Oral polypeptide composition

Abstract

The invention belongs to the field of biological medicine, and particularly relates to an oral polypeptide composition for improving gastrointestinal tract absorption of polypeptide medicine. Specifically disclosed is an oral polypeptide composition comprising polypeptide molecules, medium-chain fatty acids and salts thereof, amino acids, and N-(8-(2-hydroxybenzoyl) amino) caprylic acid (NAC) and salts thereof. The oral polypeptide preparation disclosed by the invention can effectively improve the blood concentration of the polypeptide and improve the bioavailability of the oral polypeptide.

Description

[0001] Priority Claim

[0002] This disclosure claims the priority of a Chinese patent application with the application number 202410710353.4, titled "An Oral Polypeptide Composition", filed on June 3, 2024. This disclosure incorporates the entire text of the above-mentioned Chinese patent application by reference.

[0003] This disclosure claims the priority of a Chinese patent application with the application number 202411335782.4, titled "An Oral Polypeptide Composition", filed on September 24, 2024. This disclosure incorporates the entire text of the above-mentioned Chinese patent application by reference. Technical Field

[0004] This disclosure belongs to the field of biomedicine and specifically relates to an oral polypeptide composition. Background Art

[0005] Polypeptide drugs are a class of biopolymers formed by short-chain amino acids linked by peptide bonds, usually consisting of 10 to 50 amino acids, and are an important branch in the current field of drug research and development. Polypeptide drugs can specifically bind to targets such as receptors or enzymes, and this binding usually has high affinity. This enables polypeptide drugs to precisely regulate specific biological processes without affecting other physiological functions compared to small molecule drugs. Compared with many macromolecular biopharmaceuticals, polypeptides usually have lower immunogenicity because their smaller molecular structure and characteristics closer to natural peptides make them less likely to stimulate strong immune responses. Compared with complex biopharmaceuticals, the synthesis process of polypeptide drugs is simpler and more controllable, which makes the production process more efficient and cost-effective. At the same time, natural polypeptides can also be modified by various means to enhance their efficacy, improve pharmacokinetic properties or reduce side effects.

[0006] At the present stage, the main administration method of polypeptide drugs is by injection. Injection is an invasive administration method that needs to be carried out through the skin, which may cause pain and discomfort to patients. In addition, injection usually requires the operation of medical professionals or the patients themselves, which increases the complexity and inconvenience of administration. Injection may also lead to complications such as injection site infection and local tissue damage. Especially when the operation is improper or the same site is repeatedly injected, due to the pain and inconvenience caused by injection, patients may be reluctant to receive injections regularly according to the doctor's advice, affecting the treatment effect. Therefore, it is very necessary to develop an oral dosage form of polypeptide drugs.

[0007] Although oral peptide drugs have obvious advantages in convenience and acceptance, the scientific and technological difficulties encountered in their development process are still quite severe. These challenges are mainly reflected in the generally low bioavailability of peptide drugs, mainly due to stability and absorption barriers. Under the action of gastric acid and intestinal enzymes, peptides are easily decomposed, which greatly reduces their bioavailability through the oral route. In order to achieve an effective therapeutic effect, it is necessary to ensure that sufficient amounts of drugs can stably pass through the digestive system and enter the blood circulation. In addition, due to the large size and polar characteristics of peptide drug molecules, they are difficult to pass through the intestinal mucosa. Even if the peptides can remain stable in the intestine, their absorption efficiency may still be low.

[0008] (Oral semaglutide) is the first approved oral glucagon-like peptide-1 (GLP-1) receptor agonist, marking a major breakthrough in the field of peptide therapy. The success of this study not only opens up a new path for the application of semaglutide itself, but also paves the way for the development and commercialization of other potential oral peptide drugs. It proves that through appropriate formulation and technology, some biologically active molecules that can traditionally only be administered by injection can be converted into oral form.

[0009] Developed by Emisphere Technologies technology, which achieves its effects through the use of specialized chemical carriers, which are called "Eligen carriers." Using sodium N-(8-(2-hydroxybenzoyl)amino) caprylate (SNAC) in the Eligen carrier increases the stability and absorption rate of semaglutide in the stomach by adjusting the pH value in the stomach and affecting the permeability of the gastric mucosa. However, clinical data show that The bioavailability of a drug is only about 0.8%. Bioavailability refers to the proportion of a drug that enters the systemic circulatory system from the site of administration. For a drug, low bioavailability means that only a small portion of the administered dose eventually reaches the blood circulation and takes effect. In order to overcome the problem of low blood drug concentration caused by low bioavailability, the drug dose needs to be increased. This not only increases costs, but may also increase the risk of drug side effects. Low bioavailability is often accompanied by large individual differences, which may lead to unstable or unpredictable treatment effects. If frequent dosing is required to compensate for low bioavailability, patient compliance with treatment may be reduced, leading to poor treatment effects and improper disease management.

[0010] In summary, as a revolutionary peptide therapeutic drug, It brings the convenience of oral treatment to patients, but there is still the problem of low bioavailability that needs to be solved. Summary of the invention

[0011] The object of the present disclosure is to provide an oral polypeptide composition.

[0012] Another object of the present disclosure is to provide a preparation method of an oral polypeptide composition.

[0013] Another object of the present disclosure is to provide a use of an oral polypeptide composition.

[0014] Another object of the present disclosure is to provide a pharmaceutical composition containing an oral polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor and its use.

[0015] In one aspect of the present disclosure, there is provided an oral polypeptide composition, the composition comprising: a polypeptide molecule, a medium-chain fatty acid or its salt, an amino acid, and N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt.

[0016] In some technical solutions of the present disclosure, the polypeptide is a pharmaceutically acceptable peptide.

[0017] In some technical solutions of the present disclosure, the polypeptide molecule is a compound containing multiple amino acids or having at least one peptide bond or its pharmaceutically acceptable salt.

[0018] In some technical solutions of the present disclosure, the molecular weight of the polypeptide molecule is 0.1 kDa to 20 kDa, preferably 0.1 kDa to 15 kDa, preferably 0.1 kDa to 10 kDa, preferably 0.1 kDa to 9.0 kDa, preferably 0.1 kDa to 5.0 kDa, preferably 0.1 kDa to 2.0 kDa; preferably 0.5 kDa to 20 kDa, preferably 0.5 kDa to 15 kDa, preferably 0.5 kDa to 10 kDa, preferably 0.5 kDa to 9.0 kDa, preferably 0.5 kDa to 5.0 kDa, preferably 0.5 kDa to 2.0 kDa; preferably 1.0 kDa to 20 kDa, preferably 1.0 kDa to 15 kDa, preferably 1.0 kDa to 10 kDa, preferably 1.0 kDa to 9.0 kDa, preferably 1.0 kDa to 5.0 kDa, preferably 1.0 kDa to 2.0 kDa; preferably 5.0 kDa to 20 kDa, preferably 5.0 kDa to 15 kDa, preferably 5.0 kDa to 10 kDa, preferably 5.0 kDa to 9.0 kDa; preferably 10.0 kDa to 20 kDa, preferably 10.0 kDa to 15 kDa.

[0019] In some technical solutions of the present disclosure, the molecular weight of the polypeptide molecule is 0.1 kDa, 0.5 kDa, 1 kDa, 1.5 kDa, 2 kDa, 2.5 kDa, 3 kDa, 3.5 kDa, 4 kDa, 4.5 kDa, 5 kDa, 5.5 kDa, 6 kDa, 6.5 kDa, 7 kDa, 7.5 kDa, 8 kDa, 8.5 kDa, 9 kDa, 9.5 kDa, 10 kDa, 15 kDa or 20 kDa.

[0020] In some technical solutions of the present disclosure, the polypeptide molecule includes a linear structure and a cyclic structure.

[0021] In some technical solutions of the present disclosure, the polypeptide molecule is a linear peptide, a cyclic peptide, or a peptide containing both a linear structure and a cyclic structure.

[0022] In some technical solutions of the present disclosure, the polypeptide drug molecule includes a modified peptide, a derivative peptide, and a peptidomimetic.

[0023] In some technical solutions of the present disclosure, the polypeptide molecule is selected from glucagon-like peptide-1 (GLP-1), GLP-1 analogs, GLP-1 receptor agonists, semaglutide, liraglutide, tirzepatide, exenatide, exenatide-4, lixisenatide, taspoglutide, langlenatide, GLP-1(7-37), GLP-1(7-36)NH2, GLP-2, GLP-2 agonists or analogs, somatostatin or analogs, parathyroid hormone (PTH) fragments or analogs, or a pharmaceutically acceptable salt thereof.

[0024] In some technical solutions of the present disclosure, the pharmaceutically acceptable salts include water-soluble salts and water-insoluble salts.

[0025] In some technical solutions of the present disclosure, the GLP-1 analogs are selected from acylated GLP-1 analogs, diacylated GLP-1 analogs, and long-acting albumin-binding fatty acid-derivatized GLP-1 analogs.

[0026] In some technical solutions of the present disclosure, the GLP-1 receptor agonists are selected from dual agonists of GLP-1 receptor / glucagon receptor (GCGR), dual agonists of GLP-1 receptor / glucose-dependent insulinotropic polypeptide (GIP) receptor, dual agonists of GLP-1 receptor / islet amyloid polypeptide (Amylin) receptor, and triple agonists of GLP-1 receptor / GIP receptor / GCGR.

[0027] In some technical solutions of the present disclosure, the GLP-2 agonist or analog includes teduglutide and elsiglutide.

[0028] In some technical solutions of the present disclosure, the somatostatin or analog includes octreotide.

[0029] In some technical solutions of the present disclosure, the parathyroid hormone fragment or analog includes teriparatide.

[0030] In some technical solutions of the present disclosure, the polypeptide molecules used are selected from the polypeptide drug molecules semaglutide, teriparatide, octreotide, and tirzepatide.

[0031] In some technical solutions of the present disclosure, the polypeptide molecules used are selected from the polypeptide drug molecules semaglutide, liraglutide, and tirzepatide.

[0032] In some technical solutions of the present disclosure, the medium-chain fatty acid is a fatty acid with a carbon chain length of 6 to 12 carbon atoms, and its structural formula is CH3(CH2) n COOH, where n is greater than or equal to 4 and less than or equal to 10.

[0033] In some technical solutions of the present disclosure, the medium-chain fatty acid is selected from one or more of caproic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and lauric acid.

[0034] In some technical solutions of the present disclosure, the medium-chain fatty acid salt is selected from one or more of sodium salt, potassium salt, and ammonium salt.

[0035] In some technical solutions of the present disclosure, the medium-chain fatty acid salt is sodium decanoate.

[0036] In some technical solutions of the present disclosure, the amino acid is an amino acid with a nitrogen-containing side chain.

[0037] In some technical solutions of the present disclosure, the amino acid with a nitrogen-containing side chain is selected from at least one of lysine, arginine, asparagine, glutamine, tryptophan, ornithine, citrulline, pyrrolysine, and histidine.

[0038] In some technical solutions of the present disclosure, the amino acid with a nitrogen-containing side chain is preferably selected from any one or more of citrulline and arginine.

[0039] In some technical solutions of the present disclosure, the N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) salt is selected from one or more of sodium N-(8-(2-hydroxybenzoyl)amino)octanoate, potassium N-(8-(2-hydroxybenzoyl)amino)octanoate, and ammonium N-(8-(2-hydroxybenzoyl)amino)octanoate.

[0040] In some technical solutions of the present disclosure, the salt of NAC used is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC).

[0041] In some technical solutions of the present disclosure, the ratio of the polypeptide molecule, medium-chain fatty acid or its salt, amino acid, and N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt is 0.1-100:20-1000:1-200:20-160.

[0042] In some technical solutions of the present disclosure, the action site of the oral polypeptide composition is the gastrointestinal tract.

[0043] In some technical solutions of the present disclosure, the oral polypeptide composition can promote the stable absorption of polypeptide drug molecules in the gastrointestinal tract.

[0044] In some technical solutions of the present disclosure, the oral polypeptide composition has different microstructures.

[0045] In another aspect of the present disclosure, there is provided an oral polypeptide preparation, which contains the oral polypeptide composition described in the first aspect of the present invention and a pharmaceutically acceptable excipient.

[0046] In some technical solutions of the present disclosure, the oral polypeptide preparation includes tablets, capsules, capsules within capsules, micro-patch systems within capsules, lozenges, pills, Ovules, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, pharmaceutically acceptable gums, chewable tablets, effervescent tablets, and multi-particle dosage forms.

[0047] In some technical solutions of the present disclosure, the pharmaceutically acceptable excipients include, but are not limited to, fillers, glidants, granulation binders, lubricants, and disintegrants.

[0048] In another aspect of the present disclosure, there is provided the use of the oral polypeptide composition or oral polypeptide preparation of the present disclosure for:

[0049] (i) preparing a drug for preventing and / or treating diseases;

[0050] (ii) treating diseases.

[0051] In some technical solutions of the present disclosure, the diseases include endocrine diseases, neurodegenerative diseases, vascular diseases, kidney diseases, fatty liver diseases, and cancers, polycystic ovary syndrome, bone metabolism and osteoporosis, knee osteoarthritis, sleep apnea syndrome, osteoarthropathy, acromegaly, carcinoid syndrome, insulinoma, intestinal fistula, esophageal variceal bleeding, and metabolic myopathy.

[0052] In some technical solutions of the present disclosure, the endocrine diseases include glucose metabolism disorders, diabetes, and obesity;

[0053] In some technical solutions of the present disclosure, the neurodegenerative diseases include Alzheimer's disease and other forms of dementia, Parkinson's disease, multiple sclerosis, and Huntington's disease;

[0054] In some technical solutions of the present disclosure, the cardiovascular diseases include atherosclerosis, hyper-coagulable state and hypocoagulable state, coronary artery disease, and cerebrovascular events;

[0055] In some technical solutions of the present disclosure, the kidney diseases include renal failure;

[0056] In some technical solutions of the present disclosure, the fatty liver includes non-alcoholic fatty liver.

[0057] In another aspect of the present disclosure, there is provided an oral polypeptide composition, which includes: a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor, amino acids, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt.

[0058] In one technical solution of the present disclosure, the polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0059] In one technical solution of the present disclosure, the polypeptide composition includes: a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor, amino acids, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt; the polypeptide composition does not contain a complexing molecule, and the complexing molecule is a C 6-10 aromatic ring or a C 5-10 heteroaromatic ring compound.

[0060] In one technical solution of the present disclosure, the complexing molecule is selected from nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0061] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not higher than about 55% w / w.

[0062] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not higher than about 50% w / w.

[0063] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not higher than about 45% w / w.

[0064] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not higher than about 40% w / w.

[0065] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not higher than about 35% w / w.

[0066] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is 49% w / w, 48% w / w, 47% w / w, 46% w / w, 45% w / w, 44% w / w, 43% w / w, 42% w / w, 41% w / w, 40% w / w, 39% w / w, 38% w / w, 37% w / w, 36% w / w or 35% w / w.

[0067] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not lower than about 20% w / w.

[0068] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not lower than about 25% w / w.

[0069] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not lower than about 30% w / w.

[0070] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not lower than 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 28% w / w, 29% w / w or 30% w / w.

[0071] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 20-50% w / w.

[0072] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 20-45% w / w.

[0073] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 20-40% w / w.

[0074] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 25-50% w / w.

[0075] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 25-45% w / w.

[0076] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 25-40% w / w.

[0077] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 30-50% w / w.

[0078] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 30-45% w / w.

[0079] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 30-40% w / w.

[0080] In one technical solution of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about 30-35% w / w.

[0081] In one technical solution of the present disclosure, the content of the amino acid is not higher than about 20% w / w.

[0082] In one technical solution of the present disclosure, the content of the amino acid is not higher than about 18% w / w.

[0083] In one technical solution of the present disclosure, the content of the amino acid is not higher than about 15% w / w.

[0084] In one aspect of the present disclosure, the content of the amino acid is not higher than 19% w / w, 18% w / w, 17% w / w, 16% w / w, 15% w / w, 14% w / w, 13% w / w or 12% w / w.

[0085] In one aspect of the present disclosure, the content of the amino acid is not less than about 5% w / w.

[0086] In one aspect of the present disclosure, the content of the amino acid is not less than about 7% w / w.

[0087] In one aspect of the present disclosure, the content of the amino acid is not less than about 8% w / w.

[0088] In one aspect of the present disclosure, the content of the amino acid is not less than about 9% w / w.

[0089] In one aspect of the present disclosure, the content of the amino acid is not less than about 10% w / w.

[0090] In one aspect of the present disclosure, the content of the amino acid is not less than about 5.0% w / w, 5.5% w / w, 6.0% w / w, 7.5% w / w, 7.8% w / w, 8.3% w / w, 8.5% w / w, 8.8% w / w, 9% w / w, 9.2% w / w, 9.5% w / w or 10% w / w.

[0091] In one aspect of the present disclosure, the content of the amino acid is about 5 - 20% w / w.

[0092] In one aspect of the present disclosure, the content of the amino acid is about 5 - 20% w / w.

[0093] In one aspect of the present disclosure, the content of the amino acid is about 5 - 18% w / w.

[0094] In one aspect of the present disclosure, the content of the amino acid is about 5 - 15% w / w.

[0095] In one aspect of the present disclosure, the content of the amino acid is about 8 - 20% w / w.

[0096] In one aspect of the present disclosure, the content of the amino acid is about 8 - 18% w / w.

[0097] In one aspect of the present disclosure, the content of the amino acid is about 8 - 15% w / w.

[0098] In one aspect of the present disclosure, the content of the amino acid is about 9 - 20% w / w.

[0099] In one technical solution of the present disclosure, the content of the amino acid is about 10-20% w / w.

[0100] In one technical solution of the present disclosure, the content of the amino acid is about 9-15% w / w.

[0101] In one technical solution of the present disclosure, the content of the amino acid is about 10-15% w / w.

[0102] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is not higher than about 40% w / w.

[0103] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is not higher than about 35% w / w.

[0104] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is not higher than about 39% w / w, 38% w / w, 37% w / w, 36% w / w or 35% w / w.

[0105] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is not lower than about 10% w / w.

[0106] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is not lower than about 15% w / w.

[0107] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is not lower than about 20% w / w.

[0108] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is not lower than about 25% w / w.

[0109] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is not lower than about 30% w / w.

[0110] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is not lower than about 10% w / w, 12% w / w, 14% w / w, 15% w / w, 16% w / w, 18% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 28% w / w, 29% w / w or 30% w / w.

[0111] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is about 10-40% w / w.

[0112] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is about 15-40% w / w.

[0113] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is about 15-35% w / w.

[0114] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is 20-40% w / w.

[0115] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is about 25-35% w / w.

[0116] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is about 25-40% w / w.

[0117] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is about 30-40% w / w.

[0118] In one technical solution of the present disclosure, the content of the medium-chain fatty acid or its salt is about 30-35% w / w.

[0119] In one technical solution of the present disclosure, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor does not exceed about 15% w / w.

[0120] In one technical solution of the present disclosure, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor does not exceed about 10% w / w.

[0121] In one technical solution of the present disclosure, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is about 0.1-15% w / w.

[0122] In one technical solution of the present disclosure, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is about 0.5-10% w / w.

[0123] In one technical solution of the present disclosure, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is about 0.8-10% w / w.

[0124] In one technical solution of the present disclosure, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is about 1.0-7.0% w / w.

[0125] In one technical solution of the present disclosure, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is 0.2% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 3.3% w / w, 3.4% w / w, 6.9% w / w, 7.0% w / w, 8.0% w / w, 9.0% w / w, 10.0% w / w.

[0126] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not higher than about 90% w / w.

[0127] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 85% w / w.

[0128] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not higher than about 80% w / w.

[0129] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not lower than about 50% w / w.

[0130] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not lower than about 60% w / w.

[0131] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 70% w / w.

[0132] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 50 - 80% w / w.

[0133] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 60-80% w / w.

[0134] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 70-80% w / w.

[0135] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is 60% w / w, 62% w / w, 63% w / w, 64% w / w, 65% w / w, 67% w / w, 68% w / w, 70% w / w, 71% w / w, 72% w / w, 73% w / w, 74% w / w, 75% w / w, 75.5% w / w, 75.8% w / w, 75.9% w / w, 77% w / w, 79% w / w, 80% w / w.

[0136] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content of the amino acid is not higher than that of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt and / or the medium-chain fatty acid or its salt.

[0137] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content of the amino acid is not higher than that of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt and the medium-chain fatty acid or its salt.

[0138] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content of the medium-chain fatty acid or its salt is not higher than that of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt.

[0139] In one technical solution of the present disclosure, in the polypeptide composition, the mass ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about (1-3):3:(1.5-6).

[0140] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content ratio of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt to the medium-chain fatty acid or its salt is about 1:(0.5-2), such as 1:1, 2:1, 1.5:1, 1:1.5.

[0141] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content ratio of the amino acid and N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is about (1-2):3, such as 1:3, 2:3, 1.5:3.

[0142] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 1:(2.5-3.5):(2.5-3.5).

[0143] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 1:(2.6-3.4):(2.6-3.4).

[0144] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 1:(2.7-3.3):(2.7-3.3).

[0145] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 1:(2.8-3.2):(2.8-3.2).

[0146] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 1:(2.9-3.1):(2.9-3.1).

[0147] In one technical solution of the present disclosure, in the polypeptide composition, the mass percentage content ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 1:3:3.

[0148] In one technical solution of the present disclosure, the mass percentage content of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt and medium-chain fatty acid or its salt is the same.

[0149] In one technical solution of the present disclosure, the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is a GLP-1 receptor agonist.

[0150] In one technical solution of the present disclosure, the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is semaglutide.

[0151] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, no more than about 20% w / w amino acids, no more than about 55% w / w N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt.

[0152] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, no more than about 20% w / w amino acids, no more than about 55% w / w N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and no less than about 10% w / w medium-chain fatty acid or its salt.

[0153] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, no more than about 20% w / w amino acids, no more than about 55% w / w N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and no less than about 15% w / w medium-chain fatty acid or its salt.

[0154] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, no more than about 20% w / w amino acids, no more than about 50% w / w N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and no less than about 10% w / w medium-chain fatty acid or its salt.

[0155] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-55% w / w N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and no less than about 10% w / w medium-chain fatty acid or its salt.

[0156] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and no less than about 15% w / w medium-chain fatty acid or its salt.

[0157] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, amino acids, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt, wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is no more than about 90% w.

[0158] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, no more than about 20% w / w of amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, and no less than about 10% w / w of medium-chain fatty acids or their salts. Wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts is not less than about 50% w / w.

[0159] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts is about 50-90% w / w.

[0160] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w of amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts. Wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts is not higher than about 90% w.

[0161] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w of amino acids, no less than about 20% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, and no less than about 15% w / w of medium-chain fatty acids or their salts; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts is about 50-90% w / w.

[0162] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w of amino acids, about 20-55% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, and no less than about 15% w / w of medium-chain fatty acids or their salts; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts is about 70-80% w / w.

[0163] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, and about 20-40% w / w medium-chain fatty acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 70-80% w / w.

[0164] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w of amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 50-90% w / w.

[0165] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w of amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not higher than about 80% w.

[0166] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w of amino acids, about 20-55% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not higher than about 80% w.

[0167] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-55% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and not less than about 10% w / w medium-chain fatty acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not higher than about 90% w.

[0168] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and no less than about 15% w / w medium-chain fatty acid or its salt; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is not higher than about 90% w.

[0169] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-55% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and no less than about 10% w / w medium-chain fatty acid or its salt; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is not higher than about 80% w.

[0170] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and no less than about 15% w / w medium-chain fatty acid or its salt; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is not higher than about 80% w.

[0171] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-55% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and no less than about 10% w / w medium-chain fatty acid or its salt; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0172] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and no less than about 15% w / w medium-chain fatty acid or its salt; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0173] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-55% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and about 10-40% w / w medium-chain fatty acid or its salt; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0174] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and about 15-40% w / w medium-chain fatty acid or its salt; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0175] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and about 20-40% w / w medium-chain fatty acid or its salt; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0176] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and about 20-40% w / w medium-chain fatty acid or its salt; and the mass percentage content of the medium-chain fatty acid or its salt is not higher than that of the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0177] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-55% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and about 10-40% w / w medium-chain fatty acid or its salt; and the mass percentage content of the medium-chain fatty acid or its salt is not higher than that of the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt; and the mass percentage content ratio of the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt to the medium-chain fatty acid or its salt is about 1:(0.5-2); wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is about 50-90% w / w.

[0178] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-55% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and about 10-40% w / w medium-chain fatty acid or its salt; and the mass percentage content of the medium-chain fatty acid or its salt is not higher than that of the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt; and the mass percentage content ratio of the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt to the medium-chain fatty acid or its salt is about 1:(0.5-2); wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0179] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and not less than about 15% w / w medium-chain fatty acid or its salt, and the mass percentage content ratio of the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt to the medium-chain fatty acid or its salt is about 1:(0.5-2); wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0180] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and not less than about 15% w / w medium-chain fatty acid or its salt, and the mass ratio of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about (1-3):3:(1.5-6); wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0181] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 10-20% w / w amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and not less than about 15% w / w medium-chain fatty acid or its salt, and the mass ratio of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 1:(2.5-3.5):(2.5-3.5); wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0182] In one technical solution of the present disclosure, the polypeptide composition comprises: not more than about 10% w / w of semaglutide, about 10-20% w / w amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and not less than about 15% w / w medium-chain fatty acid or its salt, and the mass ratio of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 1:(2.5-3.5):(2.5-3.5); wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt in the polypeptide composition is about 70-80% w / w.

[0183] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, not more than about 20% w / w amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, and not less than about 10% w / w medium-chain fatty acid or its salt. Wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not less than about 50% w / w.

[0184] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 5-20% w / w of amino acids, not less than about 20% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, and not less than about 15% w / w of medium-chain fatty acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 50-90% w / w.

[0185] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 5-20% w / w of amino acids, about 20-55% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, and not less than about 15% w / w of medium-chain fatty acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 70-80% w / w.

[0186] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 5-20% w / w of amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, and about 20-40% w / w of medium-chain fatty acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 70-80% w / w.

[0187] In one technical solution of the present disclosure, the polypeptide composition comprises: semaglutide, about 5-20% w / w of amino acids, about 20-50% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt, and about 20-40% w / w of medium-chain fatty acid or its salt; and the mass percentage content of the medium-chain fatty acid or its salt is not higher than that of the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt is about 70-80% w / w.

[0188] In one technical solution of the present disclosure, the medium-chain fatty acid is a fatty acid with a carbon chain length of 6 to 12 carbon atoms, and its structural formula is CH3(CH2) n COOH, where n is greater than or equal to 4 and less than or equal to 10.

[0189] In one technical solution of the present disclosure, the medium-chain fatty acid is selected from one or more of caproic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and lauric acid.

[0190] In one technical solution of the present disclosure, the medium-chain fatty acid salt is selected from one or more of sodium salt, potassium salt, and ammonium salt.

[0191] In some technical solutions of the present disclosure, the medium-chain fatty acid salt is sodium caprate.

[0192] In one technical solution of the present disclosure, the amino acid is an amino acid with a nitrogen-containing side chain.

[0193] In one technical solution of the present disclosure, the amino acid with a nitrogen-containing side chain is selected from any one or more of lysine, arginine, asparagine, glutamine, tryptophan, ornithine, citrulline, pyrrolysine, and histidine.

[0194] In one technical solution of the present disclosure, the amino acid with a nitrogen-containing side chain is selected from any one or more of citrulline and arginine.

[0195] In one technical solution of the present disclosure, the N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) salt is selected from one or more of sodium N-(8-(2-hydroxybenzoyl)amino)octanoate, potassium N-(8-(2-hydroxybenzoyl)amino)octanoate, and ammonium N-(8-(2-hydroxybenzoyl)amino)octanoate.

[0196] In one technical solution of the present disclosure, the salt of NAC is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC).

[0197] In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0198] 1-50 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0199] 20-100 parts by weight of an amino acid;

[0200] 100-300 parts by weight of a medium-chain fatty acid or its salt;

[0201] 100-300 parts by weight of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt;

[0202] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0203] 1-50 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0204] Amino acids: 30 - 100 parts by weight;

[0205] Medium-chain fatty acids or their salts: 100 - 300 parts by weight;

[0206] N-(8-[2-Hydroxybenzoyl]-amino)octanoic acid (NAC) or its salts: 100 - 300 parts by weight;

[0207] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0208] Polypeptides targeting glucagon-like peptide-1 (GLP-1) receptor: 1 - 40 parts by weight;

[0209] Amino acids: 40 - 70 parts by weight;

[0210] Medium-chain fatty acids or their salts: 120 - 200 parts by weight;

[0211] N-(8-[2-Hydroxybenzoyl]-amino)octanoic acid (NAC) or its salts: 120 - 200 parts by weight;

[0212] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0213] Polypeptides targeting glucagon-like peptide-1 (GLP-1) receptor: 1 - 32 parts by weight;

[0214] Amino acids: 50 - 70 parts by weight;

[0215] Medium-chain fatty acids or their salts: 120 - 180 parts by weight;

[0216] N-(8-[2-Hydroxybenzoyl]-amino)octanoic acid (NAC) or its salts: 120 - 180 parts by weight;

[0217] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0218] Polypeptides targeting glucagon-like peptide-1 (GLP-1) receptor: 5 - 10 parts by weight;

[0219] Amino acids: 50 parts by weight;

[0220] Medium-chain fatty acids or their salts: 150 parts by weight;

[0221] 150 parts by weight of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof;

[0222] Among them, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0223] 1-50 parts by weight of semaglutide;

[0224] 20-100 parts by weight of arginine;

[0225] 100-300 parts by weight of sodium caprate;

[0226] 100-300 parts by weight of sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC);

[0227] Among them, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0228] 1-50 parts by weight of semaglutide;

[0229] 30-100 parts by weight of arginine;

[0230] 100-300 parts by weight of sodium caprate;

[0231] 100-300 parts by weight of sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC);

[0232] Among them, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0233] 1-40 parts by weight of semaglutide;

[0234] 40-70 parts by weight of arginine;

[0235] 120-200 parts by weight of sodium caprate;

[0236] 120-200 parts by weight of sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC);

[0237] Among them, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0238] Semaglutide 1 - 32 parts by weight;

[0239] Arginine 50 - 70 parts by weight;

[0240] Sodium caprate 120 - 180 parts by weight;

[0241] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC) 120 - 180 parts by weight;

[0242] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0243] In one technical solution of the present disclosure, the polypeptide composition further comprises at least one excipient.

[0244] In one technical solution of the present disclosure, the polypeptide composition further comprises at least two excipients.

[0245] In one technical solution of the present disclosure, the content of the excipient is not higher than about 30% w / w.

[0246] In one technical solution of the present disclosure, the content of the excipient is not higher than about 25% w / w.

[0247] In one technical solution of the present disclosure, the content of the excipient is not lower than about 10% w / w.

[0248] In one technical solution of the present disclosure, the content of the excipient is not lower than about 15% w / w.

[0249] In one technical solution of the present disclosure, the excipient is selected from one or more of fillers, disintegrants, and lubricants.

[0250] In one technical solution of the present disclosure, the excipient is selected from one or more of fillers, disintegrants, lubricants, and binders.

[0251] In one technical solution of the present disclosure, the filler is selected from at least one of starch, powdered sugar, dextrin, lactose, microcrystalline cellulose, pregelatinized starch, mannitol, and calcium sulfate.

[0252] In one technical solution of the present disclosure, the filler is microcrystalline cellulose.

[0253] In one technical solution of the present disclosure, the lubricant is selected from at least one of magnesium stearate, colloidal silicon dioxide, talc powder, polyethylene glycol, and sodium lauryl sulfate.

[0254] In one technical solution of the present disclosure, the lubricant is sodium lauryl sulfate.

[0255] In one technical solution of the present disclosure, the disintegrant is selected from at least one of dry starch, sodium carboxymethyl cellulose, low-substituted carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0256] In one technical solution of the present disclosure, the disintegrant is sodium carboxymethyl starch.

[0257] In one technical solution of the present disclosure, the binder is selected from at least one of polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, gum arabic, gelatin, maltodextrin, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose.

[0258] In one technical solution of the present disclosure, the binder is polyvinylpyrrolidone.

[0259] In one technical solution of the present disclosure, the content of the filler is not less than about 10.0% w / w; for example, 11.0% w / w, 12.0% w / w, 15.0% w / w, 16.0% w / w, 17.0% w / w, 18.0% w / w, 18.5% w / w, 19.0% w / w, 19.1% w / w, 19.2% w / w, 19.3% w / w, 19.5% w / w, 19.7% w / w, 19.8% w / w, or 20.0% w / w.

[0260] In one technical solution of the present disclosure, the content of the lubricant is not higher than about 5.0% w / w.

[0261] In one technical solution of the present disclosure, the content of the lubricant is not higher than about 3.0% w / w.

[0262] In one technical solution of the present disclosure, the content of the lubricant is not higher than about 2.0% w / w.

[0263] In one technical solution of the present disclosure, the content of the lubricant is not higher than about 1.0 w / w.

[0264] In one technical solution of the present disclosure, the content of the lubricant is 1.0% w / w, 0.9% w / w, 0.96% w / w, 0.95% w / w, 0.89% w / w, 0.8% w / w, 0.7% w / w, 0.6% w / w, 0.5% w / w, 0.1% w / w, or 0.01% w / w.

[0265] In one technical solution of the present disclosure, the content of the disintegrant is not higher than about 5.0 w / w.

[0266] In one technical solution of the present disclosure, the content of the disintegrant is not higher than about 4.0 w / w.

[0267] In one technical solution of the present disclosure, the content of the disintegrant is not higher than about 3.0 w / w.

[0268] In one technical solution of the present disclosure, the content of the disintegrant is 2.5% w / w, 2.0% w / w, 1.9% w / w, 1.8% w / w, 1.7% w / w, 1.6% w / w, 1.5% w / w, 1.4% w / w, 1.2% w / w, 1.0% w / w, 0.9% w / w, 0.8% w / w, 0.5% w / w, 0.1% w / w.

[0269] In one technical solution of the present disclosure, the content of the binder is not higher than about 5.0% w / w.

[0270] In one technical solution of the present disclosure, the content of the binder is 4.0% w / w, 3.5% w / w, 3.3% w / w, 3.1% w / w, 3.0% w / w, 2.9% w / w, 2.5% w / w, 2.3% w / w, 2.0% w / w, 1.9% w / w, 1.8% w / w, 1.7% w / w, 1.6% w / w, 1.5% w / w, 1.3% w / w, 1.2% w / w, 1.0% w / w, 0.1% w / w or 0.01% w / w.

[0271] In one technical solution of the present disclosure, the excipient includes microcrystalline cellulose, sodium lauryl sulfate and sodium carboxymethyl starch.

[0272] In one technical solution of the present disclosure, the excipient includes microcrystalline cellulose, sodium lauryl sulfate, sodium carboxymethyl starch and polyvinylpyrrolidone.

[0273] In one technical solution of the present disclosure, the excipient includes not less than about 10.0% w / w and not more than about 25.0 w / w of microcrystalline cellulose.

[0274] In one technical solution of the present disclosure, the excipient includes not less than about 0.01% w / w and not more than about 3.0% w / w of sodium lauryl sulfate.

[0275] In one technical solution of the present disclosure, the excipient includes not less than about 0.1% w / w and not more than about 5.0% w / w of sodium carboxymethyl starch.

[0276] In one technical solution of the present disclosure, the excipient includes not less than about 0.01% w / w and not more than about 5.0% w / w of polyvinylpyrrolidone.

[0277] In one technical solution of the present disclosure, the excipient includes about 10.0 - 25.0% w / w of microcrystalline cellulose, about 0.01 - 3.0% w / w of sodium lauryl sulfate and about 0.1% - 5.0% w / w of sodium carboxymethyl starch.

[0278] In one technical solution of the present disclosure, the excipient includes about 10.0-25.0% w / w microcrystalline cellulose, about 0.01-3.0% w / w sodium lauryl sulfate, about 0.1-5.0% w / w sodium carboxymethyl starch, and about 0.01-5.0% w / w polyvinylpyrrolidone.

[0279] In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0280] 1-50 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0281] 20-100 parts by weight of amino acids;

[0282] 100-300 parts by weight of medium-chain fatty acids or their salts;

[0283] 100-300 parts by weight of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt;

[0284] 40-180 parts by weight of an excipient;

[0285] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0286] In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0287] 1-50 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0288] 30-100 parts by weight of amino acids;

[0289] 100-300 parts by weight of medium-chain fatty acids or their salts;

[0290] 100-300 parts by weight of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt;

[0291] 40-180 parts by weight of an excipient;

[0292] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0293] In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0294] 1-40 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0295] 40-70 parts by weight of amino acids;

[0296] 120 - 200 parts by weight of medium-chain fatty acid or its salt;

[0297] 120 - 200 parts by weight of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt;

[0298] 50 - 160 parts by weight of excipient;

[0299] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide.

[0300] In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0301] 1 - 32 parts by weight of a polypeptide targeting glucagon-like peptide-1 (GLP-1) receptor;

[0302] 50 - 70 parts by weight of amino acids;

[0303] 120 - 180 parts by weight of medium-chain fatty acid or its salt;

[0304] 120 - 180 parts by weight of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt;

[0305] 70 - 140 parts by weight of excipient;

[0306] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide.

[0307] In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0308] 5 - 10 parts by weight of a polypeptide targeting glucagon-like peptide-1 (GLP-1) receptor;

[0309] 50 parts by weight of amino acids;

[0310] 150 parts by weight of medium-chain fatty acid or its salt;

[0311] 150 parts by weight of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt;

[0312] 105 parts by weight of excipient;

[0313] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide.

[0314] In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0315] Semaglutide 1 - 50 parts by weight;

[0316] Arginine 20 - 100 parts by weight;

[0317] Sodium caprylate 100 - 300 parts by weight;

[0318] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC) 100 - 300 parts by weight;

[0319] Excipient 40 - 180 parts by weight;

[0320] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0321] Semaglutide 1 - 50 parts by weight;

[0322] Arginine 30 - 100 parts by weight;

[0323] Sodium caprylate 100 - 300 parts by weight;

[0324] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC) 100 - 300 parts by weight;

[0325] Excipient 40 - 180 parts by weight;

[0326] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0327] Semaglutide 1 - 40 parts by weight;

[0328] Arginine 40 - 70 parts by weight;

[0329] Sodium caprylate 120 - 200 parts by weight;

[0330] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC) 120 - 200 parts by weight;

[0331] Excipient 50 - 160 parts by weight;

[0332] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0333] Semaglutide 1 - 32 parts by weight;

[0334] 50 - 70 parts by weight of arginine;

[0335] 120 - 180 parts by weight of sodium caprate;

[0336] 120 - 180 parts by weight of sodium (8 - [2 - hydroxybenzoyl] - amino) octanoate (SNAC);

[0337] 70 - 140 parts by weight of excipient;

[0338] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0339] 5 parts by weight of semaglutide;

[0340] 50 parts by weight of arginine;

[0341] 150 parts by weight of sodium caprate;

[0342] 150 parts by weight of sodium (8 - [2 - hydroxybenzoyl] - amino) octanoate (SNAC);

[0343] 105 parts by weight of excipient;

[0344] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0345] 4 parts by weight of semaglutide;

[0346] 50 parts by weight of arginine;

[0347] 150 parts by weight of sodium caprate;

[0348] 150 parts by weight of sodium (8 - [2 - hydroxybenzoyl] - amino) octanoate (SNAC);

[0349] 124 parts by weight of excipient;

[0350] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0351] 8 parts by weight of semaglutide;

[0352] 50 parts by weight of arginine;

[0353] 150 parts by weight of sodium caprate;

[0354] 150 parts by weight of sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC);

[0355] 120 parts by weight of excipient;

[0356] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0357] 16 parts by weight of semaglutide;

[0358] 50 parts by weight of arginine;

[0359] 150 parts by weight of sodium caprylate;

[0360] 150 parts by weight of sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC);

[0361] 110 parts by weight of excipient;

[0362] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0363] 1 - 50 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0364] 20 - 100 parts by weight of amino acids;

[0365] 100 - 300 parts by weight of medium-chain fatty acids or their salts;

[0366] 100 - 300 parts by weight of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salts;

[0367] 50 - 150 parts by weight of filler;

[0368] 1 - 15 parts by weight of lubricant; and

[0369] 1 - 30 parts by weight of disintegrant;

[0370] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0371] 1 - 50 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0372] Amino acids 30 - 100 parts by weight;

[0373] Medium-chain fatty acids or their salts 100 - 300 parts by weight;

[0374] N-(8-[2-Hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt 100 - 300 parts by weight;

[0375] Filler 50 - 150 parts by weight;

[0376] Lubricant 1 - 15 parts by weight; and

[0377] Disintegrant 1 - 30 parts by weight;

[0378] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0379] Polypeptide targeting glucagon-like peptide-1 (GLP-1) receptor 1 - 40 parts by weight;

[0380] Amino acids 40 - 70 parts by weight;

[0381] Medium-chain fatty acids or their salts 120 - 200 parts by weight;

[0382] N-(8-[2-Hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt 120 - 200 parts by weight;

[0383] Filler 70 - 140 parts by weight;

[0384] Lubricant 1 - 15 parts by weight; and

[0385] Disintegrant 1 - 30 parts by weight;

[0386] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0387] Polypeptide targeting glucagon-like peptide-1 (GLP-1) receptor 1 - 32 parts by weight;

[0388] Amino acids 50 - 70 parts by weight;

[0389] Medium-chain fatty acids or their salts 120 - 180 parts by weight;

[0390] N-(8-[2-Hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt 120 - 180 parts by weight;

[0391] Filler: 80 - 130 parts by weight;

[0392] Lubricant: 1 - 10 parts by weight; and

[0393] Disintegrant: 1 - 15 parts by weight;

[0394] Among them, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0395] Polypeptide targeting glucagon - like peptide - 1 (GLP - 1) receptor: 5 - 10 parts by weight;

[0396] Amino acids: 50 parts by weight;

[0397] Medium - chain fatty acid or its salt: 150 parts by weight;

[0398] N-(8 - [2 - hydroxybenzoyl] - amino) octanoic acid (NAC) or its salt: 150 parts by weight;

[0399] Filler: 80 - 110 parts by weight;

[0400] Lubricant: 1 - 10 parts by weight; and

[0401] Disintegrant: 1 - 15 parts by weight;

[0402] Among them, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0403] Semaglutide: 1 - 50 parts by weight;

[0404] Arginine: 20 - 100 parts by weight;

[0405] Sodium caprate: 100 - 300 parts by weight;

[0406] Sodium N-(8 - [2 - hydroxybenzoyl] - amino) octanoate (SNAC): 100 - 300 parts by weight;

[0407] Filler: 50 - 150 parts by weight;

[0408] Lubricant: 1 - 15 parts by weight;

[0409] Disintegrant: 1 - 30 parts by weight; and

[0410] Among them, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0411] Semaglutide 1 - 50 parts by weight;

[0412] Arginine 30 - 100 parts by weight;

[0413] Sodium caprylate 100 - 300 parts by weight;

[0414] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC) 100 - 300 parts by weight;

[0415] Filler 50 - 150 parts by weight;

[0416] Lubricant 1 - 15 parts by weight; and

[0417] Disintegrant 1 - 30 parts by weight;

[0418] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0419] Semaglutide 1 - 40 parts by weight;

[0420] Arginine 40 - 70 parts by weight;

[0421] Sodium caprylate 120 - 200 parts by weight;

[0422] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC) 120 - 200 parts by weight;

[0423] Filler 70 - 140 parts by weight;

[0424] Lubricant 1 - 15 parts by weight; and

[0425] Disintegrant 1 - 30 parts by weight;

[0426] Wherein, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0427] Semaglutide 1 - 32 parts by weight;

[0428] Arginine 50 - 70 parts by weight;

[0429] Sodium caprylate 120 - 180 parts by weight;

[0430] Sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC) 120 - 180 parts by weight;

[0431] Filler: 80 - 130 parts by weight;

[0432] Lubricant: 1 - 10 parts by weight; and

[0433] Disintegrant: 1 - 15 parts by weight;

[0434] Among them, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0435] Semaglutide: 5 - 10 parts by weight;

[0436] Arginine: 50 parts by weight;

[0437] Sodium caprylate: 150 parts by weight;

[0438] Sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate (SNAC): 150 parts by weight;

[0439] Filler: 80 - 110 parts by weight;

[0440] Lubricant: 1 - 10 parts by weight; and

[0441] Disintegrant: 1 - 15 parts by weight;

[0442] Among them, the oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0443] Semaglutide: 1 - 50 parts by weight;

[0444] Arginine: 20 - 100 parts by weight;

[0445] Sodium caprylate: 100 - 300 parts by weight;

[0446] Sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate (SNAC): 100 - 300 parts by weight;

[0447] Filler: 50 - 150 parts by weight;

[0448] Lubricant: 1 - 15 parts by weight;

[0449] Disintegrant: 1 - 30 parts by weight; and

[0450] Binder: 1 - 30 parts by weight;

[0451] Among them, the oral polypeptide composition does not contain niacinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0452] Semaglutide 1-50 parts by weight;

[0453] Arginine 30-100 parts by weight;

[0454] Sodium caprylate 100-300 parts by weight;

[0455] Sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate (SNAC) 100-300 parts by weight;

[0456] Filler 50-150 parts by weight;

[0457] Lubricant 1-15 parts by weight;

[0458] Disintegrant 1-30 parts by weight; and

[0459] Binder 1-30 parts by weight;

[0460] Among them, the oral polypeptide composition does not contain niacinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide. In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0461] Semaglutide 1-40 parts by weight;

[0462] Arginine 40-70 parts by weight;

[0463] Sodium caprylate 120-200 parts by weight;

[0464] Sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate (SNAC) 120-200 parts by weight;

[0465] Filler 70-140 parts by weight;

[0466] Lubricant 1-15 parts by weight;

[0467] Disintegrant 1-30 parts by weight; and

[0468] Binder 1-30 parts by weight;

[0469] Among them, the oral polypeptide composition does not contain niacinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide.

[0470] In one technical solution of the present disclosure, the oral polypeptide composition includes:

[0471] Semaglutide 1 - 32 parts by weight;

[0472] Arginine 50 - 70 parts by weight;

[0473] Sodium caprylate 120 - 180 parts by weight;

[0474] Sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate (SNAC) 120 - 180 parts by weight;

[0475] Filler 80 - 130 parts by weight;

[0476] Lubricant 1 - 10 parts by weight;

[0477] Disintegrant 1 - 15 parts by weight;

[0478] Binder 1 - 15 parts by weight; and

[0479] Wherein, the oral polypeptide composition does not contain niacinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide.

[0480] In one technical solution of the present disclosure, the oral polypeptide composition comprises:

[0481] Semaglutide 5 - 10 parts by weight;

[0482] Arginine 50 parts by weight;

[0483] Sodium caprylate 150 parts by weight;

[0484] Sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate (SNAC) 150 parts by weight;

[0485] Filler 80 - 110 parts by weight;

[0486] Lubricant 1 - 10 parts by weight;

[0487] Disintegrant 1 - 15 parts by weight;

[0488] Binder 1 - 15 parts by weight; and

[0489] Wherein, the oral polypeptide composition does not contain niacinamide, adenosine, adenine, guanine, cytosine, trigonelline and salicylamide.

[0490] In one technical solution of the present disclosure, the oral polypeptide composition comprises: about 4.0 mg of semaglutide, about 50.0 mg of arginine, about 150.0 mg of sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate, about 150.0 mg of sodium caprylate, about 123.0 mg of excipient.

[0491] In one technical solution of the present disclosure, the oral polypeptide composition comprises: about 8.0 mg of semaglutide, about 50.0 mg of arginine, about 150.0 mg of sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate, about 150.0 mg of sodium caprate, and about 120.0 mg of excipient.

[0492] In one technical solution of the present disclosure, the oral polypeptide composition comprises: about 8.0 mg of semaglutide, about 50.0 mg of arginine, about 150.0 mg of sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate, about 150.0 mg of sodium caprate, and about 110.0 mg of excipient.

[0493] In one technical solution of the present disclosure, the oral polypeptide composition is a solid preparation.

[0494] In one technical solution of the present disclosure, the oral polypeptide composition is a tablet, a capsule, a granule, a powder, a powder for external use, a dripping pill or a pill.

[0495] In one technical solution of the present disclosure, the oral pharmaceutical composition is a tablet.

[0496] In one technical solution of the present disclosure, the specification of the tablet is about 1-50 mg,

[0497] In one technical solution of the present disclosure, the specification of the tablet is about 1-40 mg.

[0498] In one technical solution of the present disclosure, the specification of the tablet is about 1-30 mg.

[0499] In one technical solution of the present disclosure, the specification of the tablet is about 5-10 mg.

[0500] In one technical solution of the present disclosure, the specification of the tablet is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 6.5 mg, 6.8 mg, 7 mg, 7.1 mg, 7.4 mg, 7.5 mg, 7.9 mg, 8 mg, 8.6 mg, 9 mg, 10 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 28 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 40 mg.

[0501] In another aspect of the present disclosure, there is provided an oral polypeptide composition containing a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor for: (i) treating a disease; and / or (ii) preparing a drug for treating a disease;

[0502] Among them, the disease is selected from at least one of type 1 diabetes, type 2 diabetes, obesity, cardiovascular disease, non-alcoholic fatty liver disease, chronic kidney disease, Alzheimer's disease, cancer, polycystic ovary syndrome, metabolic syndrome, bone metabolism and osteoporosis, knee osteoarthritis, sleep apnea syndrome, osteoarthropathy, and metabolic myopathy.

[0503] On the other hand, the present disclosure provides a method for preparing an oral polypeptide tablet, comprising the step of directly tableting the oral polypeptide composition of the present disclosure to obtain the tablet.

[0504] On the other hand, the present disclosure provides a pharmaceutical composition, which comprises a mixture of first particles and second particles, wherein the first particles comprise a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor; the second particles comprise an amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, and a medium-chain fatty acid or a salt thereof.

[0505] In one technical solution of the present disclosure, the first particles are granulated from a composition comprising a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor; and / or, the second particles are granulated from a composition comprising an amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, and a medium-chain fatty acid or a salt thereof.

[0506] In one technical solution of the present disclosure, the first particles comprise a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor and an excipient.

[0507] In one technical solution of the present disclosure, in the first particles, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is not less than 10% w / w, such as 10% w / w, 20% w / w, 25% w / w, 30% w / w, 40% w / w, 42% w / w, 45% w / w.

[0508] In one technical solution of the present disclosure, in the first particles, the content of the excipient is not less than 50% w / w.

[0509] In one technical solution of the present disclosure, the first particles comprise a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor, a filler, and a binder.

[0510] In one technical solution of the present disclosure, the second particles comprise an amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, a medium-chain fatty acid or a salt thereof, and an excipient.

[0511] In one technical solution of the present disclosure, the second particles include amino acids, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts, fillers, lubricants, and disintegrants.

[0512] In one technical solution of the present disclosure, in the second particles, the content of the amino acids, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts is not less than 60%.

[0513] In one technical solution of the present disclosure, in the second particles, the content of the amino acids, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts is not less than 70%.

[0514] In one technical solution of the present disclosure, in the second particles, the content of the excipient is not less than 10%.

[0515] In one technical solution of the present disclosure, in the second particles, the content of the excipient is not less than 20%.

[0516] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage content of the first particles does not exceed about 20% w / w.

[0517] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage content of the first particles does not exceed about 10% w / w.

[0518] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage content of the second particles is not less than about 80% w / w.

[0519] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage content of the second particles is not less than about 90% w / w.

[0520] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt does not exceed about 50% w / w.

[0521] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt does not exceed about 45% w / w.

[0522] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt does not exceed about 40% w / w.

[0523] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not higher than about 35% w / w.

[0524] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is 49% w / w, 48% w / w, 47% w / w, 46% w / w, 45% w / w, 44% w / w, 43% w / w, 42% w / w, 41% w / w, 40% w / w, 39% w / w, 38% w / w, 37% w / w, 36% w / w or 35% w / w.

[0525] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not lower than about 20% w / w.

[0526] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not lower than about 25% w / w.

[0527] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not lower than about 30% w / w.

[0528] In one aspect of the present disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not lower than 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 28% w / w, 29% w / w or 30% w / w.

[0529] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 20 - 50% w / w.

[0530] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 20 - 45% w / w.

[0531] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 20 - 40% w / w.

[0532] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 25-50% w / w.

[0533] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 25-45% w / w.

[0534] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 25-40% w / w.

[0535] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 30-50% w / w.

[0536] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 30-45% w / w.

[0537] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 30-40% w / w.

[0538] In one aspect of the present disclosure, in the pharmaceutical composition, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 30-35% w / w.

[0539] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not higher than about 20% w / w.

[0540] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not higher than about 18% w / w.

[0541] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not higher than about 15% w / w.

[0542] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not higher than 19% w / w, 18% w / w, 17% w / w, 16% w / w, 15% w / w, 14% w / w, 13% w / w or 12% w / w.

[0543] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not less than about 5% w / w.

[0544] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not less than about 7% w / w.

[0545] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not less than about 8% w / w.

[0546] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not less than about 9% w / w.

[0547] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not less than about 10% w / w.

[0548] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is not less than 5% w / w, 5.5% w / w, 6% w / w, 7.5% w / w, 7.8 w / w, 8.3 w / w, 8.5 w / w, 8.8 w / w, 9 w / w, 9.2 w / w, 9.5 w / w or 10 w / w.

[0549] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 5 - 20% w / w.

[0550] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 5 - 18% w / w.

[0551] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 5 - 15% w / w.

[0552] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 8 - 20% w / w.

[0553] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 8 - 18% w / w.

[0554] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 8 - 15% w / w.

[0555] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 9 - 20% w / w.

[0556] In one aspect of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 10 - 20% w / w.

[0557] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 9-15% w / w.

[0558] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the amino acid is about 10-15% w / w.

[0559] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is not higher than about 40% w / w.

[0560] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is not higher than about 35% w / w.

[0561] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is not higher than 39% w / w, 38% w / w, 37% w / w, 36% w / w or 35% w / w.

[0562] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is not lower than about 15% w / w.

[0563] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is not lower than about 20% w / w.

[0564] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is not lower than about 25% w / w.

[0565] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is not lower than about 30% w / w.

[0566] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is not lower than 16% w / w, 18% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 28% w / w, 29% w / w or 30% w / w.

[0567] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is about 15-40% w / w.

[0568] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is about 15-35% w / w.

[0569] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is 20-40% w / w.

[0570] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is about 25-35% w / w.

[0571] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is about 25-40% w / w.

[0572] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is about 30-40% w / w.

[0573] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the medium-chain fatty acid or its salt is about 30-35% w / w.

[0574] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor does not exceed about 15% w / w.

[0575] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor does not exceed about 10% w / w.

[0576] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is about 0.1-15% w / w.

[0577] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is about 0.5-10% w / w.

[0578] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is about 0.8-10% w / w.

[0579] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is about 1.0-7.0% w / w.

[0580] In one technical solution of the present disclosure, in the pharmaceutical composition, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is 0.2% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 3.3% w / w, 3.4% w / w, 6.9% w / w, 7.0% w / w, 8.0% w / w, 9.0% w / w, 10.0% w / w.

[0581] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not higher than about 90% w / w.

[0582] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 85% w / w.

[0583] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not higher than about 80% w / w.

[0584] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not lower than about 50% w / w.

[0585] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not lower than about 60% w / w.

[0586] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 70% w / w.

[0587] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 50 - 80% w / w.

[0588] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 60-80% w / w.

[0589] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 70-80% w / w.

[0590] In one technical solution of the present disclosure, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is 60% w / w, 62% w / w, 63% w / w, 64% w / w, 65% w / w, 67% w / w, 68% w / w, 70% w / w, 71% w / w, 72% w / w, 73% w / w, 74% w / w, 75% w / w, 75.5% w / w, 75.8% w / w, 75.9% w / w, 77% w / w, 79% w / w, 80% w / w.

[0591] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about (1-3):3:(1.5-6).

[0592] In one technical solution of the present disclosure, in the pharmaceutical composition, in the polypeptide composition, the mass percentage content of the amino acid is not higher than that of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt and / or the medium-chain fatty acid or its salt.

[0593] In one technical solution of the present disclosure, in the pharmaceutical composition, in the polypeptide composition, the mass percentage content of the amino acid is not higher than that of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt and the medium-chain fatty acid or its salt.

[0594] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage content of the medium-chain fatty acid or its salt is not higher than that of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt.

[0595] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage content ratio of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt and the medium-chain fatty acid or its salt is about 1:(0.5-2), such as 1:1, 2:1, 1.5:1, 1:1.5.

[0596] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage ratio of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt to the amino acid is about (1-2):3, such as 1:3, 2:3, 1.5:3.

[0597] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 1:(2.5-3.5):(2.5-3.5).

[0598] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 1:(2.6-3.4):(2.6-3.4).

[0599] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 1:(2.7-3.3):(2.7-3.3).

[0600] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 1:(2.8-3.2):(2.8-3.2).

[0601] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 1:(2.9-3.1):(2.9-3.1).

[0602] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 1:3:3.

[0603] In one technical solution of the present disclosure, in the pharmaceutical composition, the mass percentage of N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt is the same as that of the medium-chain fatty acid or its salt.

[0604] In one technical solution of the present disclosure, the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is a GLP-1 receptor agonist.

[0605] In one technical solution of the present disclosure, the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is semaglutide.

[0606] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not higher than about 90% w / w.

[0607] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 85% w / w.

[0608] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not higher than about 80% w / w.

[0609] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not lower than about 50% w / w.

[0610] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is not lower than about 60% w / w.

[0611] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 70% w / w.

[0612] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 50 - 80% w / w.

[0613] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 60 - 80% w / w.

[0614] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is about 70-80% w / w.

[0615] In one technical solution of the present disclosure, in the pharmaceutical composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and the medium-chain fatty acid or its salt is 60% w / w, 62% w / w, 63% w / w, 64% w / w, 65% w / w, 67% w / w, 68% w / w, 70% w / w, 71% w / w, 72% w / w, 73% w / w, 74% w / w, 75% w / w, 75.5% w / w, 75.8% w / w, 75.9% w / w, 77% w / w, 79% w / w, 80% w / w.

[0616] In one technical solution of the present disclosure, the medium-chain fatty acid is a fatty acid with a carbon chain length of 6 to 12 carbon atoms, and its structural formula is CH3(CH2) n COOH, where n is greater than or equal to 4 and less than or equal to 10.

[0617] In one technical solution of the present disclosure, the medium-chain fatty acid is selected from one or more of caproic acid, enanthic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and lauric acid.

[0618] In one technical solution of the present disclosure, the medium-chain fatty acid salt is selected from one or more of sodium salt, potassium salt, and ammonium salt.

[0619] In some technical solutions of the present disclosure, the medium-chain fatty acid salt is sodium decanoate.

[0620] In one technical solution of the present disclosure, the amino acid is an amino acid with a nitrogen-containing side chain.

[0621] In one technical solution of the present disclosure, the amino acid with a nitrogen-containing side chain is selected from any one or more of lysine, arginine, asparagine, glutamine, tryptophan, ornithine, citrulline, pyrrolysine, and histidine.

[0622] In one technical solution of the present disclosure, the amino acid with a nitrogen-containing side chain is selected from any one or more of citrulline and arginine.

[0623] In one technical solution of the present disclosure, the N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) salt is selected from one or more of sodium N-(8-(2-hydroxybenzoyl)amino)octanoate, potassium N-(8-(2-hydroxybenzoyl)amino)octanoate, and ammonium N-(8-(2-hydroxybenzoyl)amino)octanoate.

[0624] In one technical solution of the present disclosure, the N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) salt is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC).

[0625] In one technical solution of the present disclosure, the pharmaceutical composition is used for preparing an oral polypeptide tablet.

[0626] On the other hand, the present disclosure provides a method for preparing an oral polypeptide tablet, the method comprising the step of using the pharmaceutical composition of the present disclosure to prepare the polypeptide tablet.

[0627] On the other hand, the present disclosure provides a method for preparing an oral polypeptide tablet, the method comprising the step of tabletting using the pharmaceutical composition of the present disclosure.

[0628] In one technical solution of the present disclosure, the method comprises the steps of: mixing a first granule and a second granule, and then tabletting to obtain; wherein, the first granule comprises a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor; the second granule comprises an amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, and a medium-chain fatty acid or a salt thereof.

[0629] In one technical solution of the present disclosure, the first granule is granulated from a composition comprising a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor; and / or, the second granule is granulated from a composition comprising an amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, and a medium-chain fatty acid or a salt thereof.

[0630] In one technical solution of the present disclosure, the first granule comprises a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor and an excipient.

[0631] In one technical solution of the present disclosure, in the first granule, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is not less than 10% w / w, such as 10% w / w, 20% w / w, 25% w / w, 30% w / w, 40% w / w, 42% w / w, 45% w / w.

[0632] In one technical solution of the present disclosure, in the first granule, the content of the excipient is not less than 50% w / w.

[0633] In one technical solution of the present disclosure, the first granule comprises a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor, a filler and a binder.

[0634] In one technical solution of the present disclosure, the second particles include an amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, a medium-chain fatty acid or a salt thereof, and an excipient.

[0635] In one technical solution of the present disclosure, the second particles include an amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, a medium-chain fatty acid or a salt thereof, a filler, a lubricant, and a disintegrant.

[0636] In one technical solution of the present disclosure, in the second particles, the content of the amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, and the medium-chain fatty acid or a salt thereof is not less than 60%.

[0637] In one technical solution of the present disclosure, in the second particles, the content of the amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, and the medium-chain fatty acid or a salt thereof is not less than 70%.

[0638] In one technical solution of the present disclosure, in the second particles, the content of the excipient is not less than 10%.

[0639] In one technical solution of the present disclosure, in the second particles, the content of the excipient is not less than 20%.

[0640] In one technical solution of the present disclosure, in the composition, the mass percentage content of the first particles does not exceed about 20% w / w.

[0641] In one technical solution of the present disclosure, in the composition, the mass percentage content of the first particles does not exceed about 10% w / w.

[0642] In one technical solution of the present disclosure, in the composition, the mass percentage content of the second particles is not less than about 80% w / w.

[0643] In one technical solution of the present disclosure, in the composition, the mass percentage content of the second particles is not less than about 90% w / w.

[0644] Beneficial effects:

[0645] The oral polypeptide composition provided by the present disclosure not only improves the convenience of use of the polypeptide or polypeptide drug, but also significantly improves the absorption of the polypeptide drug by the gastrointestinal tract, thereby improving the efficacy of the polypeptide drug in vivo.

[0646] Compared with , under the condition of the same specification, the oral semaglutide composition provided by the present disclosure significantly improves the oral bioavailability of semaglutide. Brief description of the drawings

[0647] Figure 1 It is the cumulative dissolution-time curve of semaglutide tablets.

[0648] Figure 2 It is the C in beagle dogs of semaglutide tablets max Comparison.

[0649] Figure 3 It is the C in beagle dogs of semaglutide tablets prepared by different processes max Comparison.

[0650] Figure 4 It is the C in cynomolgus monkeys of semaglutide tablets at different doses max Comparison.

[0651] Figure 5 It is the detection and analysis of the content of semaglutide in the plasma of beagle dogs after administration.

[0652] Figure 6 It is the detection and analysis of the content of teriparatide in the plasma of beagle dogs after administration.

[0653] Figure 7 It is the detection and analysis of the content of teprotide in the plasma after administration.

[0654] Figure 8 It is the detection and analysis of the content of octreotide in the plasma after administration. Specific embodiments

[0655] According to the above content of the present disclosure, and in accordance with the common general knowledge and customary means in the art, without departing from the above basic technical idea of the present disclosure, various other forms of modification, substitution or variation can also be made.

[0656] I. Definitions

[0657] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or variations thereof such as "comprises" or "comprising" will be understood to include the stated element or component, without excluding other elements or other components.

[0658] The term "optional" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation.

[0659] As used herein, the term "about" means approximately, nearly, roughly, or around. When the term "about" is used in connection with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. Generally, the term "about" is used herein to modify a value by a deviation of up to 20% above and below a value. Additionally, particularly for biological systems or processes, the term can mean up to one order of magnitude or up to 5-fold of a numerical value. Unless otherwise specified, when a specific value appears in this application and the claims, the meaning of "about" or "substantially comprises" should be assumed to be within the acceptable error range of that specific value.

[0660] Oral polypeptide composition

[0661] As used herein, the terms "polypeptide" and "protein" are used interchangeably, and these terms encompass both naturally occurring polypeptides and non-naturally occurring polypeptides, as well as their fragments, mutants, derivatives, and analogs as provided herein or as commonly known in the art. The polypeptides also include polypeptides of pharmaceutical molecules and nucleic acids encoding polypeptides, recombinant microorganisms for preparing polypeptides, vectors for expressing polypeptides, and polypeptides prepared using recombinant microorganisms.

[0662] In some embodiments, the polypeptide comprises at least 30, at least 40, at least 50 amino acid residues. In some embodiments, the polypeptide comprises 20 - 500 amino acid residues. In some embodiments, the polypeptide includes one or more modified amino acid residues and / or non-protein amino acid residues.

[0663] In one embodiment, the polypeptide is a polypeptide that targets the glucagon-like peptide-1 (GLP-1) receptor.

[0664] As used herein, the term "polypeptide that targets the glucagon-like peptide-1 (GLP-1) receptor" refers to those polypeptides that have a polypeptide containing at least one domain that binds to the GLP-1 receptor and are capable of selectively binding to the glucagon-like peptide-1 (GLP-1) receptor, thereby mimicking or enhancing the physiological functions of native GLP-1. In some embodiments, the amino acid sequence of the polypeptide that targets the glucagon-like peptide-1 (GLP-1) receptor can have at least 70%, 80%, 90% or higher sequence homology with native GLP-1 (such as human GLP-1 (7 - 36) amide), or its stability, oral bioavailability, or pharmacodynamic properties can be optimized by modifications (such as amino acid substitution, deletion or addition; fatty acid chain modification, PEGylation, cyclization, etc.).

[0665] In one embodiment, the polypeptide is Semaglutide. In one embodiment, the oral polypeptide composition of the present disclosure contains 0.01-15.0% w / w of Semaglutide, such as 0.2% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 3.3% w / w, 3.4% w / w, 6.9% w / w, 7.0% w / w, 8.0% w / w, 9.0% w / w, 10.0% w / w. Compared with Novo Nordisk's oral semaglutide tablets, the oral polypeptide composition of the present disclosure has a higher oral bioavailability at the same specification, a lower content of Semaglutide when the oral bioavailability is the same, and less gastrointestinal side effects.

[0666] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment and without excessive toxicity, irritation, allergic reaction or other problems or complications commensurate with the reasonable benefit / risk ratio.

[0667] As used herein, the salts in the term "pharmaceutically acceptable salts" refer to both water-soluble salts and water-insoluble salts, such as acetate, aminosulphonate (4,4-diaminostilbene-2,2'-disulphonate), benzenesulphonate, benzoate, bicarbonate, bisulphate, bitartrate, borate, bromide, butyrate, calcium edetate, dextro-camphorsulphonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, ethanedisulphonate, lauryl sulphate propionate, ethanesulphonate, fumarate, glucoheptonate, gluconate, glutamate, glycouylarsanilate, hexafluorophosphate, hexylresorcinolate, heptaminol, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiocyanate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyhiitrate, methyl sulphate, galactarate, naphthalenesulphonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1'-methylene-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulphonate, salicylate, stearate, basic acetate, succinate, sulphate, sulphonylsalicylate, suramate, tannate, tartrate, theophylline acetate, toluenesulphonate, triethyl iodide and valerate.

[0668] As used herein, the term "absorption enhancer" refers to a class of excipients or compounds that can enhance the absorption efficiency of drugs in the gastrointestinal tract through physical, chemical, or biological mechanisms. In some embodiments, the absorption enhancer is a polypeptide oral absorption enhancer. The term "polypeptide oral absorption enhancer" is a class of excipients or compounds specifically used to improve the oral absorption efficiency of polypeptide drugs. In particular, absorption enhancers are different from excipients herein.

[0669] In some embodiments, the absorption enhancer includes amino acids, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salts, and medium-chain fatty acids or their salts. In some embodiments, the oral polypeptide composition of the present disclosure includes no more than about 90% w / w, about 85% w / w, about 80% w / w of the absorption enhancer; and / or includes no less than about 50% w / w, about 60% w / w, about 70% w / w of the absorption enhancer. In some embodiments, the oral polypeptide composition of the present disclosure includes about 70% w / w, 71% w / w, 72% w / w, 73% w / w, 74% w / w, 75% w / w, 76% w / w, 77% w / w, 78% w / w, 79% w / w, 80% w / w of the absorption enhancer. In some embodiments, the oral polypeptide composition of the present disclosure includes about 50% w / w, 49% w / w, 48% w / w, 47% w / w, 46% w / w, 45% w / w, 44% w / w, 43% w / w, 42% w / w, 41% w / w, 40% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salts; and / or no less than about 20% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 27% w / w, 28% w / w, 29% w / w, 30% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salts. In some embodiments, the oral polypeptide composition of the present disclosure includes about 25% w / w, 26% w / w, 27% w / w, 28% w / w, 29% w / w, 30% w / w, 31% w / w, 32% w / w, 33% w / w, 34% w / w, 35% w / w, 36% w / w, 37% w / w, 38% w / w, 39% w / w, 40% w / w of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salts.

[0670] As used herein, the term "medium-chain fatty acid" refers to a class of straight-chain saturated monocarboxylic acids containing 6-12 carbon atoms, such as caproic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and lauric acid. In some embodiments, the medium-chain fatty acid is a fatty acid with a carbon chain length of 6 to 12 carbon atoms, and its structural formula is CH3(CH2) nCOOH, where n is greater than or equal to 4 and less than or equal to 10.

[0671] In some embodiments, the oral polypeptide composition of the present disclosure comprises a medium-chain fatty acid or its salt at no higher than about 40% w / w, about 39% w / w, about 38% w / w, about 37% w / w, about 36% w / w or about 35% w / w; and / or comprises a medium-chain fatty acid or its salt at no less than 16% w / w, 18% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 28% w / w, 29% w / w or 30% w / w. In some embodiments, the oral polypeptide composition of the present disclosure comprises about 16% w / w, 17% w / w, 18% w / w, 19% w / w, 20% w / w, 21% w / w,

[0672] 22% w / w, 23% w / w, 24% w / w, 25% w / w, 26% w / w, 28% w / w, 29% w / w, 30% w / w, 31% w / w, 32% w / w, 33% w / w, 34% w / w, 35% w / w of a medium-chain fatty acid or its salt.

[0673] As used herein, the term "amino acid" includes natural and unnatural amino acids. The term "natural amino acid" refers to the 20 conventional amino acids, namely alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W) and tyrosine (Y). The term "unnatural 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, an unnatural amino acid can be a purely synthetic compound. Examples of unnatural amino acids include, but are not limited to, hydroxyproline, γ-carboxyglutamic acid, O-phosphoserine, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminoheptanedioic acid, tert-butylglycine, 2,4-diaminoisobutyric acid (Dap), desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid (Dab), N-ethylglycine, N-methylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloisoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine (Orn), D-ornithine, D-arginine, p-aminophenylalanine, pentylglycine, pipecolic acid and thioproline. In addition, the term also includes derivatives obtained by chemically modifying the C-terminal carboxyl group (or the N-terminal amino group and / or its side chain functional groups) of a natural amino acid (or an unnatural amino acid).

[0674] In some embodiments, the amino acid is an amino acid with a nitrogen-containing side chain. The term "amino acid with a nitrogen-containing side chain" refers to an amino acid in which the R group in the general formula H2N-CH(R)-C(O)OH contains N, for example, the R group contains =N + H2, -NH2, -NH-, -N=CH-, etc. In some embodiments, the amino acid with a nitrogen-containing side chain is selected from any one or more of lysine, arginine, asparagine, glutamine, tryptophan, ornithine, citrulline, pyrrolysine and histidine. In some embodiments, the amino acid is arginine.

[0675] In some embodiments, the oral polypeptide composition of the present disclosure comprises no more than about 20% w / w, about 19% w / w, about 18% w / w, about 17% w / w, about 16% w / w, about 15% w / w of amino acids; and / or comprises no less than about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w of amino acids. In some embodiments, the oral polypeptide composition of the present disclosure comprises about 7.5% w / w, 7.8% w / w, 8.3% w / w, 8.5% w / w, 8.8% w / w, 9% w / w, 9.2% w / w, 9.5% w / w, 10% w / w, 10.5% w / w, 11% w / w, 11.5% w / w, 12% w / w, 12.5% w / w, 13% w / w, 13.5% w / w, 14% w / w, 14.5% w / w, 15% w / w of amino acids.

[0676] As used herein, the term "excipient" refers to a substance added to a pharmaceutical composition to impart certain shape, size, or physical properties to the drug. Examples of excipients include, but are not limited to, carriers, fillers, binders, disintegrants, lubricants, glidants, taste masking and flavoring agents, stabilizers, dispersants, film formers, and preservatives. Suitable excipients can be selected based on factors such as the nature, type, route of administration, and therapeutic purpose of the drug. In some embodiments, the excipient is a filler. In some embodiments, the excipient is a filler, disintegrant, and lubricant. In some embodiments, the excipient is a filler, disintegrant, lubricant, and binder.

[0677] In some embodiments, the oral polypeptide composition of the present disclosure comprises no more than about 30% w / w, 29% w / w, 28% w / w, 27% w / w, 26% w / w, 25% w / w of excipients; and / or, comprises no less than about 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, 15% w / w of excipients. In some embodiments, the oral polypeptide composition of the present disclosure comprises about 15% w / w, 16% w / w, 17% w / w, 18% w / w, 19% w / w, 20% w / w, 21% w / w, 22% w / w, 23% w / w, 24% w / w, 25% w / w of excipients.

[0678] The term "filler" refers to an auxiliary material used to increase the weight and volume of a tablet and facilitate tableting. Examples of fillers include, but are not limited to, starch, powdered sugar, dextrin, lactose, microcrystalline cellulose, pregelatinized starch, mannitol, calcium sulfate, etc. In one embodiment, the filler is microcrystalline cellulose.

[0679] The term "disintegrant" refers to an excipient that helps a tablet break into fine particles in gastrointestinal fluids. Examples of disintegrants include, but are not limited to, dry starch, sodium carboxymethyl cellulose, low-substituted carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch. In one embodiment, the disintegrant is sodium carboxymethyl starch.

[0680] The term "lubricant" refers to an excipient used to reduce the friction between particles, prevent the raw and auxiliary materials from adhering to the punch surface, or reduce the friction between the tablet and the die wall. Examples of lubricants include, but are not limited to, magnesium stearate, colloidal silicon dioxide, talc powder, polyethylene glycol, sodium lauryl sulfate, etc. In one embodiment, the lubricant is sodium lauryl sulfate.

[0681] The terms "adhesive" and "binder" are used interchangeably and refer to a viscous substance added to solve the problem of low viscosity of the raw materials themselves, such as polyvinylpyrrolidone (povidone), etc. In one embodiment, the adhesive is povidone.

[0682] The term "solid dosage form" refers to a solid pharmaceutical preparation with strong cohesive force and shape stability. The forms of solid preparations include, but are not limited to, tablets, capsules, granules, powders, powders, dripping pills, and pills. The solid preparation can be an ordinary preparation, a sustained-release or rapid-release preparation (such as osmotic pump tablets, sustained-release tablets, sustained-release capsules, rapidly disintegrating tablets, etc.). In some embodiments, the pharmaceutical composition of the present disclosure is a tablet, a capsule, or a granule. In some embodiments, the pharmaceutical composition of the present disclosure is a tablet.

[0683] The term "tablet" refers to a round or shaped solid preparation made from the active ingredient and suitable excipients. Tablets are mainly oral ordinary tablets (including sugar-coated tablets and film-coated tablets), and there are also buccal tablets, sublingual tablets, oral patches, chewable tablets, dispersible tablets, soluble tablets, effervescent tablets, vaginal tablets, vaginal effervescent tablets, sustained-release tablets, controlled-release tablets, enteric-coated tablets (including enteric-coated tablets and colon-targeted enteric-coated tablets), and orally disintegrating tablets, etc. The tablets of the present disclosure can be coated by methods well known in the art.

[0684] The term "specification" or "drug specification" refers to the amount of the drug ingredient contained in a unit preparation of the drug, usually expressed as the weight or content in each unit preparation such as per tablet, per capsule, per injection, etc. It includes indicators such as the content of the main drug, potency, or filling volume.

[0685] In some embodiments, the specification of the oral polypeptide tablets is 1-50 mg, such as 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 6.5 mg, 6.8 mg, 7 mg, 7.1 mg, 7.4 mg, 7.5 mg, 7.9 mg, 8 mg, 8.6 mg, 9 mg, 10 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 28 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 40 mg, 50 mg.

[0686] The term "tablet weight" refers to the weight of a single tablet. In some embodiments, the tablet weight of the oral polypeptide tablets is 300-1000 mg, such as 300 mg, 350 mg, 400 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 600 mg, 800 mg.

[0687] The term "unit dosage form" refers to the smallest administrable unit or the smallest packaging unit that can be split in a drug, such as tablets, capsules, powders, injections, capsules within capsules, micro-patch systems within capsules, etc. These units can exist independently physically and can be precisely split in terms of dosage. The unit dosage form usually contains a predetermined amount of the active ingredient to produce the desired therapeutic effect and is used in combination with appropriate pharmaceutical excipients.

[0688] As used herein, the term "capsule within a capsule" is a special delivery system for multi-stage release formulations. After reaching the release conditions, the outer capsule is released first, and the inner capsule is released later.

[0689] As used herein, the term "micro-patch system within a capsule" means that after the capsule enters the gastrointestinal tract, the capsule shell dissolves and the micro-patch is released. The patch can adhere to the gastrointestinal wall to increase the absorption efficiency of the drug by locally releasing the drug.

[0690] The term "single-ingredient preparation" refers to a single dosage form containing only one drug or active ingredient in a prescription. In some embodiments, the oral polypeptide composition is a single-ingredient preparation.

[0691] Use

[0692] The term "treatment" includes inhibiting, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, disorder, or condition being treated.

[0693] The term "effective amount" or "therapeutically effective amount" refers to a dose sufficient to treat, inhibit, or alleviate one or more symptoms of a disease state being treated or otherwise provide the desired pharmacological and / or physiological effect. The precise dose will vary according to a variety of factors, such as variables dependent on the subject (e.g., age, immune system health, etc.), the disease or disorder, and the treatment being administered. The effect of the effective amount can be relative to a control. Such controls are known in the art and are discussed herein, and can be, for example, the condition of the subject before or without the administration of a drug or drug combination, or in the case of a drug combination, the combined effect can be compared to the effect of administering only one drug.

[0694] Indications for the oral polypeptide compositions of the present disclosure include, but are not limited to, endocrine diseases, neurodegenerative diseases, vascular diseases, kidney diseases, and fatty liver diseases. Endocrine diseases include disorders of glucose metabolism, diabetes, and obesity; said neurodegenerative diseases include Alzheimer's disease and other forms of dementia, Parkinson's disease, multiple sclerosis, and Huntington's disease; said cardiovascular diseases include atherosclerosis, hyper-coagulable state and hypocoagulable state, coronary artery disease, and cerebrovascular events; said kidney diseases include renal failure; said fatty liver includes non-alcoholic fatty liver; and cancer, polycystic ovary syndrome, bone metabolism and osteoporosis, knee osteoarthritis, sleep apnea syndrome, osteoarthropathy, acromegaly, carcinoid syndrome, insulinoma, intestinal fistula, esophageal variceal bleeding, and metabolic myopathy, etc.

[0695] In one embodiment, the polypeptide is semaglutide, and the indications are selected from diabetes, obesity, hypertension, and complications caused by diabetes or obesity, such as, by way of example, type 1 diabetes, type 2 diabetes, obesity, cardiovascular disease, non-alcoholic fatty liver disease, chronic kidney disease, Alzheimer's disease, cancer, polycystic ovary syndrome, metabolic syndrome, bone metabolism and osteoporosis, knee osteoarthritis, sleep apnea syndrome, osteoarthropathy, and metabolic myopathy, etc.

[0696] Method for preparing pharmaceutical composition and tablet

[0697] The pharmaceutical composition of the present disclosure refers to a composition for preparing an oral polypeptide tablet, which comprises a first particle and a second particle, wherein the first particle encapsulates polypeptide molecules but does not include functional additives such as absorption promoters; the second particle includes functional additives such as absorption promoters but does not include polypeptide molecules, wherein the absorption promoter includes amino acids, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt, and medium-chain fatty acids or their salts. In some embodiments, the first particle comprises polypeptide molecules and excipients but does not include functional additives such as absorption promoters; and / or, the second particle includes functional additives such as absorption promoters and excipients but does not include polypeptide molecules.

[0698] In the pharmaceutical composition of the present disclosure, the first particle and the second particle can be produced in a manner known to those skilled in the art, for example, using wet granulation methods known for producing "combined" particles or "disintegrated" particles. The method of forming combined particles can be operated continuously and includes, for example, simultaneously spraying granulating substances with a granulating solution and drying, such as in a drum granulator, in a disk granulator, on a disk granulator, in a fluidized bed, by spray drying-drying or spray solidification, or discontinuously, such as in a fluidized bed, in a rotary fluidized bed, in an intermittent mixer, such as a high-shear mixer or a low-shear mixer, or in a spray drying drum. The method of preparing broken particles, which can be carried out discontinuously, wherein the granulating substances first form wet aggregates with the granulating solution, and then they are crushed or otherwise formed into particles of the desired size, and the particles can then be dried. Suitable equipment for the granulation step is a planetary mixer, a low-shear mixer, a high-shear mixer, an extruder, and a spheronizer. The granules can also be formed by dry granulation techniques, wherein the pharmaceutical active ingredient is compressed together with the excipient to form a larger molded article, such as by grinding crushed lumps or strips, and the ground material is used as the tablet pressing material for later compaction.

[0699] The method of using the pharmaceutical composition to prepare an oral polypeptide tablet is well known to those skilled in the art. To compress the tablet pressing material into a solid oral dosage form, such as a tablet, a tablet press can be used. In the tablet press, the tablet pressing material is filled (e.g., forced feeding or gravity feeding) into the die cavity. Then the tablet pressing material is compacted by a punch with pressure. Subsequently, the obtained tablet or tablet is ejected from the tablet press. The above compression process is hereinafter referred to as the "compression process". Suitable tablet presses include, but are not limited to, rotary tablet presses and eccentric tablet presses.

[0700] The process for preparing the oral polypeptide tablet of the present disclosure is not limited thereto. For example, tablets can be obtained by direct compression. Using the pharmaceutical composition of the present disclosure to prepare an oral polypeptide tablet can significantly improve the oral bioavailability of the tablet compared to the polypeptide tablet obtained by direct compression when the compositions are exactly the same.

[0701] II. Examples

[0702] The present disclosure will be further illustrated with reference to the embodiments. The description of the specific exemplary embodiments of the present disclosure is for the purpose of illustration and exemplification. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it is obvious that many changes and variations can be made in accordance with the teachings of the present disclosure specification. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present disclosure and its practical applications, so that those skilled in the art can implement and utilize various different exemplary embodiments of the present disclosure, as well as various different selections and changes.

[0703] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods.

[0704] Unless otherwise specified, the materials, reagents, etc. used in the following examples can all be obtained through commercial channels.

[0705] The specific embodiments of the present invention will be further described below. It should be noted here that the description of these embodiments is for helping to understand the present invention, but does not constitute a limitation to the present invention. In addition, the technical features involved in the following described embodiments can be combined with each other as long as they do not conflict with each other.

[0706] Unless otherwise specified, the experimental methods in the following examples are all conventional methods, and unless otherwise specified, the test materials used in the following examples can all be purchased through conventional commercial channels.

[0707] Example 1: Preparation of semaglutide tablets

[0708] 1) Mixing: Take the raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass ratio. After weighing, use a three-dimensional mixer to mix (rotation speed 50 rpm, time 300 s).

[0709] The formula of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium caprylate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprylate:arginine = 5:150:150:50

[0710] 2) Tableting: After mixing, take the material for tableting. Use a flat punch die with a diameter of 10 mm for tableting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10-mm round flat tablets with a semaglutide content of 5 mg.

[0711] Example 2: Preparation of semaglutide tablets

[0712] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the mass ratio shown below. After weighing, mix them evenly using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0713] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 43.48% w / w SNAC, 21.74% w / w sodium caprylate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprylate:arginine = 5:200:100:50

[0714] 2) Tableting: After mixing evenly, take the material for tableting. Use a flat punch die with a diameter of 10 mm for tableting, and charge 460 mg for each tablet. Take out the tablets from the die to obtain 10-mm round tablets with a semaglutide content of 5 mg.

[0715] Example 3: Preparation of semaglutide tablets

[0716] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the mass ratio shown below. After weighing, mix them evenly using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0717] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 54.35% w / w SNAC, 10.87% w / w sodium caprylate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprylate:arginine = 5:250:50:50

[0718] 2) Tableting: After mixing evenly, take the material for tableting. Use a flat punch die with a diameter of 10 mm for tableting, and charge 460 mg for each tablet. Take out the tablets from the die to obtain 10-mm round tablets with a semaglutide content of 5 mg.

[0719] Example 4: Preparation of semaglutide tablets

[0720] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the mass ratio shown below. After weighing, mix them evenly using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0721] The formulation of the pharmaceutical composition containing semaglutide is as follows: 0.98% w / w semaglutide, 29.41% w / w arginine, 29.41% w / w SNAC, 29.41% w / w sodium caprate, 8.08% w / w microcrystalline cellulose, 0.9% w / w sodium dodecyl sulfate, 1.8% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprate:arginine = 5:150:150:150

[0722] 2) Tabletting: After mixing evenly, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 510 mg per tablet. Take out the tablets from the die to obtain 10 mm round tablets with a semaglutide content of 5 mg.

[0723] Example 5: Preparation of semaglutide tablets

[0724] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass ratio, and use a three-dimensional mixer to mix evenly (rotation speed 50 rpm, time 300 s).

[0725] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 13.04% w / w arginine, 39.13% w / w SNAC, 39.13% w / w sodium caprate, 4.61% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprate:arginine = 5:180:180:60

[0726] 2) Tabletting: After mixing evenly, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10 mm round tablets with a semaglutide content of 5 mg.

[0727] Example 6: Preparation of semaglutide tablets

[0728] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass ratio, and use a three-dimensional mixer to mix evenly (rotation speed 50 rpm, time 300 s).

[0729] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 5.43% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium caprate, 25.26% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprate:arginine = 5:150:150:25

[0730] 2) Tabletting: After mixing, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10 mm round tablets with a semaglutide content of 5 mg.

[0731] Comparative Example 1: Preparation of Semaglutide Tablets

[0732] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass configuration ratio. After weighing, use a three-dimensional mixer to mix (rotation speed 50 rpm, time 300 s).

[0733] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 65.22% w / w sodium caprylate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide: sodium caprylate: arginine = 5:300:50

[0734] 2) Tabletting: After mixing, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10 mm round tablets with a semaglutide content of 5 mg.

[0735] Comparative Example 2: Preparation of Semaglutide Tablets

[0736] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass configuration ratio. After weighing, use a three-dimensional mixer to mix (rotation speed 50 rpm, time 300 s).

[0737] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 65.22% w / w SNAC, 19.82% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide: SNAC: arginine = 5:300:50

[0738] 2) Tabletting: After mixing, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10 mm round tablets with a semaglutide content of 5 mg.

[0739] Comparative Example 3: Preparation of Semaglutide Tablets

[0740] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass configuration ratio. After weighing, mix them using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0741] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 32.61% w / w SNAC, 32.61% w / w sodium caprylate, 30.69% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprylate = 5:150:150

[0742] Tabletting: After mixing, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10-mm round tablets with a semaglutide content of 5 mg.

[0743] Comparative Example 4: Preparation of semaglutide tablets

[0744] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass configuration ratio. After weighing, mix them using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0745] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 65.22% w / w sodium caprylate, 30.69% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:sodium caprylate = 5:300

[0746] 2) Tabletting: After mixing, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10-mm round tablets with a semaglutide content of 5 mg.

[0747] Comparative Example 5: Preparation of semaglutide tablets

[0748] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass configuration ratio. After weighing, mix them using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0749] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 65.22% w / w SNAC, 30.69% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC = 5:300

[0750] 2) Tabletting: After mixing, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10 mm round tablets with a semaglutide content of 5 mg.

[0751] Comparative Example 6: Preparation of Semaglutide Tablets

[0752] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass configuration ratio. After weighing, mix with a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0753] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 85.04% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:arginine = 5:50

[0754] 2) Tabletting: After mixing, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10 mm round tablets with a semaglutide content of 5 mg.

[0755] Comparative Example 7: Preparation of Semaglutide Tablets

[0756] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass ratio. After weighing, mix with a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0757] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 10.87% w / w SNAC, 54.35% w / w sodium caprylate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprylate:arginine = 5:50:250:50

[0758] 2) Tabletting: After mixing, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the die to obtain 10 mm round tablets with a semaglutide content of 5 mg.

[0759] Comparative Example 8: Preparation of Semaglutide Tablets

[0760] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass ratio. After weighing, mix them evenly using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0761] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 21.74% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium caprylate, 8.96% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprylate:arginine = 5:150:150:100

[0762] 2) Tabletting: After mixing evenly, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg for each tablet. Take out the tablets from the die to obtain 10-mm round tablets with a semaglutide content of 5 mg.

[0763] Comparative Example 9: Preparation of semaglutide tablets

[0764] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass ratio. After weighing, mix them evenly using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0765] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 6.52% w / w arginine, 19.57% w / w SNAC, 19.57% w / w sodium caprylate, 50.25% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprylate:arginine = 5:90:90:30

[0766] 2) Tabletting: After mixing evenly, take the material for tabletting. Use a flat punch die with a diameter of 10 mm for tabletting, and charge 460 mg for each tablet. Take out the tablets from the die to obtain 10-mm round tablets with a semaglutide content of 5 mg.

[0767] Comparative Example 10: Preparation of semaglutide tablets

[0768] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass ratio. After weighing, mix them evenly using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0769] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.09% w / w semaglutide, 95.91% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, 2% w / w sodium carboxymethyl starch.

[0770] 2) Tableting: After mixing evenly, take the material for tableting. A flat punch die with a diameter of 10 mm is used for tableting, and 460 mg of the material is fed per tablet. The tablets are taken out of the die to obtain 10 mm round tablets with a semaglutide content of 5 mg.

[0771] Test Example 1

[0772] Determined according to the dissolution and release determination method (General Chapter 0931, Method 2, Volume IV, Chinese Pharmacopoeia 2020 Edition). The specific method is as follows: Using 0.05% Solution - pH 6.8 phosphate buffer solution (weigh 6.8 g of anhydrous potassium dihydrogen phosphate, 0.896 g of sodium hydroxide and 0.5 g, dissolve in 1000 ml of water, and adjust the pH to 6.8 with phosphoric acid or sodium hydroxide) 500 ml as the dissolution medium, and the rotation speed is 70 revolutions per minute. At 0 min, the samples prepared in Example 1 and Comparative Examples 3 - 5 are put in, 3 tablets in each group. Samples are taken at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min. After the sampling at 60 min is completed, the dissolution cup is sampled by ultrasonic wave for 5 min. Test solution: Take 4.5 ml of the dissolution solution, filter it, and take the subsequent filtrate (the initial filtrate is 3 ml, if it is turbid, it can be centrifuged) to obtain it. Reference solution: Take an appropriate amount of semaglutide reference substance, weigh it accurately, dissolve it with the dissolution medium and quantitatively dilute it to prepare a solution containing about 32 μg of semaglutide per 1 ml.

[0773] The injection volume of the reference solution is 25 μl, and the injection volumes of the test solution are 100 μl (4 mg specification), 50 μl (8 mg specification), and 25 μl (16 mg specification). Use octadecylsilane chemically bonded silica gel as the filler (Phenomenex Kinetex C18, 150x4.6 mm, 2.6 μm or a chromatographic column with equivalent efficiency); use 0.1 mol / L diammonium hydrogen phosphate buffer solution (weigh 23.76 g of diammonium hydrogen phosphate, add an appropriate amount of water to completely dissolve it, then add water to 1800 ml, adjust the pH to 3.6 with concentrated phosphoric acid, filter) - acetonitrile (9∶1) as mobile phase A, and use acetonitrile - isopropanol - water (3∶1∶1) as mobile phase B, and perform linear gradient elution according to the following table; the detection wavelength is 215 nm; the column temperature is 35 °C; the injection tray temperature is 6 °C; the flow rate is 0.5 ml per minute; the injection volume is 10 μl.

[0774] The sample was detected using an Agilent 1260 Infinity II high performance liquid chromatograph. The injection volume of the reference solution was 25 μl, and the injection volume of the test solution was 80 μl. Octadecylsilyl silica gel was used as the filler (Phenomenex Kinetex C18, 150 x 4.6 mm, 2.6 μm or a chromatographic column of equivalent efficiency); 0.1 mol / L diammonium hydrogen phosphate buffer solution (weigh 23.76 g of diammonium hydrogen phosphate, add appropriate amount of water to dissolve completely, add water to 1800 ml, adjust the pH to 3.6 with concentrated phosphoric acid, filter) - acetonitrile (9:1) was used as mobile phase A, and acetonitrile - isopropanol - water (3:1:1) was used as mobile phase B, and linear gradient elution was carried out according to Table 1; the detection wavelength was 215 nm; the column temperature was 35 °C; the injection tray temperature was 6 °C; the flow rate was 0.5 ml per minute.

[0775] Table 1

[0776] Time (min) Mobile phase A (%) Mobile phase B (%) 0 47 53 14 47 53 14.1 0 100 16 0 100 16.1 47 53 20 47 53

[0777] The dissolution test results of the above semaglutide tablets are shown in Table 2 below and Figure 1 . The results showed that when SNAC, sodium caprylate and arginine were simultaneously contained in the formulation, the dissolution rate of semaglutide was the fastest.

[0778] Table 2

[0779]

[0780] Test Example 2

[0781] Test the absorption of the above-prepared semaglutide tablets after oral administration to beagle dogs. The specific method is as follows: Experimental animals (weighing 10 - 12 kg) need to be fasted for 12 hours and water-deprived for 6 hours before administration, and the fasting and water deprivation are lifted 1 hour after administration. Before administration, 1 ml of blank blood is collected using an EDTA-K2 blood collection tube as the 0-point blood sample standard for the experiment. The tablets prepared in Examples 1 - 6 and Comparative Examples 1 - 10 are orally administered to beagle dogs by gavage, and 15 ml of water is given simultaneously to ensure successful swallowing. Each group has 5 animals, all male, and the average weight of each group is ensured to be the same during grouping. Subsequently, blood is collected from the forearm vein of beagle dogs using an EDTA-K2 blood collection tube at the following time points after administration: 0.5 h, 1 h, 2 h, 3 h, and the blood collection volume at each blood collection point is 1 ml. The whole blood of beagle dogs is collected and centrifuged, and the supernatant plasma blood sample is taken after centrifugation and stored at -20 °C for subsequent mass spectrometry detection and analysis. The mass spectrometry detection is carried out after verification according to the method described in the published literature "Quantitative Analysis of Semaglutide and Tirzepatide in Rat Plasma by SCIEX LC-MS / MS System".

[0782] The absorption test results of the above semaglutide tablets after oral administration to beagle dogs are shown in Table 3 below and Figure 2 。

[0783] Table 3

[0784]

[0785] BLQ = below the lower limit of quantification (2 ng / ml)

[0786] Example 7: Preparation of semaglutide tablets

[0787] 1) Mixing: Take the raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, the components are precisely weighed according to the following mass configuration ratio, and after weighing, they are mixed using a three-dimensional mixer (rotation speed 50 rpm, time 300 s).

[0788] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.74% w / w semaglutide, 10.87% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium caprylate, 19.17% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. Among them, semaglutide:SNAC:sodium caprylate:arginine = 8:150:150:50

[0789] 2) Tabletting: After mixing, take the material for tabletting. Use a shallow arc-shaped punch of 13.5 * 7.5 mm for tabletting, and charge 460 mg per tablet. Take out the tablets from the mold to obtain oval tablets with 8 mg of semaglutide content.

[0790] Example 8: Preparation of Semaglutide Tablets

[0791] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass configuration ratio, transfer it into a PE bag after weighing, mix 1 - 2 times, and shake 100 - 200 times each time.

[0792] Material A: 10.53% w / w semaglutide, 68.42% w / w microcrystalline cellulose, 21.05% w / w polyvinylpyrrolidone K90

[0793] Material B: 11.38% w / w arginine, 34.12% w / w SNAC, 34.12% w / w sodium caprate, 17.24% w / w microcrystalline cellulose, 1.05% w / w sodium dodecyl sulfate, 2.09% w / w sodium carboxymethyl starch

[0794] 2) Granulation: Set the cooling water temperature of the dry granulator at 10 - 25 °C, the pressure of the pressure roller at 70 ± 30 bar, the feeding speed at 20 - 60 rpm, the rotation speed of the pressure roller at 6 - 12 rpm, the granulation speed at 60 - 100 rpm, and the screen specification at 16 / 20 mesh; turn on the equipment to trial granulate Material A. If it does not meet the requirements, adjust the equipment parameters appropriately and then trial granulate again. After meeting the requirements, carry out formal granulation. Record the actual parameters during the granulation process until all the powder is granulated to obtain Granule A.

[0795] Use the same process to granulate Material B to obtain Granule B.

[0796] 3) Tabletting: Accurately weigh each component according to the mass configuration ratio of 14.67% w / w Granule A, 84.83% w / w Granule B, and 0.5% w / w magnesium stearate. Transfer it into a PE bag after weighing, mix 1 - 2 times, and shake 100 - 200 times each time. After mixing, take the material for tabletting. Use a shallow arc-shaped punch of 13.5 * 7.5 mm for tabletting, and charge 518.2 mg per tablet. Take out the tablets from the mold to obtain oval tablets with 8 mg of semaglutide content.

[0797] Example 9: Preparation of Semaglutide Tablets

[0798] 1) Mixing: Take raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40-mesh sieve, accurately weigh each component according to the following mass configuration ratio, transfer it into a PE bag after weighing, mix 1 - 2 times, and shake 100 - 200 times each time.

[0799] Material A: 42.11% w / w semaglutide, 36.84% w / w microcrystalline cellulose, 21.05% w / w povidone K90

[0800] Material B: 11.38% w / w arginine, 34.12% w / w SNAC, 34.12% w / w sodium caprate, 17.24% w / w microcrystalline cellulose, 1.05% w / w sodium lauryl sulfate, 2.09% w / w sodium carboxymethyl starch

[0801] 2) Granulation: Set the cooling water temperature of the dry granulator at 10 - 25°C, the pressure of the roller at 70 ± 30 bar, the feeding speed at 20 - 60 rpm, the roller speed at 6 - 12 rpm, the screening speed at 60 - 100 rpm, and the screen specification at 16 / 20 mesh; start the equipment to conduct trial granulation on Material A. If it does not meet the requirements, appropriately adjust the equipment parameters and conduct trial granulation again. After meeting the requirements, conduct formal granulation and record the actual parameters during the granulation process until all the powder is granulated to obtain Granule A.

[0802] Use the same process to granulate Material B to obtain Granule B.

[0803] 3) Tableting: Weigh each component precisely according to the mass configuration ratio of 4.12% w / w Granule A, 95.36% w / w Granule B, and 0.52% w / w magnesium stearate. After weighing, transfer it into a PE bag and mix it 1 - 2 times, shaking it 100 - 200 times each time. After mixing evenly, take the material for tableting. Use a 13.5 * 7.5 mm shallow arc special-shaped punch for tableting, and charge 461 mg for each tablet. Take out the tablets from the mold to obtain oval tablets with a semaglutide content of 8 mg.

[0804] Test Example 3

[0805] Test the absorption of the prepared semaglutide tablets after oral administration to beagle dogs. The specific method is as follows: Experimental animals (weighing 10 - 12 kg) need to be fasted for 12 hours and water-deprived for 6 hours before drug administration, and the fasting and water deprivation are lifted 1 hour after drug administration. Before drug administration, 1 ml of blank blood is collected using an EDTA-K2 blood collection tube as the 0-time blood sample standard for the experiment. The tablets prepared in Examples 7 - 9 are orally administered to beagle dogs by gavage, and 15 ml of water is given simultaneously to ensure successful swallowing. Each group has 5 animals, all male, and the average weight of each group is ensured to be the same during grouping. Subsequently, blood is collected from the forearm vein of beagle dogs using an EDTA-K2 blood collection tube at the following time points after drug administration: 0.5 h, 1 h, 2 h, 3 h, and the blood collection volume at each blood collection point is 1 ml. The whole blood of beagle dogs is collected and centrifuged, and the supernatant plasma blood sample is taken after centrifugation and frozen at -20 °C for subsequent mass spectrometry detection and analysis. The mass spectrometry detection is carried out after verification according to the method described in the public literature "Quantitative Analysis of Semaglutide and Tirzepatide in Rat Plasma by SCIEX LC-MS / MS System".

[0806] The absorption test results of the above semaglutide tablets after oral administration to beagle dogs are shown in Table 4 below and Figure 3 .

[0807] Table 4

[0808]

[0809] From the data in the above table, it can be seen that the preparation processes of Examples 8 and 9 significantly improve the oral blood drug concentration of semaglutide tablets in beagle dogs.

[0810] Example 10

[0811] 1) Mixing: Take raw materials to prepare the powder of the drug preparation system. After passing the powder of each component through a 40-mesh sieve, precise weighing of each component is carried out according to the following mass preparation ratio. After weighing material A, it is all transferred into a PE bag and mixed 1 - 2 times, with shaking 100 - 200 times each time; after weighing material B, it is transferred into the PE bag in ascending order of mass, and shaken 100 - 200 times each time after adding each material for mixing.

[0812] Material A: 10.53% w / w semaglutide, 68.42% w / w microcrystalline cellulose, 21.05% w / w polyvinylpyrrolidone K90

[0813] Material B: 11.38% w / w arginine, 34.12% w / w SNAC, 34.12% w / w sodium caprate, 17.24% w / w microcrystalline cellulose, 1.05% w / w sodium dodecyl sulfate, 2.09% w / w sodium carboxymethyl starch

[0814] 2) Granulation: Set the cooling water temperature of the dry granulator at 10 - 25°C, the pressure of the roller at 50 ± 30 bar, the feeding speed at 10 - 30 rpm, the rotation speed of the roller at 5 - 10 rpm, the sizing speed at 60 - 100 rpm, and the screen specification at 16 / 20 mesh; start the equipment to trial granulate Material A. If the requirements are not met, adjust the equipment parameters appropriately and then trial granulate again. After meeting the requirements, conduct formal granulation. Record the actual parameters during the granulation process until all the powder is granulated to obtain Granule A.

[0815] Use the same process to granulate Material B to obtain Granule B.

[0816] 3) Tabletting: Weigh each component precisely according to the mass formulation ratio of 7.92% w / w Granule A, 91.58% w / w Granule B, and 0.5% w / w magnesium stearate. After weighing, transfer them into a PE bag, mix 1 - 2 times, and shake 100 - 200 times each time. After mixing evenly, take the material for tabletting. Use a 13.5 * 7.5 mm shallow arc special-shaped punch for tabletting, and charge 480 mg for each tablet. Take out the tablets from the mold to obtain oval tablets with a semaglutide content of 4 mg.

[0817] 4) Coating: Use Prepare a coating solution with a solid content of 15% using a film coating premix, with a coating gain of 4% - 5%. Set the inlet air temperature of the coating machine at 35°C, the outlet air temperature at 30°C, the inlet air rotation speed at 1100 - 1300 rpm, the exhaust rotation speed at 1300 - 1500 rpm, the main machine rotation speed at 10 - 15 rpm, the spray pump speed at 2 - 10 rpm, the atomization pressure at 0.18 MPa, and the spray gun pressure at 0.2 MPa. It is necessary to fully preheat before coating and dry and cure after coating.

[0818] Example 11

[0819] 1) Mixing: Take the raw materials to prepare the powder of the pharmaceutical preparation system. After passing each component powder through a 40 - mesh sieve, weigh each component precisely according to the following mass formulation ratio. After weighing Material A, transfer it all into a PE bag, mix 1 - 2 times, and shake 100 - 200 times each time; after weighing Material B, transfer it into the PE bag in ascending order of mass, and shake 100 - 200 times each time after adding each material for mixing.

[0820] Material A: 21.05% w / w semaglutide, 57.89% w / w microcrystalline cellulose, 21.05% w / w polyvinylpyrrolidone K90

[0821] Material B: 11.38% w / w arginine, 34.12% w / w SNAC, 34.12% w / w sodium caprate, 17.24% w / w microcrystalline cellulose, 1.05% w / w sodium dodecyl sulfate, 2.09% w / w sodium carboxymethyl starch

[0822] 2) Granulation: Set the cooling water temperature of the dry granulator at 10 - 25°C, the pressure of the roller at 50 ± 30 bar, the feeding speed at 10 - 30 rpm, the rotation speed of the roller at 5 - 10 rpm, the sizing speed at 60 - 100 rpm, and the screen specification at 16 / 20 mesh; start the equipment to conduct trial granulation on Material A. If the requirements are not met, adjust the equipment parameters appropriately and conduct trial granulation again. After meeting the requirements, conduct formal granulation. Record the actual parameters during the granulation process until all the powder is granulated to obtain Granule A.

[0823] Use the same process to granulate Material B to obtain Granule B.

[0824] 3) Tabletting: Weigh each component precisely according to the mass preparation ratio of 7.92% w / w Granule A, 91.58% w / w Granule B, and 0.5% w / w magnesium stearate. After weighing, transfer them into a PE bag, mix 1 - 2 times, and shake 100 - 200 times each time. After mixing evenly, take the material for tabletting. Use a 13.5 * 7.5 mm shallow arc special-shaped punch for tabletting, and charge 480 mg for each tablet. Take out the tablets from the mold to obtain oval tablets with a semaglutide content of 8 mg.

[0825] 4) Coating: Use The film coating premix is used to prepare a coating solution with a solid content of 15%, and the coating gain is 4% - 5%. Set the inlet air temperature of the coating machine at 35°C, the outlet air temperature at 30°C, the inlet air rotation speed at 1100 - 1300 rpm, the exhaust rotation speed at 1300 - 1500 rpm, the main machine rotation speed at 10 - 15 rpm, the spray pump speed at 2 - 10 rpm, the atomization pressure at 0.18 MPa, and the spray gun pressure at 0.2 MPa. It is necessary to fully preheat before coating and dry and cure after coating.

[0826] Example 12

[0827] 1) Mixing: Take the raw materials to prepare the powder of the pharmaceutical preparation system. After passing the powder of each component through a 40 - mesh sieve, weigh each component precisely according to the following mass preparation ratio. After weighing Material A, transfer it all into a PE bag, mix 1 - 2 times, and shake 100 - 200 times each time; after weighing Material B, transfer it into the PE bag in ascending order of mass, and shake 100 - 200 times each time after adding each material for mixing.

[0828] Material A: 42.11% w / w semaglutide, 36.84% w / w microcrystalline cellulose, 21.05% w / w polyvinylpyrrolidone K90

[0829] Material B: 11.38% w / w arginine, 34.12% w / w SNAC, 34.12% w / w sodium caprate, 17.24% w / w microcrystalline cellulose, 1.05% w / w sodium lauryl sulfate, 2.09% w / w sodium carboxymethyl starch

[0830] 2) Granulation: Set the cooling water temperature of the dry granulator at 10 - 25°C, the pressure of the roller at 50 ± 30 bar, the feeding speed at 10 - 30 rpm, the rotational speed of the roller at 5 - 10 rpm, the sizing speed at 60 - 100 rpm, and the screen specification at 16 / 20 mesh; start the equipment to conduct trial granulation on Material A. If the requirements are not met, adjust the equipment parameters appropriately and conduct trial granulation again. After meeting the requirements, conduct formal granulation. Record the actual parameters during the granulation process until all the powder is granulated to obtain Granule A.

[0831] Use the same process to granulate Material B to obtain Granule B.

[0832] 3) Tabletting: Weigh each component precisely according to the mass formulation ratio of 7.92% w / w Granule A, 91.58% w / w Granule B, and 0.5% w / w magnesium stearate. After weighing, transfer them into a PE bag and mix 1 - 2 times, shaking 100 - 200 times each time. After mixing evenly, take the material for tabletting. Use a 13.5 * 7.5 mm shallow arc special-shaped punch for tabletting, and charge 480 mg for each tablet. Take out the tablets from the mold to obtain oval tablets with a semaglutide content of 16 mg.

[0833] 4) Coating: Use A film coating premix to prepare a coating solution with a solid content of 15%, a coating gain of 4% - 5%. Set the inlet air temperature of the coating machine at 35°C, the outlet air temperature at 30°C, the inlet air rotational speed at 1100 - 1300 rpm, the exhaust rotational speed at 1300 - 1500 rpm, the main machine rotational speed at 10 - 15 rpm, the spraying pump speed at 2 - 10 rpm, the atomization pressure at 0.18 MPa, and the spray gun pressure at 0.2 MPa. It is necessary to fully preheat before coating and dry and cure after coating.

[0834] Test Example 4

[0835] Test the absorption of the prepared semaglutide tablets after oral administration to cynomolgus monkeys. The specific method is as follows: The experimental animals need to be fasted for 12 hours and water-deprived for 6 hours before drug administration, and the fasting and water deprivation are lifted 1 hour after drug administration. Before drug administration, a certain amount of blank blood is collected using an EDTA-K2 blood collection tube as the 0-hour blood sample for the experiment, and the animal body weight is weighed. The tablets prepared in Examples 10-12 are orally administered to cynomolgus monkeys, and 15 ml of water is given simultaneously to ensure successful swallowing. In another group, semaglutide is intravenously administered to cynomolgus monkeys at a dose of 0.05 mg / kg per animal. A total of 6 cynomolgus monkeys are used in each group, with 3 females and 3 males. Subsequently, venous blood is collected using an EDTA-K2 blood collection tube at the following time points after drug administration: 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h, 336 h. The whole blood of cynomolgus monkeys is collected and centrifuged to obtain plasma samples. The samples are frozen at -20 °C and subsequently used for mass spectrometry detection and analysis. The mass spectrometry detection is carried out after verification according to the method described in the public literature "Quantitative Analysis of Semaglutide and Tirzepatide in Rat Plasma by SCIEX LC-MS / MS System".

[0836] The absorption test results of the above semaglutide tablets after oral administration to cynomolgus monkeys are shown in Table 5 below and Figure 4 . The average bioavailability calculated after body weight calibration is 1.75%.

[0837] Table 5

[0838]

[0839] Example 13. Preparation of semaglutide tablets

[0840] First, prepare the powder of the drug preparation system according to the scheme in Table 6. Specifically, weigh each component according to the mass configuration ratio shown in the following table, and mix well after weighing.

[0841] Table 6 Semaglutide drug preparation system table

[0842] Drug preparation system Component ratio OLP-A001 1.52% semaglutide, 10.87% arginine, 32.61% SNAC, 32.61% sodium caprylate, 22.39% microcrystalline cellulose OLP-A003 1.52% semaglutide, 10.87% citrulline, 32.61% SNAC, 32.61% sodium caprylate, 22.39% microcrystalline cellulose OLP-A004 1.52% semaglutide, 10.87% niacinamide, 32.61% SNAC, 32.61% sodium caprylate, 22.39% microcrystalline cellulose OLP-A005 1.52% semaglutide, 65.22% SNAC, 33.26% microcrystalline cellulose OLP-A006 1.52% semaglutide, 10.87% lysine, 21.74% SNAC, 43.48% sodium caprylate, 22.39% microcrystalline cellulose

[0843] Use a flat punch die for tableting, and take out the tablets from the die to obtain 10-mm round flat tablets with a semaglutide content of 7 mg.

[0844] Test Example 5. Beagle dog test of semaglutide tablets

[0845] Before administration, blank blood was taken as the 0-point blood sample for the experiment. The tablets prepared in Example 13 and the original research oral semaglutide tablets of Novo Nordisk ( , 7 mg specification) were administered to beagle dogs by gavage, with 6 dogs in each group. Subsequently, blood was collected from the cephalic vein of the forelimb of beagle dogs at the following time points after administration: 0.5 h, 1 h, 2 h, and 3 h. The whole blood of beagle dogs was collected and centrifuged, and the supernatant plasma blood sample was frozen after centrifugation for subsequent mass spectrometry detection and analysis.

[0846] The experimental results are shown in Table 6-1. The experimental results show that the absorption of semaglutide in the drug formulation system OLP-A001 by beagle dogs is significantly better than that of ( Figure 5 ).

[0847] Table 6-1 Detection and analysis of the content of semaglutide in the plasma of beagle dogs after administration

[0848]

[0849] Example 14, Preparation of teriparatide tablets

[0850] First, the powder of the drug formulation system was prepared according to the scheme in Table 7. Specifically, each component was weighed according to the mass configuration ratio shown in the following table and mixed after weighing.

[0851] Table 7 Teriparatide drug formulation system table

[0852] Drug preparation system Component ratio OLP-B001 1.52% teriparatide, 10.87% arginine, 32.61% SNAC, 32.61% sodium caprylate, 22.39% microcrystalline cellulose OLP-B002 1.52% teriparatide, 98.48% microcrystalline cellulose OLP-B003 1.52% teriparatide, 65.22% SNAC, 33.26% microcrystalline cellulose

[0853] A flat punch die was used for tableting, and the tablets were taken out of the die to obtain 10 mm round flat tablets with a teriparatide content of 7 mg.

[0854] Test Example 6, Teriparatide tablet beagle dog test

[0855] Before administration, 1 ml of blank blood was taken as the 0-point blood sample for the experiment. The tablets prepared in Example 14 were administered to beagle dogs. Subsequently, blood was collected from the cephalic vein of the forelimb of beagle dogs at the following time points after administration: 0.25 h, 0.5 h, 1 h, 2 h, and 3 h. The whole blood of beagle dogs was collected and centrifuged, and the supernatant plasma blood sample was frozen after centrifugation for subsequent mass spectrometry detection and analysis.

[0856] The experimental results are shown in Table 7-1. The experimental results show that the absorption of teriparatide in the drug formulation system OLP-B001 by beagle dogs is significantly better than that of OLP-B003 ( Figure 6 ).

[0857] Table 7-1 Detection and analysis of the content of teriparatide in the plasma of beagle dogs after administration

[0858]

[0859]

[0860] Example 15, Preparation of Tirzepatide Capsules

[0861] First, prepare the powder of the pharmaceutical preparation system according to the scheme in Table 8. Specifically, weigh each component according to the mass configuration ratio shown in the following table, and mix them evenly after weighing.

[0862] Table 8 Tirzepatide Pharmaceutical Preparation System Table

[0863] Drug preparation system Component ratio OLP-C001 3.04% tizopatide, 10.87% arginine, 32.61% SNAC, 32.61% sodium caprylate, 20.87% microcrystalline cellulose OLP-C002 3.04% tizopatide, 96.96% microcrystalline cellulose OLP-C003 3.04% tizopatide, 65.22% SNAC, 31.74% microcrystalline cellulose OLP-C004 3.04% tizopatide, 10.87% niacinamide, 32.61% SNAC, 32.61% sodium caprylate, 20.87% microcrystalline cellulose OLP-C005 3.04% tizopatide, 10.87% citrulline, 32.61% SNAC, 32.61% sodium caprylate, 20.87% microcrystalline cellulose

[0864] Use a flat punch die for tabletting. Take out the tablets from the die to obtain 8 mm round flat tablets with a tirzepatide content of 4.86 mg. Grind the above tablets and pass them through an 80-mesh sieve, and weigh 13.16 mg of the sieved powder and fill it into a No. 9 gelatin capsule to obtain a No. 9 capsule with a tirzepatide content of 0.4 mg.

[0865] Test Example 7, Tirzepatide Capsule Rat Experiment

[0866] Before administration, take the blank blood of the rats as the 0-point blood sample standard for the experiment. After anesthetizing the rats, perform abdominal hair shaving and laparotomy operations. Find the small intestine about 12 cm away from the cecum of the rats, carefully cut open the rat intestine with a blade, and administer 1 capsule prepared in Example 15 to the rats through the incision. Push the capsule 2 cm towards the cecum direction to avoid the wound, and then suture the rat intestine and abdomen. Take blood from the rats at the following time points after administration: 0.5 h, 1 h, 2 h, 3 h, 4 h, and the blood collection volume at each blood collection point is 0.5 ml. Collect the whole blood of the rats for centrifugation, and take the supernatant plasma blood sample for freezing storage after centrifugation, which will be used for mass spectrometry detection and analysis later.

[0867] The experimental results are shown in Table 8-1. The experimental results show that the absorption of tirzepatide in the pharmaceutical preparation systems OLP-C001 and OLP-C005 by rats is better than that in OLP-C003 and OLP-C004 ( Figure 7 ).

[0868] Table 8-1 Detection and Analysis of the Content of Tirzepatide in Plasma after Administration

[0869]

[0870] Example 16, Preparation of Octreotide Capsules

[0871] First, prepare the powder of the pharmaceutical preparation system according to the scheme in Table 9. Specifically, weigh each component according to the mass configuration ratio shown in the following table, and mix them evenly after weighing.

[0872] Table 9 Octreotide Pharmaceutical Preparation System Table

[0873] Drug preparation system Component ratio OLP-D001 3.04% octreotide, 10.87% arginine, 32.61% SNAC, 32.61% sodium caprylate, 22.39% microcrystalline cellulose OLP-D002 3.04% octreotide, 96.96% microcrystalline cellulose OLP-D003 3.04% octreotide, 65.22% SNAC, 31.74% microcrystalline cellulose OLP-D004 3.04% octreotide, 10.87% citrulline, 32.61% SNAC, 32.61% sodium caprylate, 22.39% microcrystalline cellulose

[0874] Tabletting is carried out using a flat punch die, and the tablets are taken out of the die to obtain 8 mm round flat tablets with an octreotide content of 4.86 mg. The above-mentioned tablets are ground and passed through an 80-mesh sieve, and 13.16 mg of the sieved powder is weighed and filled into No. 9 gelatin capsules to obtain No. 9 capsule preparations with an octreotide content of 0.4 mg.

[0875] Test Example 8: Octreotide Capsule Rat Experiment

[0876] Before administration, blank rat blood is taken as the 0-point blood sample standard for the experiment. After the rats are anesthetized, abdominal hair removal and laparotomy are performed. Then, the small intestine about 12 cm away from the cecum of the rats is found, and the intestinal tract of the rats is carefully cut open with a blade, and 1 capsule described in Example 16 is given to the rats through the incision. The capsule is pushed 2 cm towards the cecum direction to avoid the wound, and then the intestinal tract and abdomen of the rats are sutured. Blood is taken from the rats at the following time points after administration: 0.5 h, 1 h, 2 h, 3 h, 4 h, and the blood collection volume at each blood collection point is 0.5 ml. The whole blood of the rats is collected and centrifuged, and the supernatant serum blood sample is taken after centrifugation and frozen for subsequent mass spectrometry detection and analysis.

[0877] The experimental results are shown in Table 9-1. The experimental results show that the absorption of octreotide in the drug preparation systems OLP-D001 and OLP-D004 by rats is significantly better than that of OLP-D003 ( Figure 8 ).

[0878] Table 9-1 Detection and Analysis of Octreotide Content in Plasma after Administration

[0879]

[0880] Test Example 9: Composition Characterization

[0881] Weigh the powder according to the protocol in Table 9, add PBS and vortex. After vortexing, centrifuge the sample and take the supernatant and add it to the sample cell, and analyze it using a particle size analyzer.

[0882] Table 9 Combined Drug System

[0883] Drug system Component OLP-S001 10 mg semaglutide OLP-S002 10 mg semaglutide, 37.5 mg arginine, 112.5 mg sodium caprate, 112.5 mg SNAC OLP-S003 10 mg semaglutide, 225 mg SNAC

[0884] The experimental results show that the polypeptide in the drug system OLP-S002 can form micelles with an average particle size of 2.84.

[0885] Table 10 Peak Mean of Particle Size Number Distribution of Combined Drugs

[0886] Drug system Mean value (nm) ± SD of particle size number distribution peak OLP-S001 4.48±0.09 OLP-S002 2.84±0.51 OLP-S003 697.13±67.67

Claims

1. An oral polypeptide composition, wherein: The polypeptide composition comprises: semaglutide, no more than about 20% w / w amino acids, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid or its salt and no less than about 10% w / w medium-chain fatty acids or their salts, wherein in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (NAC) or its salt and the medium-chain fatty acids or their salts is no less than about 50% w / w.

2. The polypeptide composition according to claim 1, wherein The polypeptide composition comprises: semaglutide, about 5-20% w / w amino acids, not less than about 20% w / w N-(8-[2-hydroxybenzoyl]-amino) caprylic acid or its salt, and not less than about 15% w / w medium-chain fatty acids or their salts; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (NAC) or its salt, and the medium-chain fatty acids or their salts is about 50-90% w / w.

3. The polypeptide composition according to claim 2, wherein: The polypeptide composition comprises: semaglutide, about 5-20% w / w amino acid, about 20-55% w / w N-(8-[2-hydroxybenzoyl]-amino) caprylic acid or its salt and not less than about 15% w / w medium-chain fatty acid or its salt; wherein, in the polypeptide composition, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (NAC) or its salt and the medium-chain fatty acid or its salt is about 70-80%. w / w.

4. The polypeptide composition according to claim 3, wherein: The polypeptide composition comprises: semaglutide, about 5-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino) caprylic acid or its salt and about 20-40% w / w medium-chain fatty acids or their salts; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (NAC) or its salt and the medium-chain fatty acids or their salts is about 70-80% w / w.

5. The polypeptide composition according to claim 4, wherein: The polypeptide composition comprises: semaglutide, about 5-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino) caprylic acid or its salt and about 20-40% w / w medium-chain fatty acids or its salt; and the mass percentage content of the medium-chain fatty acids or its salts is not higher than that of the N-(8-[2-hydroxybenzoyl]-amino) caprylic acid or its salt; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (NAC) or its salt and the medium-chain fatty acids or its salts is about 70-80% w / w.

6. The polypeptide composition according to any one of claims 1 to 4, wherein: In the polypeptide composition, the mass percentage ratio of the N-(8-[2-hydroxybenzoyl]-amino) caprylic acid or its salt to the medium-chain fatty acid or its salt is about 1:(0.5-2).

7. The polypeptide composition according to any one of claims 1 to 4, wherein: In the polypeptide composition, the mass percentage ratio of the amino acid to the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or its salt is approximately (1-2):

3.

8. The polypeptide composition according to any one of claims 1 to 4, wherein The mass percentage ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid or its salt, and medium-chain fatty acid or its salt is about 1:(2.5-3.5):(2.5-3.5).

9. The polypeptide composition according to claim 8, wherein: In the polypeptide composition, the mass percentage ratio of the amino acid, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid or its salt, and medium-chain fatty acid or its salt is about 1:3:

3.

10. The polypeptide composition according to any one of claims 1 to 4, wherein: The medium-chain fatty acid salt is sodium caprate; and / or the amino acid is arginine; and / or the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid is N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

11. The polypeptide composition according to claim 10, wherein: The oral polypeptide composition comprises: 1-50 parts by weight of semaglutide; Arginine 20-100 parts by weight; Sodium caprate 100-300 parts by weight; 100-300 parts by weight of sodium N-(8-[2-hydroxybenzoyl]-amino)caprylate.

12. The polypeptide composition according to claim 10, wherein: The oral polypeptide composition comprises: 1-32 parts by weight of semaglutide; Arginine 50-70 parts by weight; Sodium caprate 120-180 parts by weight; 120-180 parts by weight of sodium N-(8-[2-hydroxybenzoyl]-amino)caprylate.

13. The polypeptide composition according to any one of claims 1-5, 11-12, wherein: The polypeptide composition further comprises at least one excipient.

14. The polypeptide composition according to claim 13, wherein: The excipient is present in an amount not greater than about 30% w / w.

15. The polypeptide composition according to claim 14, wherein: The oral polypeptide composition comprises: about 4.0 mg semaglutide, about 50.0 mg arginine, about 150.0 mg sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate, about 150.0 mg sodium decanoate, and about 123.0 mg excipients.

16. The polypeptide composition according to claim 14, wherein The oral polypeptide composition comprises: about 8.0 mg semaglutide, about 50.0 mg arginine, about 150.0 mg sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate, about 150.0 mg sodium decanoate, and about 120.0 mg excipients.

17. The polypeptide composition according to claim 14, wherein: The oral polypeptide composition comprises: about 16.0 mg semaglutide, about 50.0 mg arginine, about 150.0 mg sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate, about 150.0 mg sodium decanoate, and about 110.0 mg excipients.

18. The polypeptide composition according to any one of claims 1-5, 11-12, 15-17, wherein The oral polypeptide composition is a solid preparation.

19. The polypeptide composition according to claim 18, wherein: The oral pharmaceutical composition is a tablet.

20. The polypeptide composition according to claim 19, wherein: The specification of the tablet is about 1-50 mg.

21. The use of the polypeptide composition according to any one of claims 1 to 20, for: (i) treatment of disease; and / or (ii) preparing a medicament for treating a disease; in, The disease is selected from at least one of type 1 diabetes, type 2 diabetes, obesity, cardiovascular disease, non-alcoholic fatty liver disease, chronic kidney disease, Alzheimer's disease, cancer, polycystic ovary syndrome, metabolic syndrome, bone metabolism and osteoporosis, knee osteoarthritis, sleep apnea syndrome, osteoarthritis and metabolic muscle disease.

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