / w, more preferably 1% w / w-10% w / w, and most preferably 1% w / w-5% w / w, calculated based on the total mass of the composition.

[0990] Implementation Scheme 14: The pharmaceutical composition according to any one of Implementation Schemes 1-13 further includes one or more of a filler, a lubricant, and a flow aid;

[0991] Preferably, the filler is selected from sorbitol, the lubricant is selected from magnesium stearate, and the flow aid is selected from colloidal silica.

[0992] Implementation Scheme 15: A pharmaceutical composition comprising:

[0993] Group 1:

[0994] (a) polypeptide;

[0995] (b) Sodium octanoate;

[0996] (c) The compound of formula (C) or its pharmaceutically acceptable salt, preferably a sodium salt;

[0997] (d) Sodium carboxymethyl starch;

[0998] Optionally, it also includes at least one of a filler, a lubricant, and a flow aid;

[0999] Group 2:

[1000] (a) 0.1% w / w-30% w / w polypeptide;

[1001] (b) 5% w / w-70% w / w sodium octanoate;

[1002] (c) 10% w / w-90% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[1003] (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch;

[1004] Optionally, it also includes:

[1005] (e) 0.01% w / w - 20% w / w filler;

[1006] (f) 0.01% w / w - 15% w / w lubricant;

[1007] (g) 0.01% w / w - 20% w / w gliding agent;

[1008] Group 3:

[1009] (a) 0.5% w / w-20% w / w polypeptide;

[1010] (b) 10% w / w-60% w / w sodium octanoate;

[1011] (c) 20% w / w-80% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[1012] (d) 0.5% w / w-20% w / w sodium carboxymethyl starch;

[1013] Optional, also includes

[1014] (e) 0.05% w / w - 15% w / w filler;

[1015] (f) 0.05% w / w - 10% w / w lubricant;

[1016] (g) 0.05% w / w - 15% w / w gliding agent;

[1017] Group 4:

[1018] (a) 1% w / w - 10% w / w peptides;

[1019] (b) 20% w / w-50% w / w sodium octanoate;

[1020] (c) 30% w / w-70% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[1021] (d) 1% w / w-15% w / w sodium carboxymethyl starch;

[1022] Optional, also includes

[1023] (e) 0.1% w / w - 10% w / w filler;

[1024] (f) 0.1% w / w - 8% w / w lubricant;

[1025] (g) 0.1% w / w-10% w / w gliding agent;

[1026] Group 5:

[1027] (a) 1% w / w-5% w / w peptides;

[1028] (b) 25% w / w-45% w / w sodium octanoate;

[1029] (c) 35% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt;

[1030] (d) 2% w / w-10% w / w sodium carboxymethyl starch;

[1031] Optional, also includes

[1032] (e) 0.5% w / w - 8% w / w filler;

[1033] (f) 0.5% w / w - 5% w / w lubricant;

[1034] (g) 0.5% w / w - 5% w / w gliding agent;

[1035] Implementation Scheme 16: The pharmaceutical composition according to Implementation Scheme 15, wherein the filler is sorbitol, the lubricant is magnesium stearate, and the flow aid is colloidal silica.

[1036] Implementation Scheme 17. The use according to any one of Implementation Schemes 1-16, wherein the polypeptide is a GLP-1 receptor agonist, preferably a dual agonist of GLP-1 receptor and GIP receptor.

[1037] Implementation Scheme 18: A pharmaceutical composition according to any one of Implementation Schemes 1-17, wherein the polypeptide is a GLP-1 analog or a pharmaceutically acceptable salt thereof as shown in (a) general formula (I), R1-X1-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -Glu-Phe-X 23 -X 24 -Trp-Leu-X 27 -X 28 -X 29 -X 30 -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2(I)

[1038] in:

[1039] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, pGlu, or absent;

[1040] R2 is -NH2, -OH, or does not exist;

[1041] X1 is selected from amino acid residues of Tyr or His.

[1042] X2 is selected from amino acid residues of Aib or D-Ala;

[1043] X 10 Amino acid residues selected from Val or Tyr or Y1;

[1044] X 12 Amino acid residues selected from Ser or Ile or Y1;

[1045] X 13 Amino acid residues selected from Tyr or Ala or Y1;

[1046] X 14 Amino acid residues selected from Leu or Nle or Y1;

[1047] X 15 Amino acid residues selected from Asp or Glu;

[1048] X 16 Amino acid residues selected from Arg, Glu, Gly, Lys, or Aib, or Y1;

[1049] X 17 Amino acid residues selected from Glu, Ile, or Gln, or Y1;

[1050] X 18 Amino acid residues selected from Ala, Aib, or His;

[1051] X 19 Amino acid residues selected from Ala, Aib, or Gln;

[1052] X 20 Amino acid residues selected from Gln, Glu, and Lys;

[1053] X 23 Amino acid residues selected from Ile or Val;

[1054] X 24 Amino acid residues selected from Ala, Asn, or Gln;

[1055] X 27 Amino acid residues selected from Val, Leu, or Ile;

[1056] X 28 Amino acid residues selected from Arg or Ala;

[1057] X 29 Amino acid residues selected from Gly or Gln;

[1058] X 30 Amino acid residues selected from Gly and Lys;

[1059] Y1 is a Lys, Orn, Dap, Dab, or Cys residue containing a substituent on its side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl}. a -(γ-Glu) b -CO-(CH2) c -COOH;

[1060] a is an integer between 1 and 3;

[1061] b is 1 or 2;

[1062] c is an integer between 10 and 30;

[1063] Preferably,

[1064] X1 is selected from amino acid residues of Tyr;

[1065] X2 is selected from amino acid residues of Aib;

[1066] X 10 Amino acid residues selected from Tyr;

[1067] X 12 Amino acid residues selected from Ile;

[1068] X 13 Amino acid residues selected from Tyr;

[1069] X 14 Selected from amino acid residues of Leu or Y1;

[1070] X 15 Amino acid residues selected from Asp or Glu;

[1071] X 16 Amino acid residues selected from Arg or Lys or Y1;

[1072] X 17 Amino acid residues selected from Ile;

[1073] X 18 Amino acid residues selected from Ala;

[1074] X 19 Amino acid residues selected from Ala;

[1075] X 20 Amino acid residues selected from Gln;

[1076] X 23 Amino acid residues selected from Ile or Val;

[1077] X 24 Amino acid residues selected from Asn;

[1078] X 27 Amino acid residues selected from Leu or Ile;

[1079] X 28 Amino acid residues selected from Ala;

[1080] X 29 Amino acid residues selected from Gly;

[1081] X 30 Amino acid residues selected from Gly;

[1082] Y1 is as defined in claim 18.

[1083] Implementation Scheme 19: The pharmaceutical composition according to Implementation Scheme 18, wherein: X1 is Tyr;

[1084] X2 is Aib;

[1085] X 10 For Tyr;

[1086] X 12 For Ile;

[1087] X 13 For Tyr;

[1088] X 14 Y1;

[1089] X 15 For Asp or Glu;

[1090] X 16 For Arg or Lys;

[1091] X 17 For Ile;

[1092] X 18 For Ala;

[1093] X 19 For Ala;

[1094] X 20 For Gln;

[1095] X 23 For Ile or Val;

[1096] X 24 For Asn;

[1097] X 27 For Ile or Leu;

[1098] X 28 For Ala;

[1099] X 29 For Gly;

[1100] X 30 For Gly;

[1101] Y1 is as defined in Implementation Scheme 18;

[1102] Preferably,

[1103] X 16 For Lys;

[1104] X 23 For Val;

[1105] X 27 For Leu.

[1106] Implementation Scheme 20: The pharmaceutical composition according to Implementation Scheme 18, wherein:

[1107] X1 is Tyr;

[1108] X2 is either Aib or D-Ala;

[1109] X 10 For Tyr;

[1110] X 12 For Ile;

[1111] X 13 For Tyr;

[1112] X 14 Y1;

[1113] X 15 For Glu;

[1114] X 16 For Arg or Lys;

[1115] X 17 For Ile;

[1116] X 18 For Ala;

[1117] X 19 For Ala;

[1118] X 20 For Gln or Lys;

[1119] X 23 For Ile or Val;

[1120] X 24 For Asn or Gln;

[1121] X 27 For Ile or Leu;

[1122] X 28 For Ala;

[1123] X 29 For Gly;

[1124] X 30 For Gly;

[1125] Y1 is as defined in Implementation Scheme 18;

[1126] Preferably,

[1127] X2 is Aib;

[1128] X 20 For Gln;

[1129] X 24 It is Asn.

[1130] Implementation Scheme 21: A pharmaceutical composition according to any one of Implementation Schemes 17-20, wherein: a is 2, b is 1 or 2, c is an integer from 16 to 20, preferably c is 16, 18 or 20.

[1131] Implementation Scheme 22: A pharmaceutical composition according to any one of Implementation Schemes 17-21, wherein: Y1 is a Lys residue comprising a substituent on a side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γ-Glu) b -CO-(CH2) c -COOH;

[1132] a is 2;

[1133] b is 1 or 2;

[1134] c is 16 or 18.

[1135] Implementation Scheme 23: A pharmaceutical composition according to any one of Implementation Schemes 17-22, wherein: the substituent is covalently linked to an amino group on the side chain via an amide bond, preferably, the substituent is covalently linked to an ε-amino group on the side chain via an amide bond.

[1136] Implementation Scheme 24: A pharmaceutical composition according to any one of Implementation Schemes 17-23, wherein: Y1 is K(-OEG-OEG-γGlu-C18-OH) or K(-OEG-OEG-γGlu-C20-OH).

[1137] K(-OEG-OEG-γGlu-C18-OH) has the following structure:

[1138] Preferably, it has the following structure:

[1139] K(-OEG-OEG-γGlu-C20-OH) has the following structure:

[1140] Preferably, it has the following structure:

[1141] Implementation Scheme 25: A pharmaceutical composition according to any one of Implementation Schemes 1 to 24, wherein: the GLP-1 analogue is selected from the compounds numbered 1#-18# as follows:

[1142] Preferably, the GLP-1 analogue comprises the following structure:

[1143] Implementation Scheme 26: The pharmaceutical composition according to any one of Implementation Schemes 1-25, wherein the pharmaceutical composition is an oral preparation, preferably an oral solid preparation, more preferably a tablet or capsule.

[1144] Implementation Scheme 27: The pharmaceutical composition according to any one of Implementation Schemes 1-26 is presented in unit dosage form, preferably a tablet.

[1145] Implementation Scheme 28: A pharmaceutical composition according to any one of Implementation Schemes 1-26, which is a multi-unit dosage form comprising at least two discrete unit dosage forms as described in Implementation Scheme 27, and bound together by a coating and / or matrix, optionally wherein the coating and / or matrix disintegrates or dissolves in saliva and / or the gastrointestinal tract, thereby releasing the unit dosage form immediately after oral administration.

[1146] Implementation Scheme 29: A method for preparing a pharmaceutical composition according to any one of Implementation Schemes 1-28, comprising the step of mixing the polypeptide with a compound of formula (A) or a pharmaceutically acceptable salt thereof, a compound of formula (B) or a pharmaceutically acceptable salt thereof, and / or sodium carboxymethyl starch;

[1147] Preferably, the method includes granulation, tableting, or capsule filling steps;

[1148] More preferably, the method includes the steps of direct powder compression, wet granulation, dry granulation, tableting, or capsule filling.

[1149] Implementation Scheme 30: Use of the pharmaceutical composition according to any one of Implementation Schemes 1-29 in the preparation of a medicament for treating non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, obesity, non-alcoholic fatty liver disease, hepatic steatosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, dyslipidemia associated with insulin resistance, and / or dyslipidemia associated with diabetes.

[1150] Implementation Scheme 31: The pharmaceutical composition according to any one of Implementation Scheme 30 is prepared for the treatment of non-insulin-dependent diabetes mellitus.

[1151] Implementation Scheme 32: The pharmaceutical composition according to any one of Implementation Scheme 30 is prepared for the treatment of obesity. Attached Figure Description

[1152] Figure 1 shows the structure of an exemplary compound of this disclosure. Detailed Implementation

[1153] To facilitate understanding of this disclosure, some technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[1154] The amino acid sequences disclosed herein contain standard single-letter or three-letter codes for twenty amino acids. Unless otherwise specified, all amino acid residues in this disclosure are preferably configured in the L-type. Additionally, Aib is α-aminoisobutyric acid, D-Ala is D-alanine, Orn is ornithine, Dap is 2,3-diaminopropionic acid, and Dab is 2,4-diaminobutyric acid.

[1155] The term "agonist" is defined as a substance that activates the GLP-1 receptor or the GIP receptor.

[1156] The term “GLP-1 / GIP dual agonist” refers to a substance or ligand that can activate both GLP-1 and GIP receptors.

[1157] The term "treatment" includes suppressing, slowing down, stopping, or reversing existing symptoms or the progression or severity of a patient's condition.

[1158] The term "natural amino acids" refers to 20 common amino acids: 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).

[1159] The term "non-natural amino acid" refers to an amino acid that is not naturally encoded or is not found in the genetic code of any organism. For example, non-natural amino acids can be 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. Furthermore, the term also includes derivatives obtained by chemically modifying the C-terminal carboxyl group (or N-terminal amino group and / or its side chain functional groups) of natural (or non-natural) amino acids.

[1160] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, such as an alkyl group containing 1 to 8 carbon atoms, an alkyl group containing 1 to 6 carbon atoms, or 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. Alkyl groups can be, for example, lower alkyl groups containing 1 to 6 carbon atoms, and 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. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any accessible connection point. The substituent can be one or more 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. The substituted alkyl group disclosed herein can be methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, or hydroxy-substituted alkyl.

[1161] In this disclosure, the different terms such as "X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[1162] The “modification” of amino acids as described in this disclosure refers to the substitution, addition or deletion of amino acids, including the substitution or addition of any one or more of 20 natural amino acids.

[1163] The term "natural GLP-1" refers to a naturally occurring molecule of the glucagon family of peptides or the venom exopeptide family, wherein: the glucagon family of peptides is encoded by the proglucagonogenamic gene and includes three highly homologous small peptides, namely glucagon (1-29), GLP-1 (1-37), and GLP-2 (1-33); and venom exopeptides are peptides expressed in lizards and, similar to GLP-1, are insulin-stimulating. In some embodiments, the term "natural GLP-1" also refers to human GLP-1 (7-37) and human GLP-1 (7-36).

[1164] The term "GLP-1 analogue" refers to an amino acid modification or chemical modification having, compared to natural GLP-1 (particularly compared to human GLP-1 (7-37) and human GLP-1 (7-36)), up to 25, up to 24, up to 23, up to 22, up to 21, up to 20, up to 19, up to 18, up to 17, up to 16, up to 15, up to 14, up to 13, up to 12, up to 11, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2, or 1 amino acid modification or chemical modification, wherein the amino acid modification may be an amino acid substitution, addition, and / or deletion; and the chemical modification may be a chemical modification selected from the following groups: amide, carbohydrate, alkyl, acyl, ester, polyethylene glycol (PEG) group, sialylated group, glycosylated group, etc.

[1165] The term "substitution" of an amino acid residue as used in this disclosure refers to the substitution of an amino acid residue by a different substance.

[1166] The term "polyethylene glycol" or "PEG" refers to a mixture of condensation polymers of ethylene oxide and water, existing in linear or branched form, with the general formula H(OCH2CH2). n OH indicates that n is at least equal to 9. Unless otherwise specified, this term includes polymers of polyethylene glycol with an average total molecular weight selected from 5,000 to 40,000 Daltons.

[1167] The term "fatty acid" refers to a carboxylic acid having a long fatty acid tail (chain), which may be saturated or unsaturated; in this disclosure, fatty acids are carboxylic acids having a straight-chain or branched aliphatic group with C4-C30.

[1168] The term "peptide" encompasses the category of peptides with modified amino and carboxyl terms. For example, amino acid chains containing terminal carboxylic acids with amide groups substituted are also included in the amino acid sequences named as natural amino acids.

[1169] All hydrogen atoms described in this disclosure can be replaced by their isotopes (protium, deuterium, tritium), and any hydrogen atom in the compounds disclosed herein can also be replaced by isotopic atoms.

[1170] The terms “optional” or “optionally” mean that the event or environment described below may, but does not have to, occur, and the description includes the possibility that the event or environment may or may not occur. For example, “optionally alkyl-substituted heterocyclic group” means that an 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.

[1171] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, that are independently substituted by a substituent. Substituents are only considered in their possible chemical positions, and those skilled in the art can determine (experimentally or theoretically) 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).

[1172] The term "agonist activity" refers to the ability of compounds according to this disclosure to activate human GIP receptors and human GLP-1 receptors. In some examples, "agonist activity" is expressed as relative activity, specifically referring to the ratio of the activation ability of the compounds of this disclosure for GLP-1R to their activation ability for GIP receptors.

[1173] The term "medicinal salt" refers to the salts of the compounds disclosed herein, which are safe and effective in mammalian use and possess the intended biological activity. Commonly used acids that form acid addition salts include: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid; the salts include sulfates, pyrosulfates, trifluoroacetates, sulfites, bisulfites, phosphates, hydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, bromides, iodides, acetates, propionates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptarates, and propynates. Oxalate, malonate, succinate, octanoate, fumarate, maleate, butyn-1,4-diacidate, hexyn-1,6-diacidate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc., such as trifluoroacetate. Basic substances can also form salts with GLP-1 analogs; these basic substances include ammonium, alkali metal or alkaline earth metal hydroxides, and carbonates and bicarbonates, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, etc.

[1174] Semaglutide is a GLP-1 receptor monoagonal peptide drug developed by Novo Nordisk of Denmark.

[1175] Telboride is a GIP receptor / GLP-1 receptor dual agonist peptide drug developed by Eli Lilly and Company. Its structure is as follows:

[1176] YAibEGTFTSDYSIAibLDKIAQKAFVQWLIAGGPSSGAPPPS-NH2, containing the following fatty acids. Modify the 20th bit K.

[1177] "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 its biological activity. In this document, "pharmaceutical composition" and "formulation" are used interchangeably.

[1178] As used herein, the term "excipient" refers to any component other than the active therapeutic ingredient. Excipients can be inert, inactive, and / or pharmaceutically inactive substances. Excipients can be used for a variety of purposes, such as as carriers, fillers, binders, lubricants, flow aids, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, emulsifiers, and / or to improve the administration and / or absorption of the active ingredient. Those skilled in the art can select one or more of the above-mentioned excipients through routine experimentation without any undue burden, based on the specific desired performance of the solid oral dosage form. The amount of each excipient used can vary within the range conventionally practiced in the art. The techniques and excipients that can be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 6th edition, Rowe et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain (2009); and Remington: the Science and Practice of Pharmacy, 21st edition, Gennaro, Ed., Lippincott Williams & Wilkins (2005).

[1179] As used herein, the terms “about” or “approximately” mean a numerical value within an acceptable margin of error for a specific value 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, in every practice in the art, “about” may mean within or above a standard deviation of 1. Alternatively, “about” or “substantially comprises” may mean a range of up to ±20%, for example, about 5.5 pH means pH 5.5 ± 1.1. Furthermore, particularly for biological systems or processes, the term may mean up to an order of magnitude or up to five times the numerical value. Unless otherwise stated, when a specific value appears in this application and claims, the meaning of “about” or “substantially comprises” should be assumed to be within an acceptable margin of error for that specific value.

[1180] The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[1181] Example

[1182] To illustrate this disclosure in more detail, the following specific embodiments are provided, but the embodiments of this disclosure are not limited thereto. Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions; or under conditions recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[1183] Table 1. Some experimental instruments and their sources

[1184] The formulations in Tables 2-7 of the following examples can be formulated into single tablets or multiple unit tablets according to the tableting parameters. The content of each component in the formulations shown in Tables 2-7 is the total content required for each formulation unit. For example, the content of each component in Formulation F1 in Table 2 is the total content required for 6 tablets. For example, the content of each component in Formulation F15 in Table 5 is the total content required for 1 tablet.

[1185] Example 1. Preparation of GLP-1 analogs

[1186] The GLP-1 analogue is compound 18# prepared in Example 1 of WO2023083301 (which is incorporated herein by reference in its entirety).

[1187] The molecular structure of compound 18# is as follows:

[1188] H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAP PPS-NH2

[1189] The structural formula is as follows:

[1190] Example 2. Preparation of the pharmaceutical composition

[1191] The formulations for F1-F19 are shown in Table 2-5:

[1192] Table 2: Formulations for F1-F4

[1193] Table 3: Formulations for F5-F7

[1194] Table 4: Formulations for F8-F14

[1195] Table 5: Formulations for F15-F19

[1196] Table 6: Formulation of F20-F25

[1197] Table 7: Formulation of F26-F37

[1198] Tablets were prepared according to the following process based on the prescription in Table 2-5: Sodium 8-(2-hydroxybenzamide)octanoate (SNAC), API (compound 18#), sodium octanoate, sodium carboxymethyl starch, sorbitol, colloidal silica and magnesium stearate (added internally) were mixed evenly, then dry granulated, and then magnesium stearate was added externally and mixed evenly before tableting.

[1199] Tablets were prepared according to the following process based on the prescription in Table 6-7: Sodium 8-(2-hydroxybenzamide)octanoate (SNAC), API (compound 18#), sodium octanoate, sodium carboxymethyl starch, sorbitol and gelled silica were mixed evenly, dry granulation was performed, magnesium stearate was added and mixed evenly, and then tableted.

[1200] Example 3. In vivo oral absorption and delivery experiment of GLP-1 agonist formulation in dogs (I)

[1201] Experimental Methods: A single oral administration experiment was conducted on beagles, divided into 3 groups of 6 males each. Animals were fasted overnight but allowed free access to water. 30 minutes prior to administration, all animals were given 10 μg / kg of pentagastrin via intramuscular injection. The test dogs were given the corresponding numbered tablet on an empty stomach according to the administration method in Table 6. The tablet was placed at the back of the dog's mouth to prevent chewing, then the mouth was closed, and 10 mL of tap water was administered via syringe to promote swallowing. Alternatively, 40 mL of water was given via force-feeding immediately before tablet administration, followed by 10 mL of tap water via syringe after tablet administration (water volume strictly controlled) to promote swallowing. Animals were allowed free access to food 4 hours after administration; water intake was restricted from 1 hour before administration until 4 hours after administration, but free access to water was permitted at the rest of the time period. Venous blood samples were collected at 0 h before administration and at 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 144 h, and 168 h after administration. The plasma drug concentration of compound 18# was determined by HPLC / MS-MS. Pharmacokinetic parameters in vivo were calculated using Analyst (version 1.7.3), Watson LIMS (version 7.6.1), and WinNonlin (version 8.1) software.

[1202] Table 8: Administration methods for dogs

[1203] Table 9: Pharmacokinetic Results in Dogs I

[1204] Table 9 shows the in vivo pharmacokinetic results in dogs. The results indicate that the F1 formulation (containing SNAC, sodium octanoate, and sodium carboxymethyl starch) had a higher in vivo exposure compared to the F2 formulation (containing SNAC and sodium carboxymethyl starch) or the F3 formulation (containing sodium octanoate and sodium carboxymethyl starch), suggesting that the formulation containing the combination of SNAC, sodium octanoate, and sodium carboxymethyl starch has better bioavailability.

[1205] Example 4. In vivo oral absorption and delivery experiment of GLP-1 agonist formulation in dogs (II)

[1206] A single oral administration trial was conducted in beagles, divided into three groups of six males each. Animals were fasted overnight but allowed free access to water. Thirty minutes prior to administration, all animals received an intramuscular injection of 6 μg / kg of pentagastrin. The test dogs were given the corresponding numbered tablet on an empty stomach according to the administration method described in Table 8. The tablet was placed at the back of the dog's mouth to prevent chewing, then the mouth was closed, and 10 mL of tap water was administered via syringe to facilitate swallowing. Alternatively, 40 mL of water was given via force-feeding immediately before tablet administration, followed by 10 mL of tap water via syringe after tablet administration to facilitate swallowing. Free access to food was permitted four hours after administration; water intake was restricted from one hour before administration until four hours after administration, but free access to water was permitted at the rest of the time period. Venous blood samples were collected at 0 h before administration and at 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, and 168 h after administration. The plasma drug concentration of compound 18# was determined by HPLC / MS-MS. Pharmacokinetic parameters in vivo were calculated using Analyst (version 1.7.3), Watson LIMS (version 7.6.1), and WinNonlin (version 8.1) software.

[1207] Table 10: Administration methods for dogs

[1208] Table 11: Pharmacokinetic Results in Dogs (II)

[1209] As shown in Table 11, the pharmacokinetic (PK) results in dogs indicate that, at the same API dosage, increasing the number of formulation units reduces C... max and AUC last All have been improved.

[1210] These results indicate that increasing the number of formulation units improves the in vivo exposure level of the formulation compared to a single tablet. Unexpectedly, the combination of SNAC, sodium caprylate, and sodium carboxymethyl starch in the formulation significantly improved the oral bioavailability of the peptide, and the addition of sodium carboxymethyl starch further improved the delivery capabilities of SNAC and sodium caprylate.

[1211] Example 5. In vivo oral absorption and delivery study of GLP-1 agonist formulation in dogs (II)

[1212] Experimental Methods: A single oral administration test was conducted on beagles, with 6 males in each group. Animals were fasted overnight but allowed free access to water. 30 minutes prior to administration, all test animals were given 10 μg / kg of pentagastrin via intramuscular injection. The test dogs were given the corresponding numbered test formulation on an empty stomach according to the administration method in Table 12. The tablet was placed at the back of the dog's mouth to prevent chewing, then the mouth was closed, and 10 mL of tap water was administered via syringe to promote swallowing. Alternatively, 40 mL of water was given via force-feeding immediately before tablet administration, followed by 10 mL of tap water via syringe after tablet administration (water volume strictly controlled) to promote swallowing. Free access to food was permitted 4 hours after administration; water intake was restricted from 1 hour before administration until 4 hours after administration, but free access to water was permitted at the rest of the time period. Venous blood samples were collected at 0 h before administration and at 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 144 h, and 168 h after administration. Plasma drug concentrations of compound 18# were determined using LC-MS / MS bioanalytical methods, and data were processed using Analyst (Applied Biosystems). A non-compartmental model was used. (Version 8.4, Pharsight, Mountain View, NCA) Analyzed blood drug concentration-time data.

[1213] Table 12: Administration methods for dogs

[1214] Table 13: Pharmacokinetic Results in Dogs (II)

[1215] Example 6. Stability study of the formulation

[1216] Place the bare tablets of F1 or F4 formulation in a transparent open petri dish and conduct light exposure, high temperature (40°C), high temperature (60°C), and high humidity (RH) (75%) tests.

[1217] Illumination conditions: Under room temperature conditions, the bare sample film is placed open inside an illumination chamber. The total illuminance of the light source should not be less than 1.2 × 10⁻⁶ lx ± 500 lx. 6 The near-ultraviolet lamp energy is no less than 200 W·hr / m³. 2 Samples were taken and tested at 5, 10, and 30 days.

[1218] High temperature 40℃: The bare sample is placed in a constant temperature device with the opening open, and the temperature is set to 40℃ (±2℃). Samples are taken for testing at 5 days, 10 days and 30 days.

[1219] High temperature 60℃: The bare sample is placed in a constant temperature device with the opening open, and the temperature is set to 60℃ (±2℃). Samples are taken for testing at 5 days, 10 days and 30 days.

[1220] High humidity RH 75%: The bare test specimen is placed open in a constant humidity device and placed at 25℃ (±2℃) and relative humidity 75%±5%. Samples are taken for testing at 5 days, 10 days and 30 days.

[1221] Table 14: Stability of the formulation

[1222] Table 14 shows that under light conditions, the growth rate of total impurities in formulation F1 containing sodium carboxymethyl starch decreased; under high humidity (RH 75%) conditions, the sample of formulation F4 without sodium carboxymethyl starch had absorbed moisture to the surface and could not be detected after 5 days of storage, indicating that the addition of sodium carboxymethyl starch to the formulation can improve the stability of the formulation.

[1223] Although the invention has been described in detail with the aid of accompanying drawings and examples for clarity of understanding, these descriptions and examples should not be construed as limiting the scope of this disclosure. All patent and scientific literature disclosures cited herein are clearly and fully incorporated by reference.

Claims

1. A pharmaceutical composition comprising: (a) polypeptide; (b) The compound represented by formula (A) or its pharmaceutically acceptable salt: RCOOH(A), wherein R is an aliphatic group; (c) The compound represented by formula (B) or its pharmaceutically acceptable salt: in, n is an integer selected from 0 to 4, preferably 0, 1, 2, 3 or 4; G 1 Independently selected from OH, NH2, NH(C) 1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), halogen, C 1-4 Alkyl or C 1-4 alkoxy groups; and L 1 For C2-C 16 Alkylene or C2-C 16 imidene group; and (d) Sodium carboxymethyl starch.

2. The pharmaceutical composition according to claim 1, wherein R in the compound represented by formula (A) is an alkyl group with 1-30 carbon atoms, preferably an alkyl group with 3-20 carbon atoms, and more preferably an alkyl group with 5-16 carbon atoms.

3. The pharmaceutical composition according to claim 1 or 2, wherein the compound represented by formula (A) is a straight-chain fatty acid with 5-16 carbon atoms, preferably caprylic acid, capric acid, or lauric acid.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the compound represented by formula (B), 1) n is 0; or 2) When n is 1, G 1 Halogen, C 1-4 Alkyl or C 1-4 Alkoxy, preferably, n is 1, G 1 It is Cl or -OCH3.

5. The pharmaceutical composition according to any one of claims 1-4, wherein in the compound represented by formula (B), L 1 C 2-16 Alkylene, preferably C 3-15 Alkylene, more preferably C 5-13 Alkylene, most preferably C 5-9 Alkylene.

6. The pharmaceutical composition according to any one of claims 1-4, wherein the compound represented by formula (B) is selected from compounds with any of the following structures. or Preferably, it is a compound represented by formula (C):

7. The pharmaceutical composition according to any one of claims 1-6, wherein, The content ratio of the compound of formula (b) or its pharmaceutically acceptable salt, the compound of formula (c) or its pharmaceutically acceptable salt, and sodium carboxymethyl starch (d) is 0.1-20:0.1-20:0.01-10, preferably 0.5-15:0.5-15:0.1-5 by weight, more preferably 1-10:1-10:0.5-3.

8. The pharmaceutical composition according to any one of claims 1-6, wherein, The sum of the contents of the compound represented by formula (b) (A) or its pharmaceutically acceptable salt and the compound represented by formula (c) (B) or its pharmaceutically acceptable salt is 50% w / w-98% w / w, and the content of sodium carboxymethyl starch (d) is 0.5% w / w-20%. Preferably, the sum of the contents of the compound represented by formula (b) (A) or its pharmaceutically acceptable salt and the compound represented by formula (c) (B) or its pharmaceutically acceptable salt is 65% w / w to 95% w / w, and the content of sodium carboxymethyl starch (d) is 1% w / w to 15% w / w; More preferably, the sum of the contents of the compound represented by formula (b) (A) or its pharmaceutically acceptable salt and the compound represented by formula (c) (B) or its pharmaceutically acceptable salt is 70% w / w to 90% w / w, and the content of sodium carboxymethyl starch (d) is 2% w / w to 10%.

9. The pharmaceutical composition according to any one of claims 1-8, comprising: b) Caprylic acid or its medicinal salts, and c) The compound of formula (C) or its pharmaceutically acceptable salt. Preferably, it includes b) Sodium octanoate, and c) The sodium salt of the compound described in formula (C), 10. The pharmaceutical composition according to any one of claims 1-9, wherein, The content of the compound represented by formula (A) or its pharmaceutically acceptable salt is 5% w / w to 70% w / w, preferably 10% w / w to 60% w / w or 15% w / w to 65% w / w, more preferably 20% w / w to 50% w / w or 25% w / w to 60% w / w, and most preferably 25% w / w to 45% w / w or 30% w / w to 60% w / w, calculated based on the total mass of the composition.

11. The pharmaceutical composition according to any one of claims 1-10, wherein, The content of the compound represented by formula (B) or its pharmaceutically acceptable salt is 10% w / w to 90% w / w, preferably 20% w / w to 80% w / w or 15% w / w to 75% w / w, more preferably 30% w / w to 70% w / w or 20% w / w to 65% w / w, and most preferably 35% w / w to 55% w / w or 25% w / w to 55% w / w, based on the total mass of the composition.

12. The pharmaceutical composition according to any one of claims 1-11, wherein, The sodium carboxymethyl starch content is 0.1% w / w-30% w / w, preferably 0.5% w / w-20% w / w, more preferably 1% w / w-15% w / w, and most preferably 2% w / w-10% w / w, calculated based on the total mass of the composition.

13. The pharmaceutical composition according to any one of claims 1-12, wherein, The content of the polypeptide is 0.1% w / w-30% w / w, preferably 0.5% w / w-20% w / w, more preferably 1% w / w-10% w / w, and most preferably 1% w / w-5% w / w, calculated based on the total mass of the composition.

14. The pharmaceutical composition according to any one of claims 1-13, further comprising one or more of a filler, a lubricant, and a flow aid; Preferably, the filler is selected from sorbitol, the lubricant is selected from magnesium stearate, and the flow aid is selected from colloidal silica or gel silica.

15. A pharmaceutical composition comprising: Group 1: (a) polypeptide; (b) Sodium octanoate; (c) The compound of formula (C) or its pharmaceutically acceptable salt, preferably a sodium salt; (d) Sodium carboxymethyl starch; Optionally, it also includes at least one of a filler, a lubricant, and a flow aid; Group 2: (a) 0.1% w / w-30% w / w polypeptide; (b) 5% w / w-70% w / w sodium octanoate; (c) 10% w / w-90% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt; (d) 0.1% w / w - 30% w / w sodium carboxymethyl starch; Optionally, it also includes: (e) 0.01% w / w - 20% w / w filler; (f) 0.01% w / w - 15% w / w lubricant; (g) 0.01% w / w - 20% w / w gliding agent; Group 3: (a) 0.5% w / w-20% w / w polypeptide; (b) 10% w / w-60% w / w sodium octanoate; (c) 20% w / w-80% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt; (d) 0.5% w / w-20% w / w sodium carboxymethyl starch; Optional, also includes (e) 0.05% w / w - 15% w / w filler; (f) 0.05% w / w - 10% w / w lubricant; (g) 0.05% w / w - 15% w / w gliding agent; Group 4: (a) 1% w / w - 10% w / w peptides; (b) 20% w / w-50% w / w sodium octanoate; (c) 30% w / w-70% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt; (d) 1% w / w-15% w / w sodium carboxymethyl starch; Optional, also includes (e) 0.1% w / w - 10% w / w filler; (f) 0.1% w / w - 8% w / w lubricant; (g) 0.1% w / w-10% w / w gliding agent; Group 5: (a) 1% w / w-5% w / w peptides; (b) 25% w / w-45% w / w sodium octanoate; (c) 35% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt; (d) 2% w / w-10% w / w sodium carboxymethyl starch; Optional, also includes (e) 0.5% w / w - 8% w / w filler; (f) 0.5% w / w - 5% w / w lubricant; (g) 0.5% w / w - 5% w / w gliding agent; Group 6: (a) 0.5% w / w-25% w / w polypeptide; (b) 15% w / w-65% w / w sodium octanoate; (c) 15% w / w-75% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt; (d) 0.5% w / w-20% w / w sodium carboxymethyl starch; Optional, also includes (e) 0.05% w / w - 15% w / w filler; (f) 0.05% w / w - 10% w / w lubricant; (g) 0.05% w / w - 15% w / w gliding agent; Group 7: (a) 0.5% w / w-20% w / w polypeptide; (b) 25% w / w-60% w / w sodium octanoate; (c) 20% w / w-65% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt; (d) 1% w / w-15% w / w sodium carboxymethyl starch; Optional, also includes (e) 0.1% w / w - 10% w / w filler; (f) 0.1% w / w - 8% w / w lubricant; (g) 0.1% w / w-10% w / w gliding agent; Group 8: (a) 0.5% w / w-15% w / w polypeptide; (b) 30% w / w-60% w / w sodium octanoate; (c) 25% w / w-55% w / w of the compound of formula (C) or a pharmaceutically acceptable salt thereof, preferably a sodium salt; (d) 2% w / w-10% w / w sodium carboxymethyl starch; Optional, also includes (e) 0.5% w / w - 8% w / w filler; (f) 0.5% w / w - 5% w / w lubricant; (g) 0.5% w / w - 5% w / w gliding agent.

16. The pharmaceutical composition of claim 15, wherein the filler is sorbitol, the lubricant is magnesium stearate, and the flow aid is colloidal silica or gel silica.

17. The use according to any one of claims 1-16, wherein the polypeptide is a GLP-1 receptor agonist, preferably a dual agonist of GLP-1 receptor and GIP receptor.

18. The pharmaceutical composition according to any one of claims 1-17, wherein the polypeptide is a GLP-1 analog as shown in (a) general formula (I) or a pharmaceutically acceptable salt thereof, R1-X1-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X19-X 20 -Glu-Phe-X 23 -X 24 -Trp-Leu-X 27 -X 28 -X 29 -X 30 -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (I) in: R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, pGlu, or absent; R2 is -NH2, -OH, or does not exist; X1 is selected from amino acid residues of Tyr or His. X2 is selected from amino acid residues of Aib or D-Ala; X 10 Amino acid residues selected from Val or Tyr or Y1; X 12 Amino acid residues selected from Ser or Ile or Y1; X 13 Amino acid residues selected from Tyr or Ala or Y1; X 14 Amino acid residues selected from Leu or Nle or Y1; X 15 Amino acid residues selected from Asp or Glu; X 16 Amino acid residues selected from Arg, Glu, Gly, Lys, or Aib, or Y1; X 17 Amino acid residues selected from Glu, Ile, or Gln, or Y1; X 18 Amino acid residues selected from Ala, Aib, or His; X 19 Amino acid residues selected from Ala, Aib, or Gln; X 20 Amino acid residues selected from Gln, Glu, and Lys; X 23 Amino acid residues selected from Ile or Val; X 24 Amino acid residues selected from Ala, Asn, or Gln; X 27 Amino acid residues selected from Val, Leu, or Ile; X 28 Amino acid residues selected from Arg or Ala; X 29 Amino acid residues selected from Gly or Gln; X 30 Amino acid residues selected from Gly and Lys; Y1 is a Lys, Orn, Dap, Dab, or Cys residue containing a substituent on its side chain, said substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl}. a -(γ-Glu) b -CO-(CH2) c -COOH; a is an integer between 1 and 3; b is 1 or 2; c is an integer between 10 and 30; Preferably, X1 is selected from amino acid residues of Tyr; X2 is selected from amino acid residues of Aib; X 10 Amino acid residues selected from Tyr; X 12 Amino acid residues selected from Ile; X 13 Amino acid residues selected from Tyr; X 14 Selected from amino acid residues of Leu or Y1; X 15 Amino acid residues selected from Asp or Glu; X 16 Amino acid residues selected from Arg or Lys or Y1; X 17 Amino acid residues selected from Ile; X 18 Amino acid residues selected from Ala; X 19 Amino acid residues selected from Ala; X 20 Amino acid residues selected from Gln; X 23 Amino acid residues selected from Ile or Val; X 24 Amino acid residues selected from Asn; X 27 Amino acid residues selected from Leu or Ile; X 28 Amino acid residues selected from Ala; X 29 Amino acid residues selected from Gly; X 30 Amino acid residues selected from Gly; Y1 is as defined in claim 18.

19. The pharmaceutical composition according to claim 18, wherein: X1 is Tyr; X2 is Aib; X 10 For Tyr; X 12 For Ile; X 13 For Tyr; X 14 Y1; X 15 For Asp or Glu; X 16 For Arg or Lys; X 17 For Ile; X 18 For Ala; X 19 For Ala; X 20 For Gln; X 23 For Ile or Val; X 24 For Asn; X 27 For Ile or Leu; X 28 For Ala; X 29 For Gly; X 30 For Gly; Y1 is as defined in claim 18; Preferably, X 16 For Lys; X 23 For Val; X 27 For Leu.

20. The pharmaceutical composition according to claim 18, wherein: X1 is Tyr; X2 is either Aib or D-Ala; X 10 For Tyr; X 12 For Ile; X 13 For Tyr; X 14 Y1; X 15 For Glu; X 16 For Arg or Lys; X 17 For Ile; X 18 For Ala; X 19 For Ala; X 20 For Gln or Lys; X 23 For Ile or Val; X 24 For Asn or Gln; X 27 For Ile or Leu; X 28 For Ala; X 29 For Gly; X 30 For Gly; Y1 is as defined in claim 18; Preferably, X2 is Aib; X 20 For Gln; X 24 It is Asn.

21. The pharmaceutical composition according to any one of claims 17-20, wherein: a is 2, b is 1 or 2, and c is an integer from 16 to 20. Preferably, c is 16, 18 or 20.

22. The pharmaceutical composition according to any one of claims 17-21, wherein: Y1 is a Lys residue containing a substituent on its side chain, the substituent having the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl}. a -(γ-Glu) b -CO-(CH2) c -COOH; a is 2; b is 1 or 2; c is 16 or 18.

23. The pharmaceutical composition according to any one of claims 17-22, wherein: The substituent is covalently linked to the amino group on the side chain via an amide bond, preferably, the substituent is covalently linked to the ε-amino group on the side chain via an amide bond.

24. The pharmaceutical composition according to any one of claims 17-23, wherein: Y1 is K(-OEG-OEG-γGlu-C18-OH) or K(-OEG-OEG-γGlu-C20-OH), K(-OEG-OEG-γGlu-C18-OH) has the following structure: Preferably, it has the following structure: K(-OEG-OEG-γGlu-C20-OH) has the following structure: Preferably, it has the following structure:

25. The pharmaceutical composition according to any one of claims 1 to 24, wherein: The GLP-1 analogues mentioned are selected from the compounds numbered 1#-18# below: Preferably, the GLP-1 analogue comprises the following structure:

26. The pharmaceutical composition according to any one of claims 1-25, wherein the pharmaceutical composition is an oral dosage form, preferably an oral solid dosage form, more preferably a tablet or capsule.

27. The pharmaceutical composition according to any one of claims 1-26, wherein it is presented in unit dosage form, preferably a tablet.

28. The pharmaceutical composition according to any one of claims 1-26, which is a multi-unit dosage form comprising at least two discrete unit dosage forms as described in claim 27, and bound together by a coating and / or matrix, optionally said coating and / or matrix disintegrating or dissolving in saliva and / or the gastrointestinal tract, thereby releasing said unit dosage form immediately after oral administration.

29. A method for preparing a pharmaceutical composition according to any one of claims 1-28, comprising the step of mixing the polypeptide with a compound of formula (A) or a pharmaceutically acceptable salt thereof, a compound of formula (B) or a pharmaceutically acceptable salt thereof, and / or sodium carboxymethyl starch; Preferably, the method includes granulation, tableting, or capsule filling steps; More preferably, the method includes the steps of direct powder compression, wet granulation, dry granulation, tableting, or capsule filling.

30. Use of the pharmaceutical composition according to any one of claims 1-29 in the preparation of a medicament for treating non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, obesity, non-alcoholic fatty liver disease, hepatic steatosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, dyslipidemia associated with insulin resistance, and / or dyslipidemia associated with diabetes.

31. The pharmaceutical composition according to any one of claims 30 in the preparation of a treatment for non-insulin-dependent diabetes mellitus.

32. The pharmaceutical composition according to any one of claims 30 is used in the preparation of a treatment for obesity.

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