Oral polypeptide compositions

Abstract

The present disclosure belongs to the field of biological medicine, and particularly relates to an oral polypeptide composition for improving gastrointestinal absorption of polypeptide drugs; and particularly discloses an oral polypeptide composition, which comprises polypeptide molecules, medium-chain fatty acids and salts thereof, amino acids, and N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) and salts thereof. The oral polypeptide preparation of the present disclosure can effectively improve the blood drug concentration of polypeptides, and improve the bioavailability of oral polypeptides.

Description

[0001] Priority Statement

[0002] This disclosure claims priority to Chinese Patent Application No. 202410710353.4, filed on June 3, 2024, entitled "An Oral Peptide Composition". The entire contents of the aforementioned Chinese Patent Application are incorporated herein by reference.

[0003] This disclosure claims priority to Chinese Patent Application No. 202411335782.4, filed on September 24, 2024, entitled "An Oral Peptide Composition". The entire contents of the aforementioned Chinese Patent Application are incorporated herein by reference. Technical Field

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

[0005] Peptide drugs are a class of biomolecules composed of short-chain amino acids linked by peptide bonds, typically consisting of 10 to 50 amino acids, and represent an important branch of current drug development. Peptide drugs can specifically bind to targets, such as receptors or enzymes, and this binding usually exhibits high affinity. This allows peptide drugs, compared to small molecule drugs, to precisely regulate specific biological processes without affecting other physiological functions. Compared to many large-molecule biopharmaceuticals, peptides generally have lower immunogenicity because their smaller molecular structure and closer resemblance to natural peptides make them less likely to elicit a strong immune response. Compared to complex biopharmaceuticals, the synthesis of peptide drugs is simpler and more controllable, making production more efficient and cost-effective. Furthermore, natural peptides can be modified through various means to enhance their efficacy, improve pharmacokinetic properties, or reduce side effects.

[0006] Currently, the primary route of administration for peptide drugs is injection. Injection is an invasive procedure that requires penetration through the skin, which can cause pain and discomfort for patients. Furthermore, injections typically require the intervention of a healthcare professional or are performed by the patient themselves, increasing the complexity and inconvenience of administration. Injections can also lead to complications such as injection site infection and local tissue damage, especially with improper technique or repeated injections at the same site. Due to the pain and inconvenience associated with injections, patients may be reluctant to receive regular injections as prescribed, affecting treatment efficacy. Therefore, developing oral dosage forms for peptide drugs is essential.

[0007] While oral peptide drugs offer significant advantages in convenience and acceptability, their development still faces considerable technological challenges. These challenges primarily manifest in the generally low bioavailability of peptide drugs, mainly due to stability and absorption barriers. Peptides are easily broken down by gastric acid and intestinal enzymes, significantly reducing their bioavailability via oral administration. To achieve effective therapeutic effects, it is essential to ensure that a sufficient amount of drug can stably pass through the digestive system and enter the bloodstream. Furthermore, due to the large size and polarity of peptide drug molecules, they have difficulty penetrating the intestinal mucosa; even if peptides remain stable in the intestine, their absorption efficiency may still be low.

[0008] (Oral smegglutide) 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 paved the way for the application of semaglutide itself, but also for the development and commercialization of other potential oral peptide drugs. It demonstrated that, through appropriate formulation and technology, some bioactive molecules that were traditionally administered only by injection can be transformed into oral forms.

[0009] Developed by Emisphere Technologies The technology achieves its effects by using specialized chemical carriers, which are called "Eligen carriers". Using sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC) in the Eligen carrier, the stability and absorption rate of smegglutinin in the stomach are increased by adjusting the pH value in the stomach and affecting the permeability of the gastric mucosa. However, clinical data show... The bioavailability of this drug is only about 0.8%. Bioavailability refers to the proportion of a drug that enters the systemic circulation from the site of administration. For a drug, low bioavailability means that only a small portion of the administered dose ultimately reaches the bloodstream and exerts its effect. To overcome the low blood drug concentration problem 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 significant individual variability, which may lead to unstable or unpredictable treatment effects. If frequent dosing is required to compensate for low bioavailability, it may reduce patient adherence, leading to poor treatment outcomes and inadequate disease management.

[0010] In summary, as a revolutionary peptide therapeutic, although... While it offers patients the convenience of oral treatment, the problem of low bioavailability remains to be addressed. Summary of the Invention

[0011] The purpose of this disclosure is to provide an oral polypeptide composition.

[0012] Another object of this disclosure is to provide a method for preparing an oral polypeptide composition.

[0013] Another object of this disclosure is to provide the use of an orally administered polypeptide composition.

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

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

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

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

[0018] In some technical solutions disclosed herein, 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. kDa~2.0kDa; preferably 1.0kDa~20kDa, preferably 1.0kDa~15kDa, preferably 1.0kDa~10kDa, preferably 1.0kDa~9.0kDa, preferably 1.0kDa~5.0kDa, preferably 1.0kDa~2.0kDa; preferably 5.0kDa~20kDa, preferably 5.0kDa~15kDa, preferably 5.0kDa~10kDa, preferably 5.0kDa~9.0kDa; preferably 10.0kDa~20kDa, preferably 10.0kDa~15kDa.

[0019] In some of the technical solutions disclosed herein, 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 of the technical solutions disclosed herein, the polypeptide molecule includes a linear structure and a cyclic structure.

[0021] In some of the technical solutions disclosed herein, the polypeptide molecule is a peptide with a straight-chain structure, a peptide with a cyclic structure, or a peptide that contains both a straight-chain structure and a cyclic structure.

[0022] In some of the technical solutions disclosed herein, the polypeptide drug molecule includes modified peptides, derived peptides, and peptide-like substances.

[0023] In some of the technical solutions disclosed herein, the polypeptide molecule is selected from glucagon-like peptide-1 (GLP-1), GLP-1 analogs, GLP-1 receptor agonists, smegglutide, 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 pharmaceutically acceptable salts thereof.

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

[0025] In some of the technical solutions disclosed herein, the GLP-1 analogue is selected from acylated GLP-1 analogues, diacylated GLP-1 analogues, and long-acting albumin-bound fatty acid-derived GLP-1 analogues.

[0026] In some of the technical solutions disclosed herein, the GLP-1 receptor agonist is selected from dual agonists of GLP-1 receptor / glucagon receptor (GCGR), dual agonists of GLP-1 receptor / glucose-dependent insulinotropic peptide (GIP) receptor, dual agonists of GLP-1 receptor / amyloid peptide (Amylin) receptor, and triple agonists of GLP-1 receptor / GIP receptor / GCGR.

[0027] In some of the technical solutions disclosed herein, the GLP-2 agonist or analogue includes teduglutide and elsiglutide.

[0028] In some of the technical solutions disclosed herein, the somatostatin or analogue includes octreotide.

[0029] In some of the technical solutions disclosed herein, the parathyroid hormone fragment or analogue includes teriparatide.

[0030] In some of the technical solutions disclosed herein, the polypeptide molecules used are selected from polypeptide drug molecules smegglutide, teriparatide, octreotide, and tirzepatide.

[0031] In some of the technical solutions disclosed herein, the polypeptide molecules used are selected from polypeptide drug molecules smegglutide, liraglutide, and tirzepatide.

[0032] In some of the technical solutions disclosed herein, 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 of the technical solutions disclosed herein, the medium-chain fatty acid is selected from one or more of the following: anhydric acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and lauric acid.

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

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

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

[0037] In some of the technical solutions disclosed herein, the nitrogen-containing amino acid in the side chain is selected from at least one of lysine, arginine, asparagine, glutamine, tryptophan, ornithine, citrulline, pyrrolidone, and histidine.

[0038] In some of the technical solutions disclosed herein, the nitrogen-containing amino acid in the side chain is preferably selected from citrulline and arginine, or one or more of them.

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

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

[0041] In some of the technical solutions disclosed herein, 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 of the technical solutions disclosed herein, the oral polypeptide composition is acted upon in the gastrointestinal tract.

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

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

[0045] In another aspect of this disclosure, an oral polypeptide formulation is provided, the formulation comprising the oral polypeptide composition described in the first aspect of the invention, and a pharmaceutically acceptable excipient.

[0046] In some of the technical solutions disclosed herein, the oral polypeptide formulation includes tablets, capsules, capsules within capsules, micropatch systems within capsules, lozenges, tablets, octylene, solutions, emulsions, suspensions, syrups, slurries, powders and granules for recombination, dispersible powders and granules, pharmaceutically acceptable gels, chewable tablets, effervescent tablets, and multigranule dosage forms.

[0047] In some of the technical solutions disclosed herein, the pharmaceutically acceptable excipients include, but are not limited to, fillers, flow aids, granulation binders, lubricants, and disintegrants.

[0048] In another aspect of this disclosure, the use of the oral polypeptide composition or oral polypeptide formulation of this disclosure for:

[0049] (i) To prepare medicines for the prevention and / or treatment of diseases;

[0050] (ii) To treat diseases.

[0051] In some of the technical solutions disclosed herein, the diseases include endocrine diseases, neurodegenerative diseases, vascular diseases, kidney diseases, fatty liver diseases, and cancer, polycystic ovary syndrome, bone metabolism and osteoporosis, knee osteoarthritis, sleep apnea syndrome, osteoarthropathy, acromegaly, carcinoid syndrome, islet cell tumor, intestinal fistula, esophageal variceal bleeding, and metabolic muscle diseases.

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

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

[0054] In some of the technical solutions disclosed herein, the cardiovascular diseases include atherosclerosis, hypercoagulable state, coronary artery disease, and cerebrovascular events;

[0055] In some of the technical solutions disclosed herein, the kidney disease includes kidney failure;

[0056] In some of the technical solutions disclosed herein, the fatty liver includes non-alcoholic fatty liver disease.

[0057] In another aspect of this disclosure, an oral polypeptide composition is provided, the polypeptide composition comprising: a polypeptide targeting a glucagon-like peptide-1 (GLP-1) receptor, 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.

[0058] In one embodiment of this disclosure, the polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

[0059] In one embodiment of this disclosure, the polypeptide composition comprises: a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor, 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; the polypeptide composition does not contain a coordinating molecule, wherein the coordinating molecule is a C-type compound containing a hydrophilic group. 6-10 Aromatic ring or C 5-10 Heteroaromatic compounds.

[0060] In one technical solution disclosed herein, the liganding molecule is selected from nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0061] In one embodiment of this 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 embodiment of this 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 embodiment of this 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 embodiment of this 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 embodiment of this 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 embodiment of this 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 embodiment of this disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not less than about 20% w / w.

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

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

[0070] In one embodiment of this disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not less 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 embodiment of this disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is about 20-50% w / w.

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

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

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

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

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

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

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

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

[0080] In one embodiment of this 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 disclosed herein, the content of the amino acid is not higher than about 20% w / w.

[0082] In one embodiment of this disclosure, the content of the amino acid is no higher than about 18% w / w.

[0083] In one technical solution disclosed herein, the content of the amino acid is no higher than about 15% w / w.

[0084] In one technical solution of this 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 technical solution disclosed herein, the content of the amino acid is not less than about 5% w / w.

[0086] In one technical solution disclosed herein, the content of the amino acid is not less than about 7% w / w.

[0087] In one technical solution disclosed herein, the content of the amino acid is not less than about 8% w / w.

[0088] In one technical solution disclosed herein, the content of the amino acid is not less than about 9% w / w.

[0089] In one technical solution disclosed herein, the content of the amino acid is not less than about 10% w / w.

[0090] In one technical solution of this 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 embodiment of this disclosure, the amino acid content is approximately 5-20% w / w.

[0092] In one embodiment of this disclosure, the amino acid content is approximately 5-20% w / w.

[0093] In one embodiment of this disclosure, the amino acid content is approximately 5-18% w / w.

[0094] In one embodiment of this disclosure, the amino acid content is approximately 5-15% w / w.

[0095] In one embodiment of this disclosure, the amino acid content is approximately 8-20% w / w.

[0096] In one embodiment of this disclosure, the amino acid content is approximately 8-18% w / w.

[0097] In one embodiment of this disclosure, the amino acid content is approximately 8-15% w / w.

[0098] In one embodiment of this disclosure, the amino acid content is approximately 9-20% w / w.

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

[0100] In one embodiment of this disclosure, the amino acid content is approximately 9-15% w / w.

[0101] In one embodiment of this disclosure, the amino acid content is approximately 10-15% w / w.

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

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

[0104] In one embodiment of this 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 embodiment of this disclosure, the content of the medium-chain fatty acid or its salt is not less than about 10% w / w.

[0106] In one embodiment of this disclosure, the content of the medium-chain fatty acid or its salt is not less than about 15% w / w.

[0107] In one embodiment of this disclosure, the content of the medium-chain fatty acid or its salt is not less than about 20% w / w.

[0108] In one embodiment of this disclosure, the content of the medium-chain fatty acid or its salt is not less than about 25% w / w.

[0109] In one embodiment of this disclosure, the content of the medium-chain fatty acid or its salt is not less than about 30% w / w.

[0110] In one embodiment of this disclosure, the content of the medium-chain fatty acid or its salt is not less 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 embodiment of this disclosure, the content of the medium-chain fatty acid or its salt is about 10-40% w / w.

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

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

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

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

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

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

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

[0119] In one embodiment of this 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 embodiment of this 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 embodiment of this 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 embodiment of this 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 embodiment of this disclosure, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is approximately 0.8-10% w / w.

[0124] In one embodiment of this 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 this 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, and 10.0% w / w.

[0126] In one embodiment of this disclosure, the total content of the amino acid, 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 / w.

[0127] In one embodiment of this disclosure, the total content of the amino acid, 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 85% w / w.

[0128] In one embodiment of this disclosure, the total content of the amino acid, 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 / w.

[0129] In one embodiment of this disclosure, the total content of the amino acid, 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 less than about 50% w / w.

[0130] In one embodiment of this disclosure, the total content of the amino acid, 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 less than about 60% w / w.

[0131] In one embodiment of this disclosure, the total content of the amino acid, 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% w / w.

[0132] In one embodiment of this disclosure, the total content of the amino acid, 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 50-80% w / w.

[0133] In one embodiment of this disclosure, the total content of the amino acid, 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 60-80% w / w.

[0134] In one embodiment of this disclosure, the total content of the amino acid, 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.

[0135] In one embodiment of this disclosure, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition 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, or 80% w / w.

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

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

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

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

[0140] In one embodiment of this disclosure, the mass percentage ratio of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt to the medium-chain fatty acid or its salt in the polypeptide composition is approximately 1:(0.5-2), for example 1:1, 2:1, 1.5:1, or 1:1.5.

[0141] In one embodiment of this disclosure, the mass percentage ratio of the amino acid to N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the polypeptide composition is approximately (1-2):3, for example, 1:3, 2:3, or 1.5:3.

[0142] In one embodiment of this disclosure, the polypeptide composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(2.5-3.5):(2.5-3.5).

[0143] In one embodiment of this disclosure, the polypeptide composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(2.6-3.4):(2.6-3.4).

[0144] In one embodiment of this disclosure, the polypeptide composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(2.7-3.3):(2.7-3.3).

[0145] In one embodiment of this disclosure, the polypeptide composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(2.8-3.2):(2.8-3.2).

[0146] In one embodiment of this disclosure, the polypeptide composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(2.9-3.1):(2.9-3.1).

[0147] In one embodiment of this disclosure, the polypeptide composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:3:3.

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

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

[0150] In one technical solution disclosed herein, the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is smegglutinin.

[0151] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, 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 a salt thereof, and medium-chain fatty acids or salts thereof.

[0152] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, 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 a salt thereof, and no less than about 10% w / w medium-chain fatty acids or a salt thereof.

[0153] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, 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 a salt thereof, and no less than about 15% w / w medium-chain fatty acids or a salt thereof.

[0154] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, 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 a salt thereof, and no less than about 10% w / w medium-chain fatty acids or a salt thereof.

[0155] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-55% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and not less than about 10% w / w medium-chain fatty acids or a salt thereof.

[0156] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and not less than about 15% w / w medium-chain fatty acids or a salt thereof.

[0157] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof, wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is not higher than about 90% w.

[0158] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, no more than about 20% w / w amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or a salt thereof, and no less than about 10% w / w medium-chain fatty acids or salts thereof, wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is no less than about 50% w / w.

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

[0160] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, approximately 10-20% w / w of amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof. The total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition does not exceed approximately 90% w.

[0161] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, not less than about 20% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or a salt thereof, and not less than about 15% w / w medium-chain fatty acids or salts thereof; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof is about 50-90% w / w.

[0162] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-55% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or a salt thereof, and not less than about 15% w / w medium-chain fatty acids or salts thereof; wherein, in the polypeptide composition, the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof is about 70-80% w / w.

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

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

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

[0166] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, 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 acids or their salts; wherein 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 in the polypeptide composition is not higher than about 80% w.

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

[0168] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and not less than about 15% w / w medium-chain fatty acids or salts thereof; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is not higher than about 90% w.

[0169] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-55% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and not less than about 10% w / w medium-chain fatty acids or salts thereof; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is not higher than about 80% w.

[0170] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and not less than about 15% w / w medium-chain fatty acids or salts thereof; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is not higher than about 80% w.

[0171] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-55% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and not less than about 10% w / w medium-chain fatty acids or salts thereof; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is about 70-80% w / w.

[0172] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and not less than about 15% w / w medium-chain fatty acids or salts thereof; wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is about 70-80% w / w.

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

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

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

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

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

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

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

[0180] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and not less than about 15% w / w medium-chain fatty acids or salts thereof, wherein the mass ratio of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition 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 a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is about 70-80% w / w.

[0181] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and not less than about 15% w / w medium-chain fatty acids or salts thereof, wherein the mass ratio of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof 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 a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is about 70-80% w / w.

[0182] In one embodiment of this disclosure, the polypeptide composition comprises: no more than about 10% w / w smegglutide, about 10-20% w / w amino acids, about 20-50% w / w N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and no less than about 15% w / w medium-chain fatty acids or salts thereof, wherein the mass ratio of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof 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 a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is about 70-80% w / w.

[0183] In one embodiment of this disclosure, the polypeptide composition comprises: smegglutinin, no more than about 20% w / w amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid or a salt thereof, and no less than about 10% w / w medium-chain fatty acids or salts thereof, wherein the total content of the amino acids, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof, and medium-chain fatty acids or salts thereof in the polypeptide composition is no less than about 50% w / w.

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

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

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

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

[0188] In one embodiment of this 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 this disclosure, the medium-chain fatty acid is selected from one or more of the following: anhydride, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and lauric acid.

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

[0191] In some of the technical solutions disclosed herein, the medium-chain fatty acid salt is sodium decanoate.

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

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

[0194] In one technical solution disclosed herein, the nitrogen-containing amino acid in the side chain is selected from any one or more of citrulline and arginine.

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

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

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

[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 amino acids;

[0200] 100-300 parts by weight of medium-chain fatty acids or their salts;

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

[0202] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

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

[0204] 30-100 parts by weight of amino acids;

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

[0206] 100-300 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt;

[0207] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0208] 1-40 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0209] 40-70 parts by weight of amino acids;

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

[0211] 120-200 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt;

[0212] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0213] 1-32 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0214] 50-70 parts by weight of amino acids;

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

[0216] 120-180 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt;

[0217] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0218] 5-10 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0219] 50 parts by weight of amino acids;

[0220] 150 parts by weight of medium-chain fatty acids or their salts;

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

[0222] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0223] Smeglucopyranoside 1-50 parts by weight;

[0224] Arginine 20-100 parts by weight;

[0225] Sodium decanoate 100-300 parts by weight;

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

[0227] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0228] Smeglucopyranoside 1-50 parts by weight;

[0229] Arginine 30-100 parts by weight;

[0230] Sodium decanoate 100-300 parts by weight;

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

[0232] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0233] Smegglutinin 1-40 parts by weight;

[0234] Arginine 40-70 parts by weight;

[0235] Sodium decanoate 120-200 parts by weight;

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

[0237] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0238] Smegglutinin 1-32 parts by weight;

[0239] Arginine 50-70 parts by weight;

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

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

[0242] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

[0243] In one embodiment of this disclosure, the polypeptide composition further includes at least one excipient.

[0244] In one embodiment of this disclosure, the polypeptide composition further includes at least two excipients.

[0245] In one embodiment of this disclosure, the content of the excipient is no higher than about 30% w / w.

[0246] In one embodiment of this disclosure, the content of the excipient is no higher than about 25% w / w.

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

[0248] In one technical solution disclosed herein, the content of the excipient is not less than about 15% w / w.

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

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

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

[0252] In one technical solution disclosed herein, the filler is microcrystalline cellulose.

[0253] In one technical solution disclosed herein, the lubricant is selected from at least one of magnesium stearate, micronized silica gel, talc, polyethylene glycol, and sodium dodecyl sulfate.

[0254] In one technical solution disclosed herein, the lubricant is sodium dodecyl sulfate.

[0255] In one technical solution disclosed herein, the disintegrant is selected from at least one of dry starch, sodium carboxymethyl cellulose, low-substituted carboxymethyl cellulose, croscarmellose, croscarmellose sodium, and sodium carboxymethyl starch.

[0256] In one technical solution disclosed herein, the disintegrant is sodium carboxymethyl starch.

[0257] In one technical solution disclosed herein, the adhesive is selected from at least one of povidone, crospovidone, gum arabic, gelatin, maltodextrin, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose.

[0258] In one technical solution disclosed herein, the adhesive is polyvinylpyrrolidone.

[0259] In one technical solution of this 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 disclosed herein, the content of the lubricant is not higher than about 5.0% w / w.

[0261] In one embodiment of this disclosure, the content of the lubricant is no higher than about 3.0% w / w.

[0262] In one embodiment of this disclosure, the content of the lubricant is no higher than about 2.0% w / w.

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

[0264] In one technical solution of this 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 disclosed herein, the content of the disintegrant is not higher than about 5.0 w / w.

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

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

[0268] In one technical solution disclosed herein, 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, or 0.1% w / w.

[0269] In one embodiment of this disclosure, the adhesive content is no higher than about 5.0% w / w.

[0270] In one technical solution of this disclosure, the adhesive content 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 disclosed herein, the excipients include microcrystalline cellulose, sodium dodecyl sulfate, and sodium carboxymethyl starch.

[0272] In one technical solution disclosed herein, the excipients include microcrystalline cellulose, sodium dodecyl sulfate, sodium carboxymethyl starch, and povidone.

[0273] In one embodiment of this disclosure, the excipient comprises microcrystalline cellulose at a concentration of not less than about 10.0% w / w and not more than about 25.0 w / w.

[0274] In one embodiment of this disclosure, the excipient comprises sodium dodecyl sulfate at a concentration of not less than about 0.01% w / w and not more than about 3.0% w / w.

[0275] In one embodiment of this disclosure, the excipient comprises sodium carboxymethyl starch at a concentration of not less than about 0.1% w / w and not more than about 5.0% w / w.

[0276] In one embodiment of this disclosure, the excipient comprises povidone at a concentration of not less than about 0.01% w / w and not more than about 5.0% w / w.

[0277] In one embodiment of this disclosure, the excipients comprise about 10.0-25.0% w / w microcrystalline cellulose, about 0.01-3.0% w / w sodium dodecyl sulfate, and about 0.1%-5.0% w / w sodium carboxymethyl starch.

[0278] In one embodiment of this disclosure, the excipients comprise about 10.0-25.0% w / w microcrystalline cellulose, about 0.01-3.0% w / w sodium dodecyl sulfate, about 0.1-5.0% w / w sodium carboxymethyl starch, and about 0.01-5.0% w / w povidone.

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

[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] Excipients: 40-180 parts by weight;

[0285] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

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

[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] Excipients: 40-180 parts by weight;

[0292] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

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

[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 acids or their salts;

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

[0298] Excipients: 50-160 parts by weight;

[0299] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

[0300] In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0301] 1-32 parts by weight of a polypeptide targeting the 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 acids or their salts;

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

[0305] Excipients: 70-140 parts by weight;

[0306] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

[0307] In one embodiment of this disclosure, the oral polypeptide composition comprises:

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

[0309] 50 parts by weight of amino acids;

[0310] 150 parts by weight of medium-chain fatty acids or their salts;

[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] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

[0314] In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0315] Smeglucopyranoside 1-50 parts by weight;

[0316] Arginine 20-100 parts by weight;

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

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

[0319] Excipients: 40-180 parts by weight;

[0320] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0321] Smeglucopyranoside 1-50 parts by weight;

[0322] Arginine 30-100 parts by weight;

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

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

[0325] Excipients: 40-180 parts by weight;

[0326] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0327] Smegglutinin 1-40 parts by weight;

[0328] Arginine 40-70 parts by weight;

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

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

[0331] Excipients: 50-160 parts by weight;

[0332] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0333] Smegglutinin 1-32 parts by weight;

[0334] Arginine 50-70 parts by weight;

[0335] Sodium decanoate 120-180 parts by weight;

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

[0337] Excipients: 70-140 parts by weight;

[0338] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0339] 5 parts by weight of smegglutinin;

[0340] 50 parts by weight of arginine;

[0341] 150 parts by weight of sodium decanoate;

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

[0343] 105 parts by weight of excipient;

[0344] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0345] 4 parts by weight of smegglutinin;

[0346] 50 parts by weight of arginine;

[0347] 150 parts by weight of sodium decanoate;

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

[0349] 124 parts by weight of excipients;

[0350] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0351] 8 parts by weight of Smeglucopyranoside;

[0352] 50 parts by weight of arginine;

[0353] 150 parts by weight of sodium decanoate;

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

[0355] 120 parts by weight of excipient;

[0356] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0357] 16 parts by weight of smegglutinin;

[0358] 50 parts by weight of arginine;

[0359] 150 parts by weight of sodium decanoate;

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

[0361] 110 parts by weight of excipient;

[0362] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this 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 salt;

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

[0368] Lubricant 1-15 parts by weight; and

[0369] Disintegrant 1-30 parts by weight;

[0370] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this 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] 30-100 parts by weight of amino acids;

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

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

[0375] 50-150 parts by weight of filler;

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

[0377] Disintegrant 1-30 parts by weight;

[0378] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0379] 1-40 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0380] 40-70 parts by weight of amino acids;

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

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

[0383] 70-140 parts by weight of filler;

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

[0385] Disintegrant 1-30 parts by weight;

[0386] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0387] 1-32 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0388] 50-70 parts by weight of amino acids;

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

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

[0391] 80-130 parts by weight of filler;

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

[0393] Disintegrant 1-15 parts by weight;

[0394] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0395] 5-10 parts by weight of a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor;

[0396] 50 parts by weight of amino acids;

[0397] 150 parts by weight of medium-chain fatty acids or their salts;

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

[0399] 80-110 parts by weight of filler;

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

[0401] Disintegrant 1-15 parts by weight;

[0402] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0403] Smeglucopyranoside 1-50 parts by weight;

[0404] Arginine 20-100 parts by weight;

[0405] Sodium decanoate 100-300 parts by weight;

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

[0407] 50-150 parts by weight of filler;

[0408] Lubricant 1-15 parts by weight;

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

[0410] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0411] Smegglutinin 1-50 parts by weight;

[0412] Arginine 30-100 parts by weight;

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

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

[0415] 50-150 parts by weight of filler;

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

[0417] Disintegrant 1-30 parts by weight;

[0418] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0419] Smegglutinin 1-40 parts by weight;

[0420] Arginine 40-70 parts by weight;

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

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

[0423] 70-140 parts by weight of filler;

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

[0425] Disintegrant 1-30 parts by weight;

[0426] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0427] Smegglutinin 1-32 parts by weight;

[0428] Arginine 50-70 parts by weight;

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

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

[0431] 80-130 parts by weight of filler;

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

[0433] Disintegrant 1-15 parts by weight;

[0434] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0435] Smegglutinin 5-10 parts by weight;

[0436] 50 parts by weight of arginine;

[0437] 150 parts by weight of sodium decanoate;

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

[0439] 80-110 parts by weight of filler;

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

[0441] Disintegrant 1-15 parts by weight;

[0442] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0443] Smegglutinin 1-50 parts by weight;

[0444] Arginine 20-100 parts by weight;

[0445] Sodium decanoate 100-300 parts by weight;

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

[0447] 50-150 parts by weight of filler;

[0448] Lubricant 1-15 parts by weight;

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

[0450] 1-30 parts by weight of adhesive;

[0451] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0452] Smeglucopyranoside 1-50 parts by weight;

[0453] Arginine 30-100 parts by weight;

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

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

[0456] 50-150 parts by weight of filler;

[0457] Lubricant 1-15 parts by weight;

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

[0459] 1-30 parts by weight of adhesive;

[0460] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide. In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0461] Smegglutinin 1-40 parts by weight;

[0462] Arginine 40-70 parts by weight;

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

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

[0465] 70-140 parts by weight of filler;

[0466] Lubricant 1-15 parts by weight;

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

[0468] 1-30 parts by weight of adhesive;

[0469] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

[0470] In one embodiment of this disclosure, the oral polypeptide composition comprises:

[0471] Smegglutinin 1-32 parts by weight;

[0472] Arginine 50-70 parts by weight;

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

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

[0475] 80-130 parts by weight of filler;

[0476] Lubricant 1-10 parts by weight;

[0477] Disintegrant 1-15 parts by weight;

[0478] 1-15 parts by weight of adhesive; and

[0479] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

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

[0481] Smegglutinin 5-10 parts by weight;

[0482] 50 parts by weight of arginine;

[0483] 150 parts by weight of sodium decanoate;

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

[0485] 80-110 parts by weight of filler;

[0486] Lubricant 1-10 parts by weight;

[0487] Disintegrant 1-15 parts by weight;

[0488] 1-15 parts by weight of adhesive; and

[0489] The oral polypeptide composition does not contain nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, or salicylamide.

[0490] In one embodiment of this disclosure, the oral polypeptide composition comprises: about 4.0 mg smegglutide, about 50.0 mg arginine, about 150.0 mg sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, about 150.0 mg sodium decanoate, and about 123.0 mg excipients.

[0491] In one embodiment of this disclosure, the oral polypeptide composition comprises: about 8.0 mg smegglutide, about 50.0 mg arginine, about 150.0 mg sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, about 150.0 mg sodium decanoate, and about 120.0 mg excipients.

[0492] In one embodiment of this disclosure, the oral polypeptide composition comprises: about 8.0 mg smegglutide, about 50.0 mg arginine, about 150.0 mg sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, about 150.0 mg sodium decanoate, and about 110.0 mg excipients.

[0493] In one technical solution disclosed herein, the oral polypeptide composition is a solid dosage form.

[0494] In one technical solution of this disclosure, the oral polypeptide composition is a tablet, capsule, granule, powder, granule, drop pill, or pill.

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

[0496] In one embodiment of this disclosure, the tablets are in a specification of approximately 1-50 mg.

[0497] In one embodiment of this disclosure, the tablets are approximately 1-40 mg in size.

[0498] In one embodiment of this disclosure, the tablets are approximately 1-30 mg in size.

[0499] In one embodiment of this disclosure, the tablets are approximately 5-10 mg in size.

[0500] In one technical solution of this disclosure, the tablets are available in specifications of approximately 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, and 40 mg.

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

[0502] 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 muscle disease.

[0503] Another aspect of this disclosure provides a method for preparing oral polypeptide tablets, comprising the step of directly compressing the oral polypeptide composition of this disclosure into tablets.

[0504] In another aspect of this disclosure, a pharmaceutical composition is provided, the composition comprising a mixture of first particles and second particles, the first particles comprising a polypeptide targeting a glucagon-like peptide-1 (GLP-1) receptor; the second particles 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.

[0505] In one embodiment of this disclosure, the first particle is formed by granulation of a composition comprising a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor; and / or, the second particle is formed by granulation of 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 embodiment of this disclosure, the first particle comprises a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor and an excipient.

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

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

[0509] In one embodiment of this disclosure, the first particle comprises a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor, a filler, and a binder.

[0510] In one embodiment of this disclosure, the second particle comprises 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 embodiment of this disclosure, the second particle comprises amino acids, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, medium-chain fatty acids or salts thereof, fillers, lubricants, and disintegrants.

[0512] In one technical solution of this disclosure, the second particle contains not less than 60% of the amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt.

[0513] In one technical solution of this disclosure, the second particle contains not less than 70% of the amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt.

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

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

[0516] In one embodiment of this disclosure, the first particle in the pharmaceutical composition has a mass percentage content of no more than about 20% w / w.

[0517] In one embodiment of this disclosure, the pharmaceutical composition contains the first particle at a mass percentage of no more than about 10% w / w.

[0518] In one embodiment of this disclosure, the pharmaceutical composition contains the second particle at a mass percentage of not less than about 80% w / w.

[0519] In one embodiment of this disclosure, the pharmaceutical composition contains the second particle at a mass percentage of not less than about 90% w / w.

[0520] In one embodiment of this disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the pharmaceutical composition is not higher than about 50% w / w.

[0521] In one embodiment of this disclosure, the content of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt in the pharmaceutical composition is not higher than about 45% w / w.

[0522] In one embodiment of this disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the pharmaceutical composition is not higher than about 40% w / w.

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

[0524] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt in the following amounts: 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 embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of not less than about 20% w / w.

[0526] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of not less than about 25% w / w.

[0527] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of not less than about 30% w / w.

[0528] In one embodiment of this disclosure, the content of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is not less 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 embodiment of this disclosure, the pharmaceutical composition contains about 20-50% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt.

[0530] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of about 20-45% w / w.

[0531] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of about 20-40% w / w.

[0532] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of about 25-50% w / w.

[0533] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of about 25-45% w / w.

[0534] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of about 25-40% w / w.

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

[0536] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of about 30-45% w / w.

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

[0538] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof at a content of about 30-35% w / w.

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

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

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

[0542] In one technical solution of this disclosure, the content of the amino acid in the pharmaceutical composition 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 embodiment of this disclosure, the content of the amino acid in the pharmaceutical composition is not less than about 5% w / w.

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

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

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

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

[0548] In one technical solution of this disclosure, the content of the amino acid in the pharmaceutical composition 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 embodiment of this disclosure, the content of the amino acid in the pharmaceutical composition is about 5-20% w / w.

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

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

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

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

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

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

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

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

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

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

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

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

[0562] In one embodiment of this disclosure, the pharmaceutical composition contains a medium-chain fatty acid or its salt at a content of not less than about 15% w / w.

[0563] In one embodiment of this disclosure, the pharmaceutical composition contains a medium-chain fatty acid or its salt at a content of not less than about 20% w / w.

[0564] In one embodiment of this disclosure, the pharmaceutical composition contains a medium-chain fatty acid or its salt at a content of not less than about 25% w / w.

[0565] In one embodiment of this disclosure, the pharmaceutical composition contains a medium-chain fatty acid or its salt at a content of not less than about 30% w / w.

[0566] In one technical solution of this disclosure, the content of the medium-chain fatty acid or its salt in the pharmaceutical composition is not 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.

[0567] In one embodiment of this disclosure, the pharmaceutical composition contains a medium-chain fatty acid or its salt at a content of about 15-40% w / w.

[0568] In one embodiment of this disclosure, the pharmaceutical composition contains a medium-chain fatty acid or its salt at a content of about 15-35% w / w.

[0569] In one embodiment of this disclosure, the pharmaceutical composition contains 20-40% w / w of medium-chain fatty acids or their salts.

[0570] In one embodiment of this disclosure, the pharmaceutical composition contains a medium-chain fatty acid or its salt at a content of about 25-35% w / w.

[0571] In one embodiment of this disclosure, the pharmaceutical composition contains about 25-40% w / w of the medium-chain fatty acid or its salt.

[0572] In one embodiment of this disclosure, the pharmaceutical composition contains about 30-40% w / w of the medium-chain fatty acid or its salt.

[0573] In one embodiment of this disclosure, the pharmaceutical composition contains about 30-35% w / w of the medium-chain fatty acid or its salt.

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

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

[0576] In one embodiment of this disclosure, the pharmaceutical composition contains a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor at a content of about 0.1-15% w / w.

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

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

[0579] In one embodiment of this disclosure, the pharmaceutical composition contains a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor at a content of about 1.0-7.0% w / w.

[0580] In one embodiment of this disclosure, the content of the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor in the pharmaceutical composition 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, or 10.0% w / w.

[0581] In one embodiment of this disclosure, the total content of the amino acid, 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 / w.

[0582] In one embodiment of this disclosure, the total content of the amino acid, 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 85% w / w.

[0583] In one embodiment of this disclosure, the total content of the amino acid, 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 / w.

[0584] In one embodiment of this disclosure, the total content of the amino acid, 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 less than about 50% w / w.

[0585] In one embodiment of this disclosure, the total content of the amino acid, 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 less than about 60% w / w.

[0586] In one embodiment of this disclosure, the total content of the amino acid, 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% w / w.

[0587] In one embodiment of this disclosure, the total content of the amino acid, 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 50-80% w / w.

[0588] In one embodiment of this disclosure, the total content of the amino acid, 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 60-80% w / w.

[0589] In one embodiment of this disclosure, the total content of the amino acid, 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.

[0590] In one embodiment of this disclosure, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the polypeptide composition 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, or 80% w / w.

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

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

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

[0594] In one embodiment of this disclosure, the pharmaceutical composition contains a medium-chain fatty acid or its salt at a mass percentage not higher than that of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt.

[0595] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt and the medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(0.5-2), for example, 1:1, 2:1, 1.5:1, or 1:1.5.

[0596] In one embodiment of this disclosure, the pharmaceutical composition contains N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt and the amino acid in a mass percentage ratio of approximately (1-2):3, for example, 1:3, 2:3, or 1.5:3.

[0597] In one embodiment of this disclosure, the pharmaceutical composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(2.5-3.5):(2.5-3.5).

[0598] In one embodiment of this disclosure, the pharmaceutical composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(2.6-3.4):(2.6-3.4).

[0599] In one embodiment of this disclosure, the pharmaceutical composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(2.7-3.3):(2.7-3.3).

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

[0601] In one embodiment of this disclosure, the pharmaceutical composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:(2.9-3.1):(2.9-3.1).

[0602] In one embodiment of this disclosure, the pharmaceutical composition contains an amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:3:3.

[0603] In one embodiment of this disclosure, the pharmaceutical composition contains the same mass percentage of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt and the medium-chain fatty acid or its salt.

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

[0605] In one technical solution disclosed herein, the polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor is smegglutinin.

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

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

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

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

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

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

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

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

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

[0615] In one embodiment of this disclosure, the total content of the amino acid, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt in the pharmaceutical composition 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, or 80% w / w.

[0616] In one technical solution disclosed herein, 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 this disclosure, the medium-chain fatty acid is selected from one or more of the following: anhydride, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and lauric acid.

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

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

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

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

[0622] In one technical solution disclosed herein, the nitrogen-containing amino acid in the side chain is selected from any one or more of citrulline and arginine.

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

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

[0625] In one aspect of this disclosure, the pharmaceutical composition is used to prepare oral polypeptide tablets.

[0626] In another aspect of this disclosure, a method for preparing an oral polypeptide tablet is provided, the method comprising the step of preparing the polypeptide tablet using a pharmaceutical composition of this disclosure.

[0627] In another aspect of this disclosure, a method for preparing oral polypeptide tablets is provided, the method comprising the step of tableting using a pharmaceutical composition of this disclosure.

[0628] In one technical solution of this disclosure, the method includes the steps of: mixing a first particle and a second particle, and then compressing them into tablets to obtain the final product; wherein the first particle comprises a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor; and the second particle 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 embodiment of this disclosure, the first particle is formed by granulation of a composition comprising a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor; and / or, the second particle is formed by granulation of 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 embodiment of this disclosure, the first particle comprises a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor and an excipient.

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

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

[0633] In one embodiment of this disclosure, the first particle comprises a polypeptide targeting the glucagon-like peptide-1 (GLP-1) receptor, a filler, and a binder.

[0634] In one embodiment of this disclosure, the second particle comprises 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 embodiment of this disclosure, the second particle comprises amino acids, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or a salt thereof, medium-chain fatty acids or salts thereof, fillers, lubricants, and disintegrants.

[0636] In one technical solution of this disclosure, the second particle contains not less than 60% of the amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt.

[0637] In one technical solution of this disclosure, the second particle contains not less than 70% of the amino acid, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or its salt, and medium-chain fatty acid or its salt.

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

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

[0640] In one embodiment of this disclosure, the composition contains the first particle at a mass percentage of no more than about 20% w / w.

[0641] In one embodiment of this disclosure, the first particle in the composition has a mass percentage content of no more than about 10% w / w.

[0642] In one embodiment of this disclosure, the composition contains the second particle at a mass percentage of not less than about 80% w / w.

[0643] In one embodiment of this disclosure, the composition contains the second particle at a mass percentage of not less than about 90% w / w.

[0644] Beneficial effects:

[0645] The oral polypeptide composition disclosed herein not only improves the ease of use of polypeptides or polypeptide drugs, but also significantly improves the absorption of polypeptide drugs by the gastrointestinal tract, thereby enhancing the efficacy of polypeptide drugs in vivo.

[0646] compared to Under the same specifications, the oral semaglutide composition provided in this disclosure significantly improves the oral bioavailability of semaglutide. Attached Figure Description

[0647] Figure 1 The cumulative dissolution-time curve for Smegglutide tablets.

[0648] Figure 2 C of Smeglucopyranoside tablets in beagle dogs max contrast.

[0649] Figure 3 C-level activity of smegglutinin tablets prepared by different processes in beagle dogs max contrast.

[0650] Figure 4 C60 levels of different doses of smegglutide tablets in cynomolgus monkeys max contrast.

[0651] Figure 5 To detect and analyze the content of smegglutinin in the plasma of beagle dogs after drug administration.

[0652] Figure 6 To detect and analyze the content of teriparatide in the plasma of beagle dogs after drug administration.

[0653] Figure 7 To detect and analyze the content of telpolide in plasma after drug administration.

[0654] Figure 8 To detect and analyze the octreotide content in plasma after drug administration. Detailed Implementation

[0655] Based on the above content of this disclosure, and in accordance with common technical knowledge and practices in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas of this disclosure.

[0656] I. Definition

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

[0658] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0659] As used herein, the term "about" means approximately, close to, roughly, or about. When the term "about" is used in conjunction with a numerical range, it is modified by extending the limits above and below the stated value. Generally, the term "about" is used herein to modify a value by a deviation of 20% above or below a value. Furthermore, particularly for biological systems or processes, the term may mean at most one order of magnitude or at most five times the numerical value. Unless otherwise stated, when a specific value appears in this application and claims, the meaning of "about" or "substantially includes" should be assumed to be within an acceptable margin of error for that specific value.

[0660] Oral polypeptide composition

[0661] As used herein, the terms “peptide” and “protein” are interchangeable, and these terms cover both naturally occurring peptides and non-naturally occurring peptides, as well as fragments, mutants, derivatives and analogs as provided herein or as commonly known in the art, said peptides also include peptides of pharmaceutical molecules, nucleic acids encoding peptides, recombinant microorganisms for preparing peptides, vectors for expressing peptides, and peptides prepared using recombinant microorganisms.

[0662] In some embodiments, the polypeptide comprises at least 30, at least 40, or 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 "peptide targeting glucagon-like peptide-1 (GLP-1) receptor" refers to peptides having at least one domain that binds to the GLP-1 receptor, enabling them to selectively bind to the GLP-1 receptor and thereby mimic or enhance the physiological function of native GLP-1. In some embodiments, the amino acid sequence of the peptide targeting the GLP-1 receptor may have at least 70%, 80%, 90%, or higher sequence homology with native GLP-1 (e.g., human GLP-1(7-36)amide), or may be optimized for stability, oral bioavailability, or pharmacodynamic properties through 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 this disclosure contains 0.01-15.0% w / w semaglutide, for example 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, and 10.0% w / w. Compared with Novo Nordisk oral semaglutide tablets, the oral polypeptide composition of this disclosure has higher oral bioavailability at the same strength, lower semaglutide content at the same oral bioavailability, and fewer gastrointestinal side effects.

[0666] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0667] As used herein, the term "pharmaceutically acceptable salt" refers to both water-soluble and water-insoluble salts, such as acetates, 4,4-diaminostilbene-2,2′-disulfonate, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium ethylenediaminetetraacetate, dextrorotatory camphor sulfonate, carbonates, chlorides, citrates, clavulanates, dihydrochlorides, ethylenediaminetetraacetate, ethanedisulfonate, propionate lauryl sulfate, ethanesulfonates, fumarates, gluconate, gluconate, glutamate, glycosylpara-aminophenylarsanilate, hexafluorophosphates, hexylresorcinol salts, hyaluronic acid, hydrobromide, hydrochloride, hydroxynaphthyl carboxylate, iodide The following are listed: isothiosulfates, lactates, lacturonates, laurates, malates, maleates, mandelates, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, galactosidates, naphthalenesulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthylcarboxylate, oleates, oxalates, palmitates, bis(hydroxynaphthyl) salts (1,1-methylene-bis-2-hydroxy-3-naphthylcarboxylate, pyrantel), pantothenates, phosphates / bisphosphates, picrates, polygalacturonates, propionates, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, theochloroate, toluenesulfonates, triethyliodide, and valerates.

[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 an oral peptide absorption enhancer. The term "oral peptide absorption enhancer" is a class of excipients or compounds specifically designed to improve the oral absorption efficiency of peptide drugs. In particular, absorption enhancers are distinct from excipients in this document.

[0669] In some embodiments, the absorption enhancer 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. In some embodiments, the oral peptide compositions of this disclosure comprise an absorption enhancer of not more than about 90% w / w, about 85% w / w, or about 80% w / w; and / or, comprise an absorption enhancer of not less than about 50% w / w, about 60% w / w, or about 70% w / w. In some embodiments, the oral peptide compositions of this disclosure comprise an absorption enhancer of 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, or 80% w / w. In some embodiments, the oral peptide compositions of this disclosure comprise 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 a salt thereof; and / or not 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 a salt thereof. In some embodiments, the oral peptide compositions of this disclosure comprise 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, and 40% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[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 hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and lauric acid. In some embodiments, medium-chain fatty acids are fatty acids with a carbon chain length of 6 to 12 carbon atoms and a structural formula of 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 peptide compositions of this disclosure comprise not more 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 of medium-chain fatty acids or salts thereof; and / or comprise not 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 of medium-chain fatty acids or salts thereof. In some embodiments, the oral peptide compositions of this disclosure comprise 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 medium chain fatty acids or salts thereof.

[0673] As used herein, the term "amino acid" includes both natural and non-natural amino acids. The term "natural amino acid" refers to the 20 common amino acids: alanine (A), cysteine ​​(C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y). The term "non-natural amino acid" refers to an amino acid that is not naturally encoded or is not found in the genetic code of any organism. For example, non-natural amino acids can be purely synthetic compounds. Examples of non-natural amino acids include, but are not limited to, hydroxyproline, γ-carboxyglutamic acid, O-phosphoserine, azacyclobutanecarboxylic acid, 2-aminohexanoic acid, 3-aminohexanoic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid (Dap), desmosine, 2,2′-diaminopimelic acid, 2,3-diaminopropionic acid (Dab), N-ethylglycine, N-methylglycine, N- Ethyl asparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, n-valine, n-leucine, ornithine, D-ornithine, D-arginine, p-aminophenylalanine, pentylglycine, pipecolic acid, and thioproline. Furthermore, the term also includes derivatives obtained by chemically modifying the C-terminal carboxyl group (or N-terminal amino group and / or its side chain functional groups) of natural (or non-natural) amino acids.

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

[0675] In some embodiments, the oral peptide compositions of this disclosure comprise amino acids of not more than about 20% w / w, about 19% w / w, about 18% w / w, about 17% w / w, about 16% w / w, or about 15% w / w; and / or comprise amino acids of not less than about 7% w / w, about 8% w / w, about 9% w / w, or about 10% w / w. In some embodiments, the oral peptide compositions of this disclosure comprise 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, and 15% w / w of amino acids.

[0676] As used herein, the term "excipient" refers to a substance added to a pharmaceutical composition to impart a shape, size, or physical property to the drug. Examples of excipients include, but are not limited to, carriers, fillers, binders, disintegrants, lubricants, flow aids, flavor masking and flavoring agents, stabilizers, dispersants, film-forming agents, and preservatives. Suitable excipients may 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, a disintegrant, and a lubricant. In some embodiments, the excipient is a filler, a disintegrant, a lubricant, and a binder.

[0677] In some embodiments, the oral peptide compositions of this disclosure include excipients of not more than about 30% w / w, 29% w / w, 28% w / w, 27% w / w, 26% w / w, or 25% w / w; and / or, include excipients of not less than about 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, or 15% w / w. In some embodiments, the oral peptide compositions of this disclosure include excipients of 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, or 25% w / w.

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

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

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

[0681] The terms "binder" and "adhesive" are used interchangeably to refer to a viscous substance added to address the difficulty of granulation due to the low viscosity of the raw material itself, such as polyvinylpyrrolidone (polyvinyl ketone). In one embodiment, the binder is polyvinyl ketone.

[0682] The term "solid dosage form" refers to a solid pharmaceutical preparation with strong cohesiveness and shape stability. Solid dosage forms include, but are not limited to, tablets, capsules, granules, powders, powders, pellets, and pills. Solid dosage forms can be conventional, sustained-release, or immediate-release formulations (e.g., osmotic pump tablets, sustained-release tablets, sustained-release capsules, rapidly disintegrating tablets, etc.). In some embodiments, the pharmaceutical composition of this disclosure is a tablet, capsule, or granule. In some embodiments, the pharmaceutical composition of this disclosure is a tablet.

[0683] The term "tablet" refers to a round or irregularly shaped solid dosage form made from a drug substance and suitable excipients. Tablets are primarily oral conventional tablets (including sugar-coated tablets and film-coated tablets), and also include lozenges, sublingual tablets, oral patches, chewable tablets, dispersible tablets, soluble tablets, effervescent tablets, vaginal tablets, vaginal effervescent tablets, sustained-release tablets, controlled-release tablets, enteric-coated tablets (including enteric-coated tablets and colon-targeted enteric-coated tablets), and orally disintegrating tablets. The tablets of this disclosure can be coated using methods well known in the art.

[0684] The term "specification" or "drug specification" refers to the amount of drug ingredients contained in a unit dosage form of a drug, usually expressed as the weight or content per unit dosage form, such as per tablet, per capsule, or per vial. It includes indicators such as the content, potency, or fill volume of the active ingredient.

[0685] In some embodiments, the oral polypeptide tablets are available in strengths of 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, and 50 mg.

[0686] The term "tablet weight" refers to the weight of a single tablet. In some implementations, oral polypeptide tablets have a tablet weight of 300-1000 mg, for example 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, and 800 mg.

[0687] The term "unit formulation" refers to the smallest unit of administration or the smallest unit of packaging in a pharmaceutical product that can be broken down, such as tablets, capsules, powders, injections, capsules within capsules, micropatch systems within capsules, etc. These units can exist independently physically and can be precisely broken down in dosage. Unit formulations typically contain a predetermined amount of active ingredient to produce the desired therapeutic effect and are used in combination with appropriate pharmaceutical excipients.

[0688] As used herein, the term "capsule-in-capsule" refers to a specific delivery system used in multi-stage release formulations. Upon reaching the release conditions, the outer capsule releases first, followed by the inner capsule.

[0689] As used herein, the term "in-capsule micropatch system" refers to a system where, after the capsule enters the gastrointestinal tract, the capsule shell dissolves, releasing micropatches. These patches can adhere to the gastrointestinal wall, increasing drug absorption efficiency through localized drug release.

[0690] The term "single-drug formulation" refers to a single dosage form containing only one drug or active ingredient in a prescription. In some embodiments, oral peptide compositions are single-drug formulations.

[0691] use

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

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

[0694] The indications for the oral peptide compositions disclosed herein include, but are not limited to, endocrine disorders, neurodegenerative diseases, vascular diseases, kidney diseases, and fatty liver diseases. Endocrine disorders include glucose metabolism disorders, diabetes, and obesity; neurodegenerative diseases include Alzheimer's disease and other forms of dementia, Parkinson's disease, multiple sclerosis, and Huntington's disease; cardiovascular diseases include atherosclerosis, hypercoagulable state, coronary artery disease, and cerebrovascular events; kidney diseases include renal failure; fatty liver includes non-alcoholic fatty liver disease; and cancer, polycystic ovary syndrome, bone metabolism and osteoporosis, knee osteoarthritis, sleep apnea syndrome, osteoarthropathy, acromegaly, carcinoid syndrome, islet cell tumor, intestinal fistula, esophageal variceal bleeding, and metabolic muscle diseases, etc.

[0695] In one embodiment, the polypeptide is smegglutinin, and the indications are selected from diabetes, obesity, hypertension, and complications caused by diabetes or obesity. These indications include, for 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, osteoarthritis, and metabolic muscle disease.

[0696] Pharmaceutical Compositions and Tablet Preparation Methods

[0697] The pharmaceutical compositions disclosed herein refer to compositions for preparing oral polypeptide tablets, comprising a first particle and a second particle, wherein the first particle contains polypeptide molecules but does not include functional additives such as absorption enhancers; the second particle contains functional additives such as absorption enhancers but does not contain polypeptide molecules, wherein the absorption enhancer includes amino acids, N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) or salts thereof, and medium-chain fatty acids or salts thereof. In some embodiments, the first particle contains polypeptide molecules and excipients but does not include functional additives such as absorption enhancers; and / or, the second particle contains functional additives such as absorption enhancers and excipients but does not contain polypeptide molecules.

[0698] In the pharmaceutical compositions disclosed herein, the first and second particles 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 "decomposed" particles. The method of forming combined particles can be continuous and includes, for example, simultaneously spraying the granulating material with a granulation solution and drying it, e.g., in a drum granulator, in a disc granulator, on a disc granulator, in a fluidized bed, by spray drying-drying or spray curing, or discontinuous operation, e.g., in a fluidized bed, in a rotating fluidized bed, in a batch mixer, e.g., in a high-shear mixer or a low-shear mixer, or in a spray drying drum. A method for preparing pulverized particles, which can be discontinuous, wherein the granulating material first forms wet aggregates with a granulation solution, which are then pulverized or otherwise formed into particles of the desired size and then dried. Suitable equipment for the granulation step is a planetary mixer, a low-shear mixer, a high-shear mixer, an extruder, and a spheronizer. Granules can also be formed using dry granulation technology, in which the pharmaceutical active agent and excipients are compressed together to form a larger molded article, such as pulverized blocks or strips, and the pulverized material is used as a compaction material for subsequent tableting.

[0699] Methods for preparing oral peptide tablets using pharmaceutical compositions are well known to those skilled in the art. To compress tableting material into a solid oral dosage form, such as tablets, a tableting machine can be used. In a tableting machine, tableting material is filled (e.g., by forced feeding or gravity feeding) into a mold cavity. The tableting material is then compressed by a pressurized punch. Subsequently, the resulting compressed tablet or tablet is ejected from the tableting machine. This compression process is hereinafter referred to herein as the "compression process". Suitable tableting machines include, but are not limited to, rotary tableting machines and eccentric tableting machines.

[0700] The process for preparing the oral peptide tablets of this disclosure is not limited to this; for example, tablets can be obtained by direct compression. Using the pharmaceutical compositions of this disclosure to prepare oral peptide tablets can significantly improve the oral bioavailability of tablets compared to peptide tablets obtained by direct compression, provided the composition is exactly the same.

[0701] II. Examples

[0702] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

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

[0704] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0705] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the embodiments described below can be combined with each other as long as they do not conflict with each other.

[0706] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0707] Example 1: Preparation of Smegglutide Tablets

[0708] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0709] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 5:150:150:50.

[0710] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0711] Example 2: Preparation of Smegglutide tablets

[0712] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0713] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 43.48% w / w SNAC, 21.74% w / w sodium decanoate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 5:200:100:50.

[0714] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0715] Example 3: Preparation of Smegglutide tablets

[0716] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0717] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 54.35% w / w SNAC, 10.87% w / w sodium decanoate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 5:250:50:50.

[0718] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0719] Example 4: Preparation of Smegglutide tablets

[0720] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0721] The pharmaceutical composition containing semaglutide is formulated as follows: 0.98% w / w semaglutide, 29.41% w / w arginine, 29.41% w / w SNAC, 29.41% w / w sodium decanoate, 8.08% w / w microcrystalline cellulose, 0.9% w / w sodium dodecyl sulfate, and 1.8% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 5:150:150:150.

[0722] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 510mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0723] Example 5: Preparation of Smegglutide tablets

[0724] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0725] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 13.04% w / w arginine, 39.13% w / w SNAC, 39.13% w / w sodium decanoate, 4.61% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 5:180:180:60.

[0726] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0727] Example 6: Preparation of Smegglutide Tablets

[0728] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0729] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 5.43% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 25.26% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 5:150:150:25.

[0730] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0731] Comparative Example 1: Preparation of Smegglutide Tablets

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

[0733] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 65.22% w / w sodium decanoate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:sodium decanoate:arginine is 5:300:50.

[0734] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0735] Comparative Example 2: Preparation of Smegglutide Tablets

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

[0737] The pharmaceutical composition containing semaglutide is formulated 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 lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:arginine is 5:300:50.

[0738] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0739] Comparative Example 3: Preparation of Smegglutide Tablets

[0740] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0741] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 30.69% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate is 5:150:150.

[0742] Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0743] Comparative Example 4: Preparation of Smegglutide Tablets

[0744] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0745] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 65.22% w / w sodium decanoate, 30.69% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide to sodium decanoate is 5:300.

[0746] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0747] Comparative Example 5: Preparation of Smegglutide Tablets

[0748] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0749] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 65.22% w / w SNAC, 30.69% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide to SNAC is 5:300.

[0750] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0751] Comparative Example 6: Preparation of Smegglutide Tablets

[0752] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0753] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 85.04% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide to arginine is 5:50.

[0754] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0755] Comparative Example 7: Preparation of Smegglutide Tablets

[0756] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0757] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 10.87% w / w arginine, 10.87% w / w SNAC, 54.35% w / w sodium decanoate, 19.82% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 5:50:250:50.

[0758] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0759] Comparative Example 8: Preparation of Smegglutide Tablets

[0760] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0761] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 21.74% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.96% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 5:150:150:100.

[0762] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0763] Comparative Example 9: Preparation of Smegglutide Tablets

[0764] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0765] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 6.52% w / w arginine, 19.57% w / w SNAC, 19.57% w / w sodium decanoate, 50.25% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 5:90:90:30.

[0766] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0767] Comparative Example 10: Preparation of Smegglutide Tablets

[0768] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, weigh each component precisely according to the mass ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0769] The pharmaceutical composition containing semaglutide is formulated as follows: 1.09% w / w semaglutide, 95.91% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[0770] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 460mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 5mg of smegglutinin.

[0771] Test Example 1

[0772] Dissolution and release were determined according to the method for determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). The specific method is as follows: using 0.05%... Solution - pH 6.8 phosphate buffer (weigh 6.8 g of anhydrous potassium dihydrogen phosphate, 0.896 g of sodium hydroxide, and...) Dissolve 0.5g in 1000ml of water, adjust pH to 6.8 with phosphoric acid or sodium hydroxide, and use 500ml of the dissolution medium at a rotation speed of 70 rpm. Add samples prepared in Examples 1 and Comparative Examples 3-5 at 0 min, 3 tablets per group. Take samples at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min. After 60 min, sonicate the dissolution vessel for 5 min. Test solution: Take 4.5ml of the dissolution solution, filter, and collect the subsequent filtrate (3ml of the initial filtrate; if turbid, centrifuge). Reference solution: Accurately weigh an appropriate amount of semaglutide reference standard, dissolve and quantitatively dilute with the dissolution medium to prepare a solution containing approximately 32μg of semaglutide per ml.

[0773] The injection volume of the reference solution was 25 μl, and the injection volumes of the test solution were 100 μl (4 mg specification), 50 μl (8 mg specification), and 25 μl (16 mg specification). Octadecylsilane-bonded silica gel was used as the stationary phase (Phenomenex Kinetex C18, 150 x 4.6 mm, 2.6 μm or equivalent column). Mobile phase A was 0.1 mol / L diammonium hydrogen phosphate buffer (23.76 g of diammonium hydrogen phosphate was dissolved in water to a final volume of 1800 ml, the pH was adjusted to 3.6 with concentrated phosphoric acid, and filtered) - acetonitrile (9:1), and mobile phase B was acetonitrile - isopropanol - water (3:1:1). Linear gradient elution was performed according to the table below. The detection wavelength was 215 nm; the column temperature was 35 °C; the injection plate temperature was 6 °C; the flow rate was 0.5 ml / min; and the injection volume was 10 μl.

[0774] Sample analysis was performed 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. Octadecylsilane-bonded silica gel was used as the stationary phase (Phenomenex Kinetex C18, 150 x 4.6 mm, 2.6 μm or equivalent column). Mobile phase A consisted of 0.1 mol / L diammonium hydrogen phosphate buffer (23.76 g of diammonium hydrogen phosphate was dissolved in water to a final volume of 1800 ml, the pH was adjusted to 3.6 with concentrated phosphoric acid, and then filtered) – acetonitrile (9:1), and mobile phase B consisted of acetonitrile – isopropanol – water (3:1:1). Linear gradient elution was performed according to Table 1. The detection wavelength was 215 nm; the column temperature was 35 °C; the injection plate temperature was 6 °C; and the flow rate was 0.5 ml / min.

[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-mentioned smegglutide tablets are shown in Table 2 below. Figure 1 The results showed that smegglutide dissolved fastest when the formulation contained SNAC, sodium decanoate, and arginine.

[0778] Table 2

[0779]

[0780] Test Example 2

[0781] The absorption of the prepared smegglutinin tablets in beagle dogs after oral administration was tested. The specific method was as follows: experimental animals (weighing 10-12 kg) were fasted for 12 hours and deprived of water for 6 hours before administration, and the fasting and water restriction were lifted 1 hour after administration. Before administration, 1 ml of blank blood was collected using an EDTA-K2 blood collection tube as the zero-point blood sample for the experiment. The tablets prepared in Examples 1-6 and Comparative Examples 1-10 were administered orally to beagle dogs via gavage, along with 15 ml of water, ensuring successful swallowing. Five male beagle dogs were used in each group, and the average weight of each group was ensured to be the same. Subsequently, blood was collected from the forearm vein of the beagle dogs using an EDTA-K2 blood collection tube at the following time points after administration: 0.5 h, 1 h, 2 h, and 3 h, with 1 ml of blood collected at each point. The collected whole blood from the beagle dogs was centrifuged, and the supernatant plasma sample was collected and stored at -20°C for subsequent mass spectrometry analysis. Mass spectrometry detection was performed after verification according to the method described in the published literature "Quantitative Analysis of Semaglutide and Tirzepatide in Rat Plasma by SCIEXLC-MS / MS System".

[0782] The absorption test results of the above-mentioned smegglutide tablets in beagle dogs after oral administration are shown in Table 3 below. Figure 2 .

[0783] Table 3

[0784]

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

[0786] Example 7: Preparation of Smegglutide Tablets

[0787] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, use a three-dimensional mixer to mix (50 rpm, 300 s).

[0788] The pharmaceutical composition containing semaglutide is formulated as follows: 1.74% w / w semaglutide, 10.87% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 19.17% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:arginine is 8:150:150:50.

[0789] 2) Tableting: After mixing, the material is compressed into tablets using a 13.5*7.5mm shallow arc-shaped punch, with 460mg of material added to each tablet. The tablet is then removed from the mold to obtain an oval tablet containing 8mg of smegglutide.

[0790] Example 8: Preparation of Smegglutide Tablets

[0791] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, transfer it into a PE bag and mix 1-2 times, shaking 100-200 times / time.

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

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

[0794] 2) Granulation: The dry granulator is set with cooling water temperature of 10-25℃, pressure roller pressure of 70±30 bar, feeding speed of 20-60 rpm, pressure roller speed of 6-12 rpm, granulation speed of 60-100 rpm, and screen size of 16 / 20 mesh. The equipment is started to granulate material A on a trial basis. If it does not meet the requirements, the equipment parameters are adjusted appropriately and the trial is repeated. If it meets the requirements, formal granulation is carried out. The actual parameters are recorded during the granulation process until all the powder is granulated and granules A are obtained.

[0795] Material B was granulated using the same process to obtain granules B.

[0796] 3) Tableting: Accurately weigh each component according to the mass ratio of 14.67% w / w granule A, 84.83% w / w granule B, and 0.5% w / w magnesium stearate. After weighing, transfer the mixture to a PE bag and mix 1-2 times, shaking 100-200 times per cycle. After thorough mixing, compress the material using a 13.5*7.5mm shallow arc-shaped die, with 518.2mg of material added to each tablet. Remove the tablet from the die to obtain an oval tablet containing 8mg of smegglutinin.

[0797] Example 9: Preparation of Smegglutide Tablets

[0798] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass configuration ratio shown below. After weighing, transfer it into a PE bag and mix 1-2 times, shaking 100-200 times / time.

[0799] Material A: 42.11% w / w smegglutide, 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 decanoate, 17.24% w / w microcrystalline cellulose, 1.05% w / w sodium dodecyl sulfate, 2.09% w / w sodium carboxymethyl starch

[0801] 2) Granulation: The dry granulator is set with cooling water temperature of 10-25℃, pressure roller pressure of 70±30 bar, feeding speed of 20-60 rpm, pressure roller speed of 6-12 rpm, granulation speed of 60-100 rpm, and screen size of 16 / 20 mesh. The equipment is started to granulate material A on a trial basis. If it does not meet the requirements, the equipment parameters are adjusted appropriately and the trial is repeated. If it meets the requirements, formal granulation is carried out. The actual parameters are recorded during the granulation process until all the powder is granulated and granules A are obtained.

[0802] Material B was granulated using the same process to obtain granules B.

[0803] 3) Tableting: Accurately weigh each component according to the mass ratio of 4.12% w / w granule A, 95.36% w / w granule B, and 0.52% w / w magnesium stearate. After weighing, transfer the mixture to a PE bag and mix 1-2 times, shaking 100-200 times per cycle. After thorough mixing, compress the material using a 13.5*7.5mm shallow arc-shaped die, feeding 461mg of material into each tablet. Remove the tablet from the die to obtain an oval tablet containing 8mg of smegglutinin.

[0804] Test Example 3

[0805] The absorption of the prepared smegglutinin tablets in beagle dogs after oral administration was tested. The specific method was as follows: experimental animals (weighing 10-12 kg) were fasted for 12 hours and deprived of water for 6 hours before administration, and the fasting and water restriction were lifted 1 hour after administration. Before administration, 1 ml of blank blood was collected using an EDTA-K2 blood collection tube as the zero-point blood sample for the experiment. The tablets prepared in Examples 7-9 were administered orally to beagle dogs via gavage, along with 15 ml of water, ensuring successful swallowing. Five male beagle dogs were used in each group, and the average weight of each group was ensured to be the same. Subsequently, blood was collected from the forearm vein of the beagle dogs using an EDTA-K2 blood collection tube at the following time points after administration: 0.5 h, 1 h, 2 h, and 3 h, with 1 ml of blood collected at each point. The collected whole blood from the beagle dogs was centrifuged, and the supernatant plasma sample was collected and stored at -20°C for subsequent mass spectrometry analysis. The mass spectrometry detection was performed 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".

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

[0807] Table 4

[0808]

[0809] As can be seen from the data in the table above, the preparation processes of Examples 8 and 9 significantly improved the oral blood concentration of smegglutide tablets in beagle dogs.

[0810] Example 10

[0811] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass ratio shown below. After weighing material A, transfer it all into a PE bag and mix 1-2 times, shaking 100-200 times each time. After weighing material B, transfer it into a PE bag in order of increasing mass, shaking 100-200 times for each material added to mix.

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

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

[0814] 2) Granulation: The dry granulator is set with cooling water temperature of 10-25℃, pressure roller pressure of 50±30 bar, feeding speed of 10-30 rpm, pressure roller speed of 5-10 rpm, granulation speed of 60-100 rpm, and screen size of 16 / 20 mesh. The equipment is started to granulate material A on a trial basis. If it does not meet the requirements, the equipment parameters are adjusted appropriately and the trial is repeated. If it meets the requirements, formal granulation is carried out. The actual parameters are recorded during the granulation process until all powder is granulated and granules A are obtained.

[0815] Material B was granulated using the same process to obtain granules B.

[0816] 3) Tableting: Accurately weigh each component according to the mass ratio of 7.92% w / w granule A, 91.58% w / w granule B, and 0.5% w / w magnesium stearate. After weighing, transfer the mixture to a PE bag and mix 1-2 times, shaking 100-200 times per cycle. After thorough mixing, compress the material using a 13.5*7.5mm shallow arc-shaped die, feeding 480mg of material into each tablet. Remove the tablet from the die to obtain an oval tablet containing 4mg of smegglutinin.

[0817] 4) Coating: using The film coating premix is ​​prepared into a coating solution with a solid content of 15%, achieving a coating gain of 4%-5%. The coating machine is set with an inlet air temperature of 35℃, an outlet air temperature of 30℃, an inlet air speed of 1100-1300 rpm, an exhaust air speed of 1300-1500 rpm, a main unit speed of 10-15 rpm, a spray pump speed of 2-10 rpm, an atomization pressure of 0.18 MPa, and a spray gun pressure of 0.2 MPa. Sufficient preheating is required before coating, and drying and curing are necessary after coating.

[0818] Example 11

[0819] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass ratio shown below. After weighing material A, transfer it all into a PE bag and mix 1-2 times, shaking 100-200 times each time. After weighing material B, transfer it into a PE bag in order of increasing mass, shaking 100-200 times for each material added to mix.

[0820] Material A: 21.05% w / w Smegglutide, 57.89% w / w microcrystalline cellulose, 21.05% w / w povidone K90

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

[0822] 2) Granulation: The dry granulator is set with cooling water temperature of 10-25℃, pressure roller pressure of 50±30 bar, feeding speed of 10-30 rpm, pressure roller speed of 5-10 rpm, granulation speed of 60-100 rpm, and screen size of 16 / 20 mesh. The equipment is started to granulate material A on a trial basis. If it does not meet the requirements, the equipment parameters are adjusted appropriately and the trial is repeated. If it meets the requirements, formal granulation is carried out. The actual parameters are recorded during the granulation process until all powder is granulated and granules A are obtained.

[0823] Material B was granulated using the same process to obtain granules B.

[0824] 3) Tableting: Accurately weigh each component according to the mass ratio of 7.92% w / w granule A, 91.58% w / w granule B, and 0.5% w / w magnesium stearate. After weighing, transfer the mixture to a PE bag and mix 1-2 times, shaking 100-200 times per cycle. After thorough mixing, compress the material using a 13.5*7.5mm shallow arc-shaped die, feeding 480mg of material per tablet. Remove the tablet from the die to obtain an oval tablet containing 8mg of smegglutinin.

[0825] 4) Coating: using The film coating premix is ​​prepared into a coating solution with a solid content of 15%, achieving a coating gain of 4%-5%. The coating machine is set with an inlet air temperature of 35℃, an outlet air temperature of 30℃, an inlet air speed of 1100-1300 rpm, an exhaust air speed of 1300-1500 rpm, a main unit speed of 10-15 rpm, a spray pump speed of 2-10 rpm, an atomization pressure of 0.18 MPa, and a spray gun pressure of 0.2 MPa. Sufficient preheating is required before coating, and drying and curing are necessary after coating.

[0826] Example 12

[0827] 1) Mixing: Take the raw materials to prepare the drug formulation system powder. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass ratio shown below. After weighing material A, transfer it all into a PE bag and mix 1-2 times, shaking 100-200 times each time. After weighing material B, transfer it into a PE bag in order of increasing mass, shaking 100-200 times for each material added to mix.

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

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

[0830] 2) Granulation: The dry granulator is set with cooling water temperature of 10-25℃, pressure roller pressure of 50±30 bar, feeding speed of 10-30 rpm, pressure roller speed of 5-10 rpm, granulation speed of 60-100 rpm, and screen size of 16 / 20 mesh. The equipment is started to granulate material A on a trial basis. If it does not meet the requirements, the equipment parameters are adjusted appropriately and the trial is repeated. If it meets the requirements, formal granulation is carried out. The actual parameters are recorded during the granulation process until all powder is granulated and granules A are obtained.

[0831] Material B was granulated using the same process to obtain granules B.

[0832] 3) Tableting: Accurately weigh each component according to the mass ratio of 7.92% w / w granule A, 91.58% w / w granule B, and 0.5% w / w magnesium stearate. After weighing, transfer the mixture to a PE bag and mix 1-2 times, shaking 100-200 times per cycle. After thorough mixing, compress the material using a 13.5*7.5mm shallow arc-shaped die, feeding 480mg of material into each tablet. Remove the tablet from the die to obtain an oval tablet containing 16mg of smegglutinin.

[0833] 4) Coating: using The film coating premix is ​​prepared into a coating solution with a solid content of 15%, achieving a coating gain of 4%-5%. The coating machine is set with an inlet air temperature of 35℃, an outlet air temperature of 30℃, an inlet air speed of 1100-1300 rpm, an exhaust air speed of 1300-1500 rpm, a main unit speed of 10-15 rpm, a spray pump speed of 2-10 rpm, an atomization pressure of 0.18 MPa, and a spray gun pressure of 0.2 MPa. Sufficient preheating is required before coating, and drying and curing are necessary after coating.

[0834] Test Example 4

[0835] The absorption of the prepared smegglutide tablets was tested in cynomolgus monkeys after oral administration. The specific method was as follows: experimental animals were fasted for 12 hours and deprived of water for 6 hours before administration, and the fasting and water restriction were lifted 1 hour after administration. A certain amount of blank blood was collected using EDTA-K2 blood collection tubes before administration as the zero-point blood sample, and the animal's weight was measured. The tablets prepared in Examples 10-12 were administered orally to the cynomolgus monkeys along with 15 ml of water to ensure successful swallowing. Another group received smegglutide intravenously to the cynomolgus monkeys at a dose of 0.05 mg / kg per monkey. Each group used 6 cynomolgus monkeys, 3 females and 3 males. Subsequently, intravenous blood was collected using EDTA-K2 blood collection tubes at the following time points after administration: 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 240h, and 336h. Whole blood was collected from cynomolgus monkeys and centrifuged to obtain plasma samples. The samples were frozen at -20°C for subsequent mass spectrometry analysis. Mass spectrometry analysis was performed after validation according to the method described in the published literature, "Quantitative Analysis of Semaglutide and Tirzepatide in Rat Plasma by SCIEX LC-MS / MS System".

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

[0837] Table 5

[0838]

[0839] Example 13: Preparation of Smegglutide tablets

[0840] First, prepare the drug formulation powder according to the scheme in Table 6. Specifically, weigh each component according to the mass ratio shown in the table below, and mix them thoroughly after weighing.

[0841] Table 6. Smegglutide drug formulation system

[0842] Pharmaceutical formulation system Ingredient ratio OLP-A001 1.52% Smegglutinin, 10.87% Arginine, 32.61% SNAC, 32.61% Sodium Decanoate, 22.39% Microcrystalline Cellulose OLP-A003 1.52% Smegglutinin, 10.87% Citrulline, 32.61% SNAC, 32.61% Sodium Decanoate, 22.39% Microcrystalline Cellulose OLP-A004 1.52% Smegglutide, 10.87% Nicotinamide, 32.61% SNAC, 32.61% Sodium Decanoate, 22.39% Microcrystalline Cellulose OLP-A005 1.52% Smegglutinin, 65.22% SNAC, 33.26% Microcrystalline cellulose OLP-A006 1.52% Smegglutinin, 10.87% Lysine, 21.74% SNAC, 43.48% Sodium decanoate, 22.39% Microcrystalline cellulose

[0843] Tableting is performed using a flat die. The tablet is removed from the die to obtain a 10mm round flat tablet containing 7mg of smegglutinin.

[0844] Test Example 5: Smegglutide tablets beagle dog test

[0845] Before administration, a blank blood sample was taken as the zero-point blood sample for the experiment. The tablets prepared in Example 13 and the original oral semaglutide tablets from Novo Nordisk were used. The drug (7 mg) was administered to six beagles via gavage. Blood samples were then collected from the forearm vein at 0.5 h, 1 h, 2 h, and 3 h post-administration. The collected whole blood was centrifuged, and the supernatant plasma was frozen for later mass spectrometry analysis.

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

[0847] Table 6-1 Analysis of smegglutinin content in beagle dog plasma after drug administration

[0848]

[0849] Example 14: Preparation of Teriparatide Tablets

[0850] First, prepare the drug formulation powder according to the scheme in Table 7. Specifically, weigh each component according to the mass ratio shown in the table below, and mix them thoroughly after weighing.

[0851] Table 7 Teriparatide Drug Formulation System

[0852] Pharmaceutical formulation system Ingredient ratio OLP-B001 1.52% Teriparatide, 10.87% Arginine, 32.61% SNAC, 32.61% Sodium Decanoate, 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] Tableting is performed using a flat die. The tablet is removed from the die to obtain a 10mm round flat tablet with a teriparatide content of 7mg.

[0854] Test Example 6: Teriparatide tablets beagle dog test

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

[0856] The experimental results are shown in Table 7-1. The results indicate that beagle dogs absorb teriparatide in the OLP-B001 drug formulation system significantly better than those in OLP-B003. Figure 6 ).

[0857] Table 7-1 Analysis of Teriparatide content in beagle plasma after drug administration

[0858]

[0859]

[0860] Example 15: Preparation of Telbopeptide Capsules

[0861] First, prepare the drug formulation powder according to the scheme in Table 8. Specifically, weigh each component according to the mass ratio shown in the table below, and mix them thoroughly after weighing.

[0862] Table 8. Table of the pharmaceutical formulation system of telpopeptide

[0863] Pharmaceutical formulation system Ingredient ratio OLP-C001 3.04% telpoeptide, 10.87% arginine, 32.61% SNAC, 32.61% sodium decanoate, 20.87% microcrystalline cellulose OLP-C002 3.04% telpoeptide, 96.96% microcrystalline cellulose OLP-C003 3.04% telpotassium peptide, 65.22% SNAC, 31.74% microcrystalline cellulose OLP-C004 3.04% telpotassium hydroxide, 10.87% nicotinamide, 32.61% SNAC, 32.61% sodium decanoate, 20.87% microcrystalline cellulose OLP-C005 3.04% telpotassium hydroxide, 10.87% citrulline, 32.61% SNAC, 32.61% sodium decanoate, 20.87% microcrystalline cellulose

[0864] Tableting is performed using a flat die. The tablets are removed from the die to obtain 8mm round tablets containing 4.86mg of telpoeptide. These tablets are then ground and passed through an 80-mesh sieve. 13.16mg of the sieved powder is weighed and filled into No. 9 gelatin capsules to obtain No. 9 capsules containing 0.4mg of telpoeptide.

[0865] Test Example 7: Rat Test with Telbopeptide Capsules

[0866] Before administration, blank blood samples were collected from rats as the zero-point blood sample for the experiment. After anesthetizing the rats, the abdomen was shaved and the laparotomy was performed. The small intestine was carefully incised with a blade at a point approximately 12 cm from the cecum, and one capsule prepared in Example 15 was administered to the rat through the incision. The capsule was pushed 2 cm toward the cecum to avoid the wound, and then the rat's intestine and abdomen were sutured. Blood samples were collected from the rats at the following time points after administration: 0.5 h, 1 h, 2 h, 3 h, and 4 h, with 0.5 ml of blood collected at each point. The collected whole blood was centrifuged, and the supernatant plasma sample was frozen for subsequent mass spectrometry analysis.

[0867] The experimental results are shown in Table 8-1. The results indicate that rats absorb telpolide in the OLP-C001 and OLP-C005 drug formulation systems better than OLP-C003 and OLP-C004. Figure 7 ).

[0868] Table 8-1 Analysis of plasma telpoide levels after drug administration

[0869]

[0870] Example 16: Preparation of Octreotide Capsules

[0871] First, prepare the drug formulation powder according to the scheme in Table 9. Specifically, weigh each component according to the mass ratio shown in the table below, and mix them thoroughly after weighing.

[0872] Table 9. Octreotide Pharmaceutical Formulation System

[0873] Pharmaceutical formulation system Ingredient ratio OLP-D001 3.04% Octreotide, 10.87% Arginine, 32.61% SNAC, 32.61% Sodium Decanoate, 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 Decanoate, 22.39% Microcrystalline Cellulose

[0874] Tableting is performed using a flat die. The tablets are removed from the die to obtain 8mm round tablets containing 4.86mg of octreotide. The tablets are then ground and passed through an 80-mesh sieve. 13.16mg of the sieved powder is weighed and filled into No. 9 gelatin capsules to obtain No. 9 capsules containing 0.4mg of octreotide.

[0875] Test Example 8: Octreotide Capsule Rat Test

[0876] Before administration, blank blood samples were collected from rats as the zero-point blood sample for the experiment. After anesthetizing the rats, the abdomen was shaved and the laparotomy was performed. Then, the small intestine was carefully incised with a blade at a point approximately 12 cm from the cecum, and one capsule as described in Example 16 was administered to the rat through the incision. The capsule was pushed 2 cm toward the cecum to avoid the wound, and then the rat's intestine and abdomen were sutured. Blood samples were collected from the rats at the following time points after administration: 0.5 h, 1 h, 2 h, 3 h, and 4 h, with 0.5 ml of blood collected at each point. The collected whole blood was centrifuged, and the supernatant serum was frozen for subsequent mass spectrometry analysis.

[0877] The experimental results are shown in Table 9-1. The results indicate that rats absorb octreotide from the OLP-D001 and OLP-D004 drug formulation systems significantly better than those from OLP-D003. Figure 8 ).

[0878] Table 9-1 Analysis of octreotide content in plasma after drug administration

[0879]

[0880] Test Example 9, Composition Characterization

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

[0882] Table 9 Combination Drug Systems

[0883] Drug system Element OLP-S001 10mg Smegglutide OLP-S002 10mg Smegglutide, 37.5mg Arginine, 112.5mg Sodium Decanoate, 112.5mg SNAC OLP-S003 10mg smegglutide, 225mg SNAC

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

[0885] Table 10 Peak mean values ​​of particle size distribution of combined drugs

[0886] Drug system Particle size distribution peak mean (nm) ± SD OLP-S001 4.48±0.09 OLP-S002 2.84±0.51 OLP-S003 697.13±67.67

Claims

1. An orally administered polypeptide composition, wherein, The formulation of the polypeptide composition is as follows: 0.5-10.0% w / w smegglutide; 5-15% w / w arginine; 25-35% w / w SNAC; 25-35% w / w sodium decanoate; and excipient; The total content of arginine, SNAC and sodium decanoate in the polypeptide composition is 70-80% w / w.

2. The oral polypeptide composition of claim 1, wherein, In the oral polypeptide composition, the mass percentage ratio of SNAC to sodium decanoate is 1:

1.

3. The oral polypeptide composition of claim 1, wherein, In the oral polypeptide composition, the mass percentage ratio of arginine to SNAC is 1:

3.

4. The oral polypeptide composition of claim 1, wherein, In the oral polypeptide composition, the mass percentage ratio of arginine, SNAC, and sodium decanoate is 1:3:

3.

5. The oral polypeptide composition of claim 1, wherein, The oral polypeptide composition comprises: Smegglutinin 1-32 parts by weight; Arginine 50-70 parts by weight; Sodium decanoate 120-180 parts by weight; SNAC120-180 parts by weight; 70-140 parts by weight of excipients.

6. The oral polypeptide composition of claim 1, wherein, The oral polypeptide composition comprises: 4.0 mg smegglutide, 50.0 mg arginine, 150.0 mg SNAC, 150.0 mg sodium decanoate, and 123.0 mg excipients.

7. The oral polypeptide composition of claim 1, wherein, The oral polypeptide composition comprises: 8.0 mg smegglutide, 50.0 mg arginine, 150.0 mg SNAC, 150.0 mg sodium decanoate, and 120.0 mg excipients.

8. The oral polypeptide composition of claim 1, wherein, The oral polypeptide composition comprises: 16.0 mg smegglutide, 50.0 mg arginine, 150.0 mg SNAC, 150.0 mg sodium decanoate, and 110.0 mg excipients.

9. The oral polypeptide composition according to any one of claims 6-8, wherein, The excipients include microcrystalline cellulose, sodium dodecyl sulfate, sodium carboxymethyl starch, and povidone.

10. The oral polypeptide composition according to any one of claims 1-8, wherein, The oral polypeptide composition is a solid dosage form.

11. The oral polypeptide composition of claim 9, wherein, The oral polypeptide composition is a solid dosage form.

12. The oral polypeptide composition of claim 10, wherein, The oral polypeptide composition is in the form of tablets.

13. The oral polypeptide composition of claim 11, wherein, The oral polypeptide composition is in the form of tablets.

14. The oral polypeptide composition of claim 12 or 13, wherein, The tablets are available in strengths of 1-50 mg.

15. Use of the oral polypeptide composition according to any one of claims 1-14 in the preparation of a medicament for treating a disease; said disease is selected from at least one of type 2 diabetes, obesity, and non-alcoholic fatty liver disease.

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