Pharmaceutical composition and preparation method therefor

Abstract

An oral pharmaceutical composition and a preparation method therefor. The oral pharmaceutical composition comprises a pharmaceutically acceptable polypeptide or protein, a complex molecule, a compound containing a nitrogen atom functional group, a medium chain fatty acid or a salt thereof, and N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof.

Description

Pharmaceutical Compositions and Preparation Methods Thereof

[0001] Cross-reference declaration

[0002] This disclosure claims priority to Chinese Patent Application No. 2024115823965, filed on November 6, 2024, entitled “Pharmaceutical Composition and Method for Preparation Thereof”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to the field of pharmaceutical formulation technology, specifically to a pharmaceutical composition and its preparation method. Background Technology

[0004] Therapeutic peptides are small molecules composed of amino acids, typically ranging from 2 to 50 amino acids in length. They possess specific biological activities and offer unique advantages compared to traditional small-molecule drugs or large-molecule biological drugs (such as antibodies), including high selectivity and targeting, low toxicity, and good tissue penetration. Due to these unique advantages, peptide drugs have experienced rapid development in the global pharmaceutical industry in recent years, with a continuous increase in the number of marketed peptide drugs and ongoing clinical research projects. To date, more than 80 peptide drugs have been marketed globally. These drugs are widely used to treat a variety of diseases, including cancer, diabetes, infectious diseases, metabolic diseases, and cardiovascular diseases. According to information from the global clinical trial database, there are currently over 700 clinical trials involving peptide drugs, covering everything from early-stage (Phase I and II) to late-stage (Phase III) clinical trials, and more drugs are expected to enter the market in the coming years.

[0005] Low oral bioavailability has been a major obstacle in the development and application of peptide drugs. The oral route offers higher patient compliance, and even if the overall efficacy is lower than parenteral administration, it can generate significant market revenue for molecules that indirectly act on the same overall biological goals. Compared to small molecule drugs, peptides are larger and more unstable, often difficult to absorb through the gastrointestinal tract. Therefore, most peptide drugs can only be administered via injection, limiting patient compliance. Researchers are constantly striving to find effective oral peptide therapies. Adding chemical penetration enhancers (PEs) is considered a routine approach to address the permeability of large molecules. Many compounds, including surfactants, bile salts, bacterial toxins, chelating agents, and medium-chain fatty acids (MCFAs), are effective PEs for poorly permeable molecules. However, adding PEs is not effective for all peptides. Extensive screening of suitable PE molecules is still needed for different peptide molecules. Even when the optimal PE molecule is found, its permeation-enhancing effect on the API is limited, resulting in a significant difference between oral and injectable formulations, making it extremely difficult to further improve the oral bioavailability of drugs.

[0006] Therefore, there is an urgent need in this field to develop a method to improve the bioavailability of oral dosage forms of peptide drugs. Summary of the Invention

[0007] The purpose of this disclosure is to provide an oral pharmaceutical composition.

[0008] The purpose of this disclosure is to provide a method for preparing an orally administered pharmaceutical composition.

[0009] Another object of this disclosure is to provide an oral pharmaceutical composition containing a polypeptide or protein that targets the glucagon-like peptide-1 (GLP-1) receptor and its use therein.

[0010] Another object of this disclosure is to provide an oral pharmaceutical composition containing a polypeptide or protein that targets glucose-dependent insulinotropic peptide (GIP) and GLP-1 receptor, and the use thereof.

[0011] Another object of this disclosure is to provide an oral pharmaceutical composition containing a polypeptide or protein that targets a parathyroid hormone (PTH) receptor and its use therein.

[0012] Another object of this disclosure is to provide an oral pharmaceutical composition containing a polypeptide or protein that targets a somatostatin receptor and its use therein.

[0013] In one aspect, this disclosure provides an oral pharmaceutical composition comprising:

[0014] (i) Medicinal polypeptides or proteins;

[0015] (ii) Coordinating molecules;

[0016] (iii) Compounds containing nitrogen-containing functional groups;

[0017] (iv) Medium-chain fatty acids or their salts;

[0018] (v) Salicylic acid derivatives or octanoic acid amine derivatives;

[0019] Wherein, the coordinating molecule is a C containing a hydrophilic group. 6- C 10 Aromatic ring or C 5- C 10 Heteroaromatic compounds;

[0020] The compound containing a nitrogen-atom functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of the substituent groups selected from -S(O)2OH and -OH.

[0021] In one embodiment of this disclosure, the pharmaceutical composition comprises:

[0022] (i) Medicinal polypeptides or proteins;

[0023] (ii) Coordinating molecules;

[0024] (iii) Compounds containing nitrogen-containing functional groups;

[0025] (iv) Medium-chain fatty acids or their salts;

[0026] (v) N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof;

[0027] Wherein, the coordinating molecule is a C containing a hydrophilic group. 6- C 10 Aromatic ring or C 5- C 10 Heteroaromatic compounds;

[0028] The compound containing a nitrogen-atom functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of the substituent groups selected from -S(O)2OH and -OH.

[0029] In one technical solution disclosed herein, both the coordinating molecule and the compound containing the nitrogen-atom functional group are small molecule compounds with a molecular weight of less than 900 Da, preferably less than 500 Da.

[0030] In one technical solution disclosed herein, the coordinating molecule is a substituted C 6- C 10 Aromatic rings or 5-10-membered heteroaromatic rings, wherein the substituents include hydrophilic groups, and optionally other substituents (e.g., methyl, ethyl, halogen, or non-hydrophilic groups such as oxo (=O)).

[0031] In one technical solution disclosed herein, the hydrophilic group includes hydroxyl, carboxyl, amino, sulfonic acid, phosphate, amide, ribose, or carboxylate groups.

[0032] In one technical solution disclosed herein, the hydrophilic group is a hydroxyl group, a carboxyl group, an amino group, a sulfonic acid group, a phosphate group, an amide group, or a carboxylic acid group.

[0033] In one technical solution disclosed herein, the coordinating molecule is: Where ring A is C 6- C 10 Aromatic ring or 5-10 membered heteroaryl ring, the ring being divided by one or more R 1 and one or more R 2 Replace, each R 1Each R is an independent hydrophilic group. 2 Independently hydrogen, methyl, ethyl, halogen, or oxo (=O). Preferably, each R 1 Each R is independently a hydroxyl, carboxyl, amino, sulfonic acid, phosphate, amide, ribose, or carboxylate group. 2 It can be hydrogen, methyl, ethyl, halogen, or oxo (=O) independently.

[0034] In one technical solution of this disclosure, ring A is a benzene ring or a 5-10 membered heteroaromatic ring, wherein the 5-10 membered heteroaromatic ring contains at least one N (e.g., 2, 3, or 4) ring atom, and the N may optionally be N2. + Ions; preferably, ring A is a benzene ring, naphthalene ring, pyrrole, imidazole, oxazole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, indole, purine, or pteridine.

[0035] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of the substituent groups selected from -S(O)2OH and -OH.

[0036] In one technical solution disclosed herein, the molecular weight of the compound containing nitrogen-atom functional groups is less than 300 Da.

[0037] In one aspect of this disclosure, the compound containing nitrogen-atom functional groups is not covalently bonded to the pharmaceutically usable polypeptide or protein.

[0038] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 0.5% w / w of a pharmaceutically acceptable polypeptide or protein.

[0039] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 10.0% w / w of a pharmaceutically acceptable polypeptide or protein.

[0040] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a pharmaceutically acceptable polypeptide or protein at a concentration of not less than about 0.5% w / w and not more than about 10.0% w / w.

[0041] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a pharmaceutically acceptable polypeptide or protein at a concentration of not less than about 0.5% w / w and not more than about 5.0% w / w.

[0042] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, 6% w / w, 6.5% w / w, 7% w / w, 7.5% w / w, 8% w / w, 9% w / w, or 10% w / w of a pharmaceutically acceptable protein or polypeptide.

[0043] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w of medium-chain fatty acids or their salts.

[0044] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 25% w / w of medium-chain fatty acids or their salts.

[0045] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30% w / w of medium-chain fatty acids or their salts.

[0046] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0047] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 45% w / w of medium-chain fatty acids or their salts.

[0048] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 40% w / w of medium-chain fatty acids or their salts.

[0049] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0050] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30.0% w / w and not more than about 40% w / w of medium-chain fatty acids or their salts.

[0051] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 20% w / w, 25% w / w, 28% w / w, 30% w / w, 33% w / w, 35% w / w, 40% w / w, 45% w / w, or 50% w / w of medium-chain fatty acids or their salts.

[0052] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0053] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 25% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0054] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0055] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 50.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0056] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 45% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0057] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 40% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0058] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50% w / w N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0059] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30.0% w / w and not more than about 40% w / w N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0060] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 20% w / w, 25% w / w, 28% w / w, 30% w / w, 33% w / w, 35% w / w, 40% w / w, 45% w / w, or 50% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0061] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 5.0% w / w of a compound containing a nitrogen-atom functional group.

[0062] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 7.0% w / w of a compound containing a nitrogen-atom functional group.

[0063] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 8.0% w / w of a compound containing a nitrogen-containing functional group.

[0064] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 9.0% w / w of a compound containing a nitrogen-containing functional group.

[0065] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 10.0% w / w of a compound containing a nitrogen-containing functional group.

[0066] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a rate not exceeding about 30.0 w / w.

[0067] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 25% w / w of a compound containing a nitrogen-containing functional group.

[0068] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 20% w / w of a compound containing a nitrogen-containing functional group.

[0069] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 18.0% of a compound containing a nitrogen-containing functional group.

[0070] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 16.0% of a compound containing a nitrogen-containing functional group.

[0071] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 15.0% of a compound containing a nitrogen-containing functional group.

[0072] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 5.0% w / w and not more than about 30.0 w / w.

[0073] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 10.0% w / w and not more than about 15.0 w / w.

[0074] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 5.0% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, 15% w / w, 16% w / w, 17% w / w, 18% w / w, 19% w / w, 20% w / w, 25% w / w, 27% w / w, and 30% w / w of a compound containing a nitrogen-atom functional group.

[0075] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 5.0% w / w.

[0076] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 7.0% w / w.

[0077] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 8.0% w / w.

[0078] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 9.0% w / w.

[0079] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 10.0% w / w.

[0080] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule at a concentration of no more than about 20.0 w / w.

[0081] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 18.0% of a coordinating molecule.

[0082] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 16.0% of a coordinating molecule.

[0083] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 15.0% of a coordinating molecule.

[0084] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule comprising not less than about 5.0% w / w and not more than about 20.0 w / w.

[0085] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule comprising not less than about 10.0% w / w and not more than about 15.0% w / w.

[0086] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 5.0% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, 15% w / w, 16% w / w, 17% w / w, 18% w / w, 19% w / w, and 20% w / w of a coordinating molecule.

[0087] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 1-50 parts by weight of a pharmaceutically acceptable polypeptide or protein.

[0088] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 1-20 parts by weight of a pharmaceutically acceptable polypeptide or protein.

[0089] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 10-200 parts by weight of a complexing molecule.

[0090] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 10-100 parts by weight of a complexing molecule.

[0091] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 10-60 parts by weight of a complexing molecule.

[0092] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-500 parts by weight of a compound containing a nitrogen-atom functional group.

[0093] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-200 parts by weight of a compound containing a nitrogen-atom functional group.

[0094] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-150 parts by weight of a compound containing a nitrogen-atom functional group.

[0095] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-100 parts by weight of a compound containing a nitrogen-atom functional group.

[0096] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 50-500 parts by weight of medium-chain fatty acids or their salts.

[0097] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 75-500 parts by weight of medium-chain fatty acids or their salts.

[0098] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-500 parts by weight of a medium-chain fatty acid or a salt thereof.

[0099] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-300 parts by weight of medium-chain fatty acids or their salts.

[0100] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 50-300 parts by weight of medium-chain fatty acids or their salts.

[0101] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 50-250 parts by weight of medium-chain fatty acids or their salts.

[0102] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 50-500 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0103] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-500 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0104] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 50-300 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0105] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-300 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0106] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 50-200 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0107] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 1-50 mg of a pharmaceutically acceptable polypeptide or protein.

[0108] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 1-20 mg of a pharmaceutically acceptable polypeptide or protein.

[0109] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 10-200 mg of a complexing molecule.

[0110] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 10-100 mg of a complexing molecule.

[0111] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 30-70 mg of a complexing molecule.

[0112] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises 10-500 mg of a compound containing a nitrogen-atom functional group.

[0113] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-200 mg of a compound containing a nitrogen-containing functional group.

[0114] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-150 mg of a compound containing a nitrogen-containing functional group.

[0115] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-100 mg of a compound containing a nitrogen-containing functional group.

[0116] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 30-70 mg of a compound containing a nitrogen-containing functional group.

[0117] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-500 mg of medium-chain fatty acids or their salts.

[0118] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-300 mg of medium-chain fatty acids or their salts.

[0119] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 130-180 mg of medium-chain fatty acids or their salts.

[0120] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises 100-500 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0121] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 100-300 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0122] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 130-180 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0123] In one technical solution of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group in the oral pharmaceutical composition is approximately 1:(0.5-4).

[0124] In one technical solution of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group in the oral pharmaceutical composition is approximately 1:(0.5-2).

[0125] In one embodiment of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-containing functional group in the oral pharmaceutical composition is approximately 1:(0.8-1.2).

[0126] In one embodiment of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing a nitrogen-containing functional group in the oral pharmaceutical composition is approximately 1:1.

[0127] In one technical solution of this disclosure, the mass percentage ratio of the pharmaceutically acceptable polypeptide or protein to the coordinating molecule in the oral pharmaceutical composition is approximately 1:(3-10).

[0128] In one embodiment of this disclosure, the mass percentage ratio of the pharmaceutically acceptable polypeptide or protein to the coordinating molecule in the oral pharmaceutical composition is approximately 1:(3-7).

[0129] In one embodiment of this disclosure, the mass percentage ratio of the medium-chain fatty acid or its salt to the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is approximately 1:(0.8-1.2).

[0130] In one embodiment of this disclosure, the oral pharmaceutical composition contains a medium-chain fatty acid or its salt in a mass percentage ratio of approximately 1:1 to N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt.

[0131] In one technical solution of this disclosure, the mass percentage ratio of the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is approximately (0.5-1.5):(0.5-1.5):(2.5-3.5):(2.5-3.5).

[0132] In one technical solution of this disclosure, the mass percentage ratio of the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is approximately (0.8-1.2):(0.8-1.2):(2.5-3.5):(2.5-3.5).

[0133] In one embodiment of this disclosure, the oral pharmaceutical composition comprises an oral medicament in which the mass percentages of the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt are approximately 1:1:3:3.

[0134] In one technical solution of this disclosure, the mass percentage ratio of the pharmaceutically acceptable polypeptide or protein, the complexing molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is (1-10):(10-100):(10-100):(100-500):(100-500).

[0135] In one technical solution of this disclosure, the mass percentage ratio of the pharmaceutically acceptable polypeptide or protein, the complexing molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is (1-10):(10-100):(10-100):(100-300):(100-300); more preferably (4-10):(30-80):(30-80):(100-200):(100-200); for example, 7:50:50:150:150.

[0136] In one technical solution of this disclosure, the mass percentage ratio of the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is (25-100):(25-200):(50-250):(50-250).

[0137] In one technical solution of this disclosure, the mass percentage ratio of the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is (25-100):(25-200):(100-300):(100-300).

[0138] In one technical solution of this disclosure, the mass percentage ratio of the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is (25-60):(25-150):(75-250):(50-250).

[0139] In one technical solution of this disclosure, the mass percentage ratio of the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is approximately 50:(50-100):150:150.

[0140] In one technical solution of this disclosure, the mass percentage ratio of the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt in the oral pharmaceutical composition is approximately 50:50:150:150, 50:50:100:200, 50:50:200:100, 50:50:250:50, 50:50:100:200, 50:50:75:225, 50:25:150:150, 25:50:150:150, 33:33:100:100, 25:25:75:75, and 50:150:150:150.

[0141] In one technical solution of this disclosure, the compound containing a nitrogen-atom functional group contains an amino group and -C(O)OH, an amino group and -C(O)OH; or contains an amino group and -S(O)2OH, an amino group and -S(O)2OH; or contains a quaternary ammonium group and -C(O)O - It may contain quaternary ammonium groups and -OH; or it may contain quaternary ammonium groups and -C(O)O. - and -OH.

[0142] In one technical solution of this disclosure, the compound containing a nitrogen-atom functional group contains an amino group and -C(O)OH; an amino group and -S(O)2OH; or contains a quaternary ammonium group and -C(O)O - It may contain quaternary ammonium groups and -OH; or it may contain quaternary ammonium groups and -C(O)O. - and -OH.

[0143] In one technical solution disclosed herein, the molecular weight of the compound containing nitrogen-atom functional groups ranges from 50 to 250 g / mol, wherein the molecular weight of the compound containing nitrogen-atom functional groups is in free form.

[0144] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is C. 1-8 Compounds containing amino, amine, or quaternary ammonium functional groups.

[0145] In one technical solution of this disclosure, the compound containing a nitrogen-atom functional group is selected from at least one of amino acids or their salts (preferably sodium salts), L-carnitine, taurine, betaine, choline, choline chloride, and carnitine, wherein the amino acids are selected from natural amino acids or synthetic amino acids.

[0146] In one technical solution disclosed herein, the amino acid is selected from at least one of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, asparagine, glutamine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, sarcosine, γ-aminobutyric acid, ornithine, and citrulline.

[0147] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, γ-aminobutyric acid, monosodium glutamate, and leucine.

[0148] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of arginine, citrulline, lysine, glutamic acid, leucine, choline, choline chloride, and carnitine.

[0149] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is an amino acid or its salt.

[0150] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is arginine, lysine, citrulline, leucine, or monosodium glutamate; arginine is preferred.

[0151] In one technical solution disclosed herein, the coordinating molecule is a C containing a hydrophilic group. 6- C 10 Aromatic rings or 5-10 membered heteroaromatic rings.

[0152] In one technical solution disclosed herein, the coordination molecule does not contain a ribose structure.

[0153] In one technical solution disclosed herein, the coordinating molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0154] In one technical solution disclosed herein, the synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide; preferably selected from at least one of nicotinamide, trigonelline, and salicylamide; and most preferably nicotinamide.

[0155] In one technical solution of this disclosure, the pharmaceutically usable polypeptide or protein is a polypeptide or protein targeting GLP-1 receptor, a polypeptide or protein targeting GIP receptor, a polypeptide or protein targeting both GIP and GLP-1 receptors, a polypeptide or protein targeting parathyroid hormone (PTH) receptor, or a polypeptide or protein targeting somatostatin receptor (SSTR).

[0156] In one technical solution disclosed herein, the polypeptide or protein targeting the GLP-1 receptor is a GLP-1 analog.

[0157] In one technical solution disclosed herein, the polypeptide or protein targeting the GLP-1 receptor is a GLP-1 receptor agonist.

[0158] In one technical solution disclosed herein, the polypeptide or protein targeting GIP and GLP-1 receptors is a dual receptor agonist of GIP and GLP-1.

[0159] In one technical solution disclosed herein, the polypeptide or protein targeting the parathyroid hormone (PTH) receptor is targeting parathyroid hormone receptor 1 (PTHR1).

[0160] In one technical solution disclosed herein, the polypeptide or protein targeting the parathyroid hormone (PTH) receptor is a parathyroid hormone analog.

[0161] In one technical solution disclosed herein, the polypeptide or protein targeting the parathyroid hormone (PTH) receptor is a parathyroid hormone receptor agonist.

[0162] In one technical solution disclosed herein, the polypeptide or protein targeting the parathyroid hormone (PTH) receptor is targeting parathyroid hormone receptor 1 (PTHR1).

[0163] In one technical solution disclosed herein, the polypeptide or protein targeting the parathyroid hormone (PTH) receptor is a parathyroid hormone analog.

[0164] In one technical solution disclosed herein, the polypeptide or protein targeting the parathyroid hormone (PTH) receptor is a parathyroid hormone receptor agonist.

[0165] In one technical solution disclosed herein, the polypeptide or protein targeting the somatostatin receptor (SSTR) is a somatostatin analogue.

[0166] In one technical solution disclosed herein, the polypeptide or protein targeting the somatostatin receptor (SSTR) is a somatostatin receptor agonist.

[0167] In one technical solution disclosed herein, the polypeptide or protein targeting the GLP-1 receptor is smegglutinin or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.

[0168] In one technical solution disclosed herein, the polypeptide or protein targeting GIP and GLP-1 receptors is telpolide or its pharmaceutically acceptable salt, ester, amide, or prodrug.

[0169] In one technical solution disclosed herein, the polypeptide or protein of the parathyroid hormone (PTH) receptor is teriparatide.

[0170] In one technical solution disclosed herein, the polypeptide or protein targeting the somatostatin receptor (SSTR) is octreotide.

[0171] In one technical solution of this disclosure, the molecular weight of the pharmaceutically usable polypeptide or protein is approximately 1000-50000 Da, for example 1000 Da, 2000 Da, 3000 Da, 3500 Da, 4000 Da, 4500 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, 10000 Da, 11000 Da, 12000 Da, 13000 Da, 14000 Da, or 15000 Da.

[0172] In one technical solution disclosed herein, the molecular weight of the pharmaceutically usable polypeptide or protein is approximately 2000-20000 Da.

[0173] In one technical solution disclosed herein, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is a sodium salt, potassium salt, or amine salt.

[0174] In one technical solution of this disclosure, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC).

[0175] In one technical solution of this disclosure, the medium-chain fatty acid or its salt is C 6- C 14 Carboxylic acid or C 6- C 14 Carboxylates.

[0176] In one technical solution of this disclosure, the medium-chain fatty acid or its salt is C 8- C 14 Carboxylic acid or C 8- C 14 Carboxylates.

[0177] In one technical solution disclosed herein, the medium-chain fatty acid or its salt is a saturated C 8- C 12 Straight-chain carboxylic acids or their salts.

[0178] In one technical solution disclosed herein, the medium-chain fatty acid is selected from octanoic acid (C8) and decanoic acid (C9). 10 ), n-Undecanoic acid (C 11 ) and n-dodecanoic acid (C 12 ).

[0179] In one technical solution disclosed herein, the medium-chain fatty acid is decanoic acid (C10-C10-C10). 10 ).

[0180] In one technical solution disclosed herein, the medium-chain fatty acid salt is a sodium salt, potassium salt, or ammonium salt.

[0181] In one technical solution disclosed herein, the medium-chain fatty acid salt is a sodium salt.

[0182] In one technical solution disclosed herein, the medium-chain fatty acid salt is sodium decanoate (SD).

[0183] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0184] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0185] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0186] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0187] Sodium decanoate, approximately 50-500 parts by weight; and

[0188] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 50-500 parts by weight.

[0189] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0190] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0191] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0192] The compound containing nitrogen-atom functional groups is approximately 10-200 parts by weight;

[0193] Sodium decanoate, approximately 50-300 parts by weight; and

[0194] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 50-300 parts by weight.

[0195] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0196] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0197] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0198] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0199] Sodium decanoate, approximately 100-500 parts by weight; and

[0200] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight.

[0201] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0202] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0203] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0204] The compound containing nitrogen-atom functional groups is approximately 10-200 parts by weight;

[0205] Sodium decanoate, approximately 100-300 parts by weight; and

[0206] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-300 parts by weight.

[0207] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0208] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0209] The molecular weight is approximately 25-100 parts by weight.

[0210] The compound containing nitrogen-atom functional groups is approximately 25-200 parts by weight;

[0211] Sodium decanoate, approximately 100-300 parts by weight; and

[0212] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-300 parts by weight.

[0213] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0214] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0215] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0216] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0217] Sodium decanoate, approximately 100-500 parts by weight; and

[0218] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0219] The ligand is selected from at least one of nicotinamide, adenine, cytosine, adenosine, trigonelline, and salicylamide.

[0220] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, carnitine, monosodium glutamate, leucine, and L-carnitine.

[0221] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient, the content of which is not higher than about 20% w / w.

[0222] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient, the content of which is not higher than about 15% w / w.

[0223] In one technical solution disclosed herein, the excipient is selected from one or more of fillers, disintegrants, and lubricants.

[0224] 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.

[0225] In one technical solution disclosed herein, the filler is microcrystalline cellulose.

[0226] 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.

[0227] In one technical solution disclosed herein, the lubricant is sodium dodecyl sulfate.

[0228] 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.

[0229] In one technical solution disclosed herein, the disintegrant is sodium carboxymethyl starch.

[0230] In one technical solution of this disclosure, the content of the filler is not higher than about 15.0 w / w; for example, 14.6 w / w, 14.5 w / w, 14.0 w / w, 13.5 w / w, 13.0 w / w, 12.7 w / w, 12.5 w / w, 12.0 w / w, 11.8 w / w, 11.6 w / w, 10.0 w / w, 9.6 w / w, 9.5 w / w, 9.3 w / w, 9.2 w / w, 9.0 w / w, 8.9 w / w, 8.8 w / w, 8.5 w / w, 8.3 w / w, 7.5 w / w, 7.3 w / w, or 7.0 w / w.

[0231] In one technical solution disclosed herein, the content of the lubricant is not higher than about 3.0 w / w; for example, 2.7 w / w, 2.4 w / w, 2.5 w / w, 2.2 w / w, 2.0, 1.9 w / w, 1.7 w / w, 1.6 w / w, 1.4 w / w, 1.3 w / w, 1.2 w / w, 1.1 w / w, or 1.0 w / w.

[0232] In one technical solution of this disclosure, the content of the disintegrant is not higher than about 5.0 w / w; for example, 5.0 w / w, 4.9 w / w, 4.7 w / w, 4.5 w / w, 4.1 w / w, 4.0 w / w, 3.8 w / w, 3.3 w / w, 3.2 w / w, 3.0 w / w, 2.7 w / w, 2.6 w / w, 2.4 w / w, 2.3 w / w, 2.2 w / w, 2.1 w / w, 2.0 w / w, 1.8 w / w, 1.9 w / w, 1.6 w / w, or 1.5 w / w.

[0233] In one technical solution disclosed herein, the excipients include microcrystalline cellulose, sodium dodecyl sulfate, and sodium carboxymethyl starch.

[0234] In one embodiment of this disclosure, the excipient comprises microcrystalline cellulose at a concentration of not less than about 5.0% w / w and not more than about 15.0 w / w.

[0235] 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.

[0236] 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.

[0237] In one embodiment of this disclosure, the excipients comprise about 5.0-10.0% 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.

[0238] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0239] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0240] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0241] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0242] Sodium decanoate, approximately 100-500 parts by weight; and

[0243] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0244] Excipients: approximately 12-150 parts by weight;

[0245] The liganding molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0246] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, monosodium glutamate, leucine, and γ-aminobutyric acid.

[0247] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0248] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0249] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0250] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0251] Sodium decanoate, approximately 100-500 parts by weight; and

[0252] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0253] Excipients: approximately 12-150 parts by weight;

[0254] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0255] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0256] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0257] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0258] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0259] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0260] Sodium decanoate, approximately 100-500 parts by weight; and

[0261] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0262] The filler is approximately 10-80 parts by weight;

[0263] Lubricant approximately 1-15 parts by weight; and

[0264] The disintegrant is approximately 1-30 parts by weight;

[0265] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0266] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0267] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0268] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0269] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0270] Approximately 10-500 parts by weight of amino acids;

[0271] Sodium decanoate, approximately 100-500 parts by weight; and

[0272] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0273] The filler is approximately 10-80 parts by weight;

[0274] Lubricant approximately 1-15 parts by weight; and

[0275] The disintegrant is approximately 1-30 parts by weight;

[0276] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0277] The amino acid is selected from at least one of arginine, citrulline, and lysine.

[0278] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0279] Approximately 1-50 parts by weight of medicinal polypeptides or proteins;

[0280] Approximately 10-200 parts by weight of nicotinamide;

[0281] Arginine: approximately 10-500 parts by weight;

[0282] Sodium decanoate, approximately 100-500 parts by weight; and

[0283] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0284] The filler is approximately 10-80 parts by weight;

[0285] Lubricant approximately 1-15 parts by weight; and

[0286] The disintegrant is approximately 1-30 parts by weight.

[0287] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0288] Approximately 20-30 parts by weight of medicinal polypeptides or proteins;

[0289] Approximately 30-70 parts by weight of nicotinamide;

[0290] Arginine: approximately 30-70 parts by weight;

[0291] Sodium decanoate, approximately 130-180 parts by weight; and

[0292] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 130-180 parts by weight;

[0293] The filler is approximately 10-80 parts by weight;

[0294] Lubricant approximately 1-15 parts by weight; and

[0295] The disintegrant is approximately 1-30 parts by weight.

[0296] In one technical solution disclosed herein, the oral pharmaceutical composition is in solid dosage form.

[0297] In one technical solution of this disclosure, the oral pharmaceutical composition is a tablet, capsule, granule, powder, powder, drop pill, or pill.

[0298] In one technical solution of this disclosure, the oral pharmaceutical composition is a tablet.

[0299] In one technical solution of this disclosure, the tablets are in the form of 1-50 mg, for example, 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 or 10 mg.

[0300] In one embodiment of this disclosure, the tablets are approximately 1-40 mg in size.

[0301] In one embodiment of this disclosure, the tablets are approximately 1-30 mg in size.

[0302] In one embodiment of this disclosure, the tablets are approximately 5-10 mg in size.

[0303] In one technical solution of this disclosure, the tablet weight is approximately 100-1000 mg, preferably 100-600 mg, such as 100 mg, 150 mg, 180 mg, 200 mg, 230 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 460 mg, 480 mg, 500 mg, 560 mg, 580 mg, 600 mg, 620 mg, 660 mg, 680 mg, 700 mg, 800 mg, 900 mg, and 1000 mg.

[0304] In another aspect, this disclosure relates to a method for preparing the above-described oral pharmaceutical composition, the method comprising the step of mixing the materials.

[0305] In one technical solution disclosed herein, the method further includes a tableting step.

[0306] In one technical solution disclosed herein, the tableting can be optionally performed by wet granulation tableting, dry granulation tableting, or direct powder tableting.

[0307] In another aspect, this disclosure relates to an oral pharmaceutical composition comprising a polypeptide or protein targeting a GLP-1 receptor, wherein the pharmaceutical composition comprises: a polypeptide or protein targeting a GLP-1 receptor, a coordinating molecule, a compound containing a nitrogen-containing functional group, a medium-chain fatty acid or a salt thereof, and N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof; wherein the coordinating molecule is a C-chain compound containing a hydrophilic group. 6- C 10Aromatic rings or 5-10 membered heteroaromatic rings; the nitrogen-containing functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of -S(O)2OH and -OH groups.

[0308] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 0.5% w / w of a polypeptide or protein targeting the GLP-1 receptor.

[0309] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 0.5% w / w and not more than about 5.0% w / w.

[0310] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w of medium-chain fatty acids or their salts.

[0311] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 25% w / w of medium-chain fatty acids or their salts.

[0312] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30% w / w of medium-chain fatty acids or their salts.

[0313] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0314] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 45% w / w of medium-chain fatty acids or their salts.

[0315] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 40% w / w of medium-chain fatty acids or their salts.

[0316] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0317] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30.0% w / w and not more than about 40% w / w of medium-chain fatty acids or their salts.

[0318] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0319] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 25% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0320] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0321] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 50.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0322] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 45% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0323] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 40% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0324] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50% w / w N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0325] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30.0% w / w and not more than about 40% w / w N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0326] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 5.0% w / w of a compound containing a nitrogen-atom functional group.

[0327] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 7.0% w / w of a compound containing a nitrogen-atom functional group.

[0328] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 8.0% w / w of a compound containing a nitrogen-containing functional group.

[0329] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 9.0% w / w of a compound containing a nitrogen-containing functional group.

[0330] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 10.0% w / w of a compound containing a nitrogen-containing functional group.

[0331] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-atom functional group at a concentration of no more than about 30.0 w / w. In another embodiment of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-atom functional group at a concentration of no more than about 25% w / w.

[0332] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 20% w / w of a compound containing a nitrogen-containing functional group.

[0333] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 18.0% of a compound containing a nitrogen-atom functional group. In another embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 16.0% of a compound containing a nitrogen-atom functional group.

[0334] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 15.0% of a compound containing a nitrogen-containing functional group.

[0335] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 5.0% w / w and not more than about 30.0 w / w.

[0336] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 10.0% w / w and not more than about 15.0 w / w.

[0337] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 5.0% w / w.

[0338] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 7.0% w / w.

[0339] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 8.0% w / w.

[0340] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 9.0% w / w.

[0341] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 10.0% w / w.

[0342] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule at a concentration of no more than about 20.0 w / w.

[0343] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 18.0% of a coordinating molecule.

[0344] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 16.0% of a coordinating molecule.

[0345] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 15.0% of a coordinating molecule.

[0346] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule comprising not less than about 5.0% w / w and not more than about 20.0 w / w.

[0347] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule comprising not less than about 10.0% w / w and not more than about 15.0% w / w.

[0348] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 1-50 parts by weight of a polypeptide or protein targeting the GLP-1 receptor.

[0349] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 1-20 parts by weight of a polypeptide or protein targeting the GLP-1 receptor.

[0350] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 10-200 parts by weight of a complexing molecule.

[0351] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 10-100 parts by weight of a complexing molecule.

[0352] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-500 parts by weight of a compound containing a nitrogen-atom functional group.

[0353] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-100 parts by weight of a compound containing a nitrogen-atom functional group.

[0354] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-500 parts by weight of a medium-chain fatty acid or a salt thereof.

[0355] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-300 parts by weight of medium-chain fatty acids or their salts.

[0356] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-500 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0357] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-300 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0358] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 1-50 mg of a polypeptide or protein targeting the GLP-1 receptor.

[0359] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 1-20 mg of a polypeptide or protein targeting the GLP-1 receptor.

[0360] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 10-200 mg of a complexing molecule.

[0361] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 10-100 mg of a complexing molecule.

[0362] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 30-70 mg of a complexing molecule.

[0363] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-500 mg of a compound containing a nitrogen-containing functional group.

[0364] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-100 mg of a compound containing a nitrogen-containing functional group.

[0365] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 30-70 mg of a compound containing a nitrogen-containing functional group.

[0366] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-500 mg of medium-chain fatty acids or their salts.

[0367] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-300 mg of medium-chain fatty acids or their salts.

[0368] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 130-180 mg of medium-chain fatty acids or their salts.

[0369] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 100-500 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0370] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 100-300 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0371] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 130-180 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0372] In one embodiment of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group in the pharmaceutical composition is approximately 1:(0.8-1.2).

[0373] In one embodiment of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group in the pharmaceutical composition is approximately 1:1.

[0374] In one embodiment of this disclosure, the oral pharmaceutical composition comprises, by mass percentage, the polypeptide or protein targeting the GLP-1 receptor, the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt, approximately (1-10):(10-100):(10-100):(100-500):(100-500).

[0375] In one embodiment of this disclosure, the oral pharmaceutical composition comprises an oral polypeptide or protein targeting the GLP-1 receptor, a coordinating molecule, a compound containing a nitrogen-containing functional group, a medium-chain fatty acid or its salt, and N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt in a mass percentage ratio of approximately (1-10):(10-100):(10-100):(100-300):(100-300); more preferably (4-10):(30-80):(30-80):(100-200):(100-200); for example, 7:50:50:150:150.

[0376] In one technical solution of this disclosure, the compound containing a nitrogen-atom functional group contains an amino group and -C(O)OH, an amino group and -C(O)OH; or contains an amino group and -S(O)2OH, an amino group and -S(O)2OH; or contains a quaternary ammonium group and -C(O)O -It may contain quaternary ammonium groups and -OH; or it may contain quaternary ammonium groups and -C(O)O. - and -OH.

[0377] In one technical solution disclosed herein, the molecular weight of the compound containing nitrogen-atom functional groups ranges from 50 to 250 g / mol, wherein the molecular weight of the compound containing nitrogen-atom functional groups is in free form.

[0378] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is C. 1-8 Compounds containing amino, amine, or quaternary ammonium functional groups.

[0379] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of amino acids, L-carnitine, taurine, betaine, choline, choline chloride, and carnitine. The amino acids are selected from natural amino acids or synthetic amino acids.

[0380] In one technical solution disclosed herein, the amino acid is selected from at least one of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, asparagine, glutamine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, sarcosine, γ-aminobutyric acid, ornithine, and citrulline.

[0381] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, and γ-aminobutyric acid.

[0382] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0383] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is an amino acid.

[0384] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is arginine, lysine, or citrulline; arginine is preferred.

[0385] In one technical solution disclosed herein, the coordinating molecule is a C containing a hydrophilic group. 6- C 10 Aromatic rings or 5-10 membered heteroaromatic rings.

[0386] In one technical solution disclosed herein, the coordination molecule does not contain a ribose structure.

[0387] In one technical solution disclosed herein, the coordinating molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0388] In one technical solution disclosed herein, the coordinating molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide; preferably nicotinamide.

[0389] In one technical solution disclosed herein, the polypeptide or protein targeting the GLP-1 receptor is a GLP-1 analog.

[0390] In one technical solution disclosed herein, the polypeptide or protein targeting the GLP-1 receptor is a GLP-1 receptor agonist.

[0391] In one technical solution disclosed herein, the polypeptide or protein targeting the GLP-1 receptor is smegglutinin or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.

[0392] In one technical solution of this disclosure, the molecular weight of the polypeptide or protein targeting the GLP-1 receptor is approximately 1000-50000 Da, such as 1000 Da, 2000 Da, 3000 Da, 3500 Da, 4000 Da, 4500 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, 10000 Da, 11000 Da, 12000 Da, 13000 Da, 14000 Da, or 15000 Da.

[0393] In one technical solution disclosed herein, the molecular weight of the polypeptide or protein targeting the GLP-1 receptor is approximately 2000-20000 Da.

[0394] In one technical solution disclosed herein, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is a sodium salt, potassium salt, or amine salt.

[0395] In one technical solution of this disclosure, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC).

[0396] In one technical solution of this disclosure, the medium-chain fatty acid or its salt is C 6- C 14 Carboxylic acid or C 6- C 14 Carboxylates.

[0397] In one technical solution of this disclosure, the medium-chain fatty acid or its salt is C 8- C 14 Carboxylic acid or C 8-C 14 Carboxylates.

[0398] In one technical solution disclosed herein, the medium-chain fatty acid or its salt is a saturated C 8- C 12 Straight-chain carboxylic acids or their salts.

[0399] In one technical solution disclosed herein, the medium-chain fatty acid is selected from octanoic acid (C8) and decanoic acid (C9). 10 ), n-Undecanoic acid (C 11 ) and n-dodecanoic acid (C 12 ).

[0400] In one technical solution disclosed herein, the medium-chain fatty acid is decanoic acid (C10-C10-C10). 10 ).

[0401] In one technical solution disclosed herein, the medium-chain fatty acid salt is a sodium salt, potassium salt, or ammonium salt.

[0402] In one technical solution disclosed herein, the medium-chain fatty acid salt is a sodium salt.

[0403] In one technical solution disclosed herein, the medium-chain fatty acid salt is sodium decanoate (SD).

[0404] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0405] Approximately 1-50 parts by weight of peptides or proteins targeting the GLP-1 receptor;

[0406] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0407] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0408] Sodium decanoate, approximately 100-500 parts by weight; and

[0409] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0410] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0411] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0412] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient, the content of which is not higher than about 20% w / w.

[0413] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient, the content of which is not higher than about 15% w / w.

[0414] In one technical solution disclosed herein, the excipient is selected from one or more of fillers, disintegrants, and lubricants.

[0415] 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.

[0416] In one technical solution disclosed herein, the filler is microcrystalline cellulose.

[0417] 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.

[0418] In one technical solution disclosed herein, the lubricant is sodium dodecyl sulfate.

[0419] 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.

[0420] In one technical solution disclosed herein, the disintegrant is sodium carboxymethyl starch.

[0421] In one technical solution of this disclosure, the content of the filler is not higher than about 15.0 w / w; for example, 14.6 w / w, 14.5 w / w, 14.0 w / w, 13.5 w / w, 13.0 w / w, 12.7 w / w, 12.5 w / w, 12.0 w / w, 11.8 w / w, 11.6 w / w, 10.0 w / w, 9.6 w / w, 9.5 w / w, 9.3 w / w, 9.2 w / w, 9.0 w / w, 8.9 w / w, 8.8 w / w, 8.5 w / w, 8.3 w / w, 7.5 w / w, 7.3 w / w, or 7.0 w / w.

[0422] In one technical solution disclosed herein, the content of the lubricant is not higher than about 3.0 w / w; for example, 2.7 w / w, 2.4 w / w, 2.5 w / w, 2.2 w / w, 2.0, 1.9 w / w, 1.7 w / w, 1.6 w / w, 1.4 w / w, 1.3 w / w, 1.2 w / w, 1.1 w / w, or 1.0 w / w.

[0423] In one technical solution of this disclosure, the content of the disintegrant is not higher than about 5.0 w / w; for example, 5.0 w / w, 4.9 w / w, 4.7 w / w, 4.5 w / w, 4.1 w / w, 4.0 w / w, 3.8 w / w, 3.3 w / w, 3.2 w / w, 3.0 w / w, 2.7 w / w, 2.6 w / w, 2.4 w / w, 2.3 w / w, 2.2 w / w, 2.1 w / w, 2.0 w / w, 1.8 w / w, 1.9 w / w, 1.6 w / w, or 1.5 w / w.

[0424] In one technical solution disclosed herein, the excipients include microcrystalline cellulose, sodium dodecyl sulfate, and sodium carboxymethyl starch.

[0425] In one embodiment of this disclosure, the excipient comprises microcrystalline cellulose at a concentration of not less than about 5.0% w / w and not more than about 15.0 w / w.

[0426] 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.

[0427] 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.

[0428] In one embodiment of this disclosure, the excipients comprise about 5.0-10.0% 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.

[0429] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0430] Approximately 1-50 parts by weight of peptides or proteins targeting the GLP-1 receptor;

[0431] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0432] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0433] Sodium decanoate, approximately 100-500 parts by weight; and

[0434] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0435] Excipients: approximately 12-150 parts by weight;

[0436] The liganding molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0437] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, and γ-aminobutyric acid.

[0438] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0439] Approximately 1-50 parts by weight of peptides or proteins targeting the GLP-1 receptor;

[0440] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0441] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0442] Sodium decanoate, approximately 100-500 parts by weight; and

[0443] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0444] Excipients: approximately 12-150 parts by weight;

[0445] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0446] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0447] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0448] Approximately 1-50 parts by weight of peptides or proteins targeting the GLP-1 receptor;

[0449] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0450] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0451] Sodium decanoate, approximately 100-500 parts by weight; and

[0452] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0453] The filler is approximately 10-80 parts by weight;

[0454] Lubricant approximately 1-15 parts by weight; and

[0455] The disintegrant is approximately 1-30 parts by weight;

[0456] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0457] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0458] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0459] Approximately 1-50 parts by weight of peptides or proteins targeting the GLP-1 receptor;

[0460] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0461] Approximately 10-500 parts by weight of amino acids;

[0462] Sodium decanoate, approximately 100-500 parts by weight; and

[0463] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0464] The filler is approximately 10-80 parts by weight;

[0465] Lubricant approximately 1-15 parts by weight; and

[0466] The disintegrant is approximately 1-30 parts by weight;

[0467] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0468] The amino acid is selected from at least one of arginine, citrulline, and lysine.

[0469] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0470] Approximately 1-50 parts by weight of peptides or proteins targeting the GLP-1 receptor;

[0471] Approximately 10-200 parts by weight of nicotinamide;

[0472] Arginine: approximately 10-500 parts by weight;

[0473] Sodium decanoate, approximately 100-500 parts by weight; and

[0474] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0475] The filler is approximately 10-80 parts by weight;

[0476] Lubricant approximately 1-15 parts by weight; and

[0477] The disintegrant is approximately 1-30 parts by weight.

[0478] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0479] Approximately 20-30 parts by weight of peptides or proteins targeting the GLP-1 receptor;

[0480] Approximately 30-70 parts by weight of nicotinamide;

[0481] Arginine: approximately 30-70 parts by weight;

[0482] Sodium decanoate, approximately 130-180 parts by weight; and

[0483] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 130-180 parts by weight;

[0484] The filler is approximately 10-80 parts by weight;

[0485] Lubricant approximately 1-15 parts by weight; and

[0486] The disintegrant is approximately 1-30 parts by weight.

[0487] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0488] Smegglutide 7±10% mg;

[0489] Nicotinamide 50±10% mg;

[0490] Arginine 50±10% mg;

[0491] Sodium decanoate 150±10% mg; and

[0492] N-(8-[2-hydroxybenzoyl]amino)octanoic acid sodium salt (SNAC) 150±10% mg; and

[0493] Excipients 53±10% mg.

[0494] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0495] Smegglutide 7mg;

[0496] Nicotinamide 50mg;

[0497] Arginine 50mg;

[0498] Sodium decanoate 150mg; and

[0499] N-(8-[2-hydroxybenzoyl]amino)octanoic acid sodium salt (SNAC) 150 mg; and

[0500] Excipient 53mg.

[0501] In one technical solution disclosed herein, the oral pharmaceutical composition is in solid dosage form.

[0502] In one technical solution of this disclosure, the oral pharmaceutical composition is a tablet, capsule, granule, powder, powder, drop pill, or pill.

[0503] In one technical solution of this disclosure, the oral pharmaceutical composition is a tablet.

[0504] In one technical solution of this disclosure, the tablets are in the form of 1-50 mg, for example, 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 or 10 mg.

[0505] In one embodiment of this disclosure, the tablets are approximately 1-40 mg in size.

[0506] In one embodiment of this disclosure, the tablets are approximately 1-30 mg in size.

[0507] In one embodiment of this disclosure, the tablets are approximately 5-10 mg in size.

[0508] In one technical solution disclosed herein, the oral pharmaceutical composition is a single-ingredient preparation or a compound preparation.

[0509] In one technical solution of this disclosure, the compound preparation contains at least two active ingredients, wherein the active ingredients include a polypeptide or protein targeting the GLP-1 receptor, and the active ingredients further include at least one selected from sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, insulin, statins, ACE inhibitors or ARBs, antidiabetic small molecule drugs (e.g., metformin, sulfonylureas), and GLP-1 receptor / GIP receptor dual agonists (e.g., Tirzepatide).

[0510] In another aspect, this disclosure relates to the use of oral pharmaceutical compositions containing peptides or proteins that target the GLP-1 receptor for (i) treating diseases related to the GLP-1 receptor; and / or (ii) preparing medicaments for diseases related to GLP-1 receptor agonism.

[0511] The pharmaceutical composition comprises: a polypeptide or protein targeting the GLP-1 receptor, a complexing molecule, a compound containing a nitrogen-containing functional group, a medium-chain fatty acid or a salt thereof, and N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof; wherein the complexing molecule is a C-chain compound containing a hydrophilic group. 6- C 10 Aromatic rings or 5-10 membered heteroaromatic rings; the nitrogen-containing functional group contains an amino group or a quaternary ammonium group, and contains a compound selected from -C(O)OH, -C(O)O - At least one of -S(O)2OH and -OH groups.

[0512] In one technical solution disclosed herein, the GLP-1 receptor-related diseases are selected from at least one of type 2 diabetes, obesity, cardiovascular disease, non-alcoholic fatty liver disease, neurodegenerative diseases, cancer, chronic kidney disease, and musculoskeletal inflammation.

[0513] In another aspect, this disclosure relates to an oral pharmaceutical composition comprising a polypeptide targeting both GIP and GLP-1 receptors, wherein the pharmaceutical composition comprises: a polypeptide targeting both GIP and GLP-1 receptors, a coordinating molecule, a compound containing a nitrogen-containing functional group, a medium-chain fatty acid or a salt thereof, and N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof; wherein the polypeptide targeting both GIP and GLP-1 receptors is a polypeptide, and the coordinating molecule is a C-chain compound containing a hydrophilic group. 6- C 10 Aromatic rings or 5-10 membered heteroaromatic rings; the nitrogen-containing functional group contains an amino group or a quaternary ammonium group, and contains a compound selected from -C(O)OH, -C(O)O - At least one of -S(O)2OH and -OH groups.

[0514] In one technical solution disclosed herein, the coordinating molecule is: Where ring A is C 6- C 10 Aromatic ring or 5-10 membered heteroaryl ring, the ring being divided by one or more R 1 and one or more R 2 Replace, each R 1 Each R is an independent hydrophilic group. 2 Independently hydrogen, methyl, ethyl, halogen, or oxo (=O). Preferably, each R 1Each R is independently a hydroxyl, carboxyl, amino, sulfonic acid, phosphate, amide, ribose, or carboxylate group. 2 It can be hydrogen, methyl, ethyl, halogen, or oxo (=O) independently.

[0515] In one technical solution of this disclosure, ring A is a benzene ring or a 5-10 membered heteroaromatic ring, wherein the 5-10 membered heteroaromatic ring contains at least one N (e.g., 2, 3, or 4) ring atom, and the N may optionally be N2. + Ions; preferably, ring A is a benzene ring, naphthalene ring, pyrrole, imidazole, oxazole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, indole, purine, or pteridine.

[0516] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 0.5% w / w of a polypeptide targeting both GIP and GLP-1 receptors.

[0517] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a polypeptide targeting both GIP and GLP-1 receptors at a concentration of not less than about 0.5% w / w and not more than about 5.0% w / w.

[0518] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w of medium-chain fatty acids or their salts.

[0519] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 25% w / w of medium-chain fatty acids or their salts.

[0520] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30% w / w of medium-chain fatty acids or their salts.

[0521] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0522] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 45% w / w of medium-chain fatty acids or their salts.

[0523] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 40% w / w of medium-chain fatty acids or their salts.

[0524] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0525] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30.0% w / w and not more than about 40% w / w of medium-chain fatty acids or their salts.

[0526] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0527] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 25% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0528] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0529] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 50.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0530] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 45% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0531] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 40% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0532] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50% w / w N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0533] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30.0% w / w and not more than about 40% w / w N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0534] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 5.0% w / w of a compound containing a nitrogen-atom functional group.

[0535] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 7.0% w / w of a compound containing a nitrogen-atom functional group.

[0536] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 8.0% w / w of a compound containing a nitrogen-containing functional group.

[0537] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 9.0% w / w of a compound containing a nitrogen-containing functional group.

[0538] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 10.0% w / w of a compound containing a nitrogen-containing functional group.

[0539] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-atom functional group at a concentration of no more than about 30.0 w / w. In another embodiment of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-atom functional group at a concentration of no more than about 25% w / w.

[0540] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 20% w / w of a compound containing a nitrogen-containing functional group.

[0541] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 18.0% of a compound containing a nitrogen-containing functional group.

[0542] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 16.0% of a compound containing a nitrogen-containing functional group.

[0543] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 15.0% of a compound containing a nitrogen-containing functional group.

[0544] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 5.0% w / w and not more than about 30.0 w / w.

[0545] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 10.0% w / w and not more than about 15.0 w / w.

[0546] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 5.0% w / w.

[0547] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 7.0% w / w.

[0548] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 8.0% w / w.

[0549] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 9.0% w / w.

[0550] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 10.0% w / w.

[0551] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule at a concentration of no more than about 20.0 w / w.

[0552] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 18.0% of a coordinating molecule.

[0553] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 16.0% of a coordinating molecule.

[0554] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 15.0% of a coordinating molecule.

[0555] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule comprising not less than about 5.0% w / w and not more than about 20.0 w / w.

[0556] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule comprising not less than about 10.0% w / w and not more than about 15.0% w / w.

[0557] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 1-50 parts by weight of a polypeptide targeting both GIP and GLP-1 receptors.

[0558] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 1-20 parts by weight of a polypeptide targeting both GIP and GLP-1 receptors.

[0559] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 10-200 parts by weight of a complexing molecule.

[0560] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 10-100 parts by weight of a complexing molecule.

[0561] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-500 parts by weight of a compound containing a nitrogen-atom functional group.

[0562] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-100 parts by weight of a compound containing a nitrogen-atom functional group.

[0563] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-500 parts by weight of a medium-chain fatty acid or a salt thereof.

[0564] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-300 parts by weight of medium-chain fatty acids or their salts.

[0565] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-500 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0566] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-300 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0567] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 1-50 mg of a polypeptide targeting both GIP and GLP-1 receptors.

[0568] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 1-20 mg of a polypeptide targeting both GIP and GLP-1 receptors.

[0569] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 10-200 mg of a complexing molecule.

[0570] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 10-100 mg of a complexing molecule.

[0571] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 30-70 mg of a complexing molecule.

[0572] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-500 mg of a compound containing a nitrogen-containing functional group.

[0573] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-100 mg of a compound containing a nitrogen-containing functional group.

[0574] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 30-70 mg of a compound containing a nitrogen-containing functional group.

[0575] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-500 mg of medium-chain fatty acids or their salts.

[0576] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-300 mg of medium-chain fatty acids or their salts.

[0577] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 130-180 mg of medium-chain fatty acids or their salts.

[0578] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 100-500 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0579] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 100-300 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0580] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 130-180 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0581] In one embodiment of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group in the pharmaceutical composition is approximately 1:(0.8-1.2).

[0582] In one embodiment of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group in the pharmaceutical composition is approximately 1:1.

[0583] In one embodiment of this disclosure, the oral pharmaceutical composition comprises, in which the mass percentages of the polypeptide targeting GIP and GLP-1 dual receptors, the ligand, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt are approximately (1-10):(10-100):(10-100):(100-500):(100-500).

[0584] In one embodiment of this disclosure, the oral pharmaceutical composition comprises, in which the mass percentages of the polypeptide targeting the GIP and GLP-1 dual receptors, the ligand, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt are approximately (1-10):(10-100):(10-100):(100-300):(100-300); more preferably (4-10):(30-80):(30-80):(100-200):(100-200); for example, 7:50:50:150:150.

[0585] In one technical solution of this disclosure, the compound containing a nitrogen-atom functional group contains an amino group and -C(O)OH, an amino group and -C(O)OH; or contains an amino group and -S(O)2OH, an amino group and -S(O)2OH; or contains a quaternary ammonium group and -C(O)O - It may contain quaternary ammonium groups and -OH; or it may contain quaternary ammonium groups and -C(O)O. - and -OH.

[0586] In one technical solution disclosed herein, the molecular weight of the compound containing nitrogen-atom functional groups ranges from 50 to 250 g / mol, wherein the molecular weight of the compound containing nitrogen-atom functional groups is in free form.

[0587] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is C. 1-8 Compounds containing nitrogen-containing functional groups.

[0588] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of amino acids, L-carnitine, taurine, betaine, choline, choline chloride, and carnitine. The amino acids are selected from natural amino acids or synthetic amino acids.

[0589] In one technical solution disclosed herein, the amino acid is selected from at least one of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, asparagine, glutamine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, sarcosine, γ-aminobutyric acid, ornithine, and citrulline.

[0590] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, and γ-aminobutyric acid.

[0591] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0592] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is an amino acid.

[0593] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is arginine, lysine, or citrulline; arginine is preferred.

[0594] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is not arginine.

[0595] In one technical solution disclosed herein, the coordinating molecule is a C containing a hydrophilic group. 6- C 10 Aromatic rings or 5-10 membered heteroaromatic rings.

[0596] In one technical solution disclosed herein, the coordination molecule does not contain a ribose structure.

[0597] In one technical solution disclosed herein, the coordinating molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0598] In one technical solution disclosed herein, the coordinating molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide; preferably nicotinamide.

[0599] In one technical solution disclosed herein, the coordinating molecule is not nicotinamide.

[0600] In one technical solution disclosed herein, the polypeptide targeting GIP and GLP-1 receptors is a dual receptor agonist of GIP and GLP-1.

[0601] In one technical solution disclosed herein, the polypeptide targeting both GIP and GLP-1 receptors is telpolide or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.

[0602] In one technical solution disclosed herein, the polypeptide targeting both GIP and GLP-1 receptors is not a compound of formula (I):

[0603] In formula (I) above, the C-terminal carboxyl group of Ser is modified by the Fa group:

[0604] In one technical solution of this disclosure, the molecular weight of the polypeptide targeting the dual receptors GIP and GLP-1 is approximately 1000-50000 Da, such as 1000 Da, 2000 Da, 3000 Da, 3500 Da, 4000 Da, 4500 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, 10000 Da, 11000 Da, 12000 Da, 13000 Da, 14000 Da, or 15000 Da.

[0605] In one technical solution disclosed herein, the molecular weight of the polypeptide targeting both GIP and GLP-1 receptors is approximately 2000-20000 Da.

[0606] In one technical solution disclosed herein, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is a sodium salt, potassium salt, or amine salt.

[0607] In one technical solution of this disclosure, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC).

[0608] In one technical solution of this disclosure, the medium-chain fatty acid or its salt is C 6- C 14 Carboxylic acid or C 6- C 14 Carboxylates.

[0609] In one technical solution of this disclosure, the medium-chain fatty acid or its salt is C 8- C 14 Carboxylic acid or C 8- C 14 Carboxylates.

[0610] In one technical solution disclosed herein, the medium-chain fatty acid or its salt is a saturated C 8- C 12 Straight-chain carboxylic acids or their salts.

[0611] In one technical solution disclosed herein, the medium-chain fatty acid is selected from octanoic acid (C8) and decanoic acid (C9). 10 ), n-Undecanoic acid (C 11 ) and n-dodecanoic acid (C 12 ).

[0612] In one technical solution disclosed herein, the medium-chain fatty acid is decanoic acid (C10-C10-C10). 10 ).

[0613] In one technical solution disclosed herein, the medium-chain fatty acid salt is a sodium salt, potassium salt, or ammonium salt.

[0614] In one technical solution disclosed herein, the medium-chain fatty acid salt is a sodium salt.

[0615] In one technical solution disclosed herein, the medium-chain fatty acid salt is sodium decanoate (SD).

[0616] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0617] Approximately 1-50 parts by weight of the peptide targeting both GIP and GLP-1 receptors;

[0618] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0619] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0620] Sodium decanoate, approximately 100-500 parts by weight; and

[0621] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0622] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0623] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0624] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient, the content of which is not higher than about 20% w / w.

[0625] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient, the content of which is not higher than about 15% w / w.

[0626] In one technical solution disclosed herein, the excipient is selected from one or more of fillers, disintegrants, and lubricants.

[0627] 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.

[0628] In one technical solution disclosed herein, the filler is microcrystalline cellulose.

[0629] 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.

[0630] In one technical solution disclosed herein, the lubricant is sodium dodecyl sulfate.

[0631] 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.

[0632] In one technical solution disclosed herein, the disintegrant is sodium carboxymethyl starch.

[0633] In one technical solution of this disclosure, the content of the filler is not higher than about 15.0 w / w; for example, 14.6 w / w, 14.5 w / w, 14.0 w / w, 13.5 w / w, 13.0 w / w, 12.7 w / w, 12.5 w / w, 12.0 w / w, 11.8 w / w, 11.6 w / w, 10.0 w / w, 9.6 w / w, 9.5 w / w, 9.3 w / w, 9.2 w / w, 9.0 w / w, 8.9 w / w, 8.8 w / w, 8.5 w / w, 8.3 w / w, 7.5 w / w, 7.3 w / w, or 7.0 w / w.

[0634] In one technical solution disclosed herein, the content of the lubricant is not higher than about 3.0 w / w; for example, 2.7 w / w, 2.4 w / w, 2.5 w / w, 2.2 w / w, 2.0, 1.9 w / w, 1.7 w / w, 1.6 w / w, 1.4 w / w, 1.3 w / w, 1.2 w / w, 1.1 w / w, or 1.0 w / w.

[0635] In one technical solution of this disclosure, the content of the disintegrant is not higher than about 5.0 w / w; for example, 5.0 w / w, 4.9 w / w, 4.7 w / w, 4.5 w / w, 4.1 w / w, 4.0 w / w, 3.8 w / w, 3.3 w / w, 3.2 w / w, 3.0 w / w, 2.7 w / w, 2.6 w / w, 2.4 w / w, 2.3 w / w, 2.2 w / w, 2.1 w / w, 2.0 w / w, 1.8 w / w, 1.9 w / w, 1.6 w / w, or 1.5 w / w.

[0636] In one technical solution disclosed herein, the excipients include microcrystalline cellulose, sodium dodecyl sulfate, and sodium carboxymethyl starch.

[0637] In one embodiment of this disclosure, the excipient comprises microcrystalline cellulose at a concentration of not less than about 5.0% w / w and not more than about 15.0 w / w.

[0638] 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.

[0639] 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.

[0640] In one embodiment of this disclosure, the excipients comprise about 5.0-10.0% 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.

[0641] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0642] Approximately 1-50 parts by weight of the peptide targeting both GIP and GLP-1 receptors;

[0643] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0644] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0645] Sodium decanoate, approximately 100-500 parts by weight; and

[0646] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0647] Excipients: approximately 12-150 parts by weight;

[0648] The liganding molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0649] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, and γ-aminobutyric acid.

[0650] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0651] Approximately 1-50 parts by weight of the peptide targeting both GIP and GLP-1 receptors;

[0652] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0653] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0654] Sodium decanoate, approximately 100-500 parts by weight; and

[0655] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0656] Excipients: approximately 12-150 parts by weight;

[0657] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0658] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0659] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0660] Approximately 1-50 parts by weight of the peptide targeting both GIP and GLP-1 receptors;

[0661] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0662] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0663] Sodium decanoate, approximately 100-500 parts by weight; and

[0664] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0665] The filler is approximately 10-80 parts by weight;

[0666] Lubricant approximately 1-15 parts by weight; and

[0667] The disintegrant is approximately 1-30 parts by weight;

[0668] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0669] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0670] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0671] Approximately 1-50 parts by weight of the peptide targeting both GIP and GLP-1 receptors;

[0672] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0673] Approximately 10-500 parts by weight of amino acids;

[0674] Sodium decanoate, approximately 100-500 parts by weight; and

[0675] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0676] The filler is approximately 10-80 parts by weight;

[0677] Lubricant approximately 1-15 parts by weight; and

[0678] The disintegrant is approximately 1-30 parts by weight;

[0679] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0680] The amino acid is selected from at least one of arginine, citrulline, and lysine.

[0681] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0682] Approximately 1-50 parts by weight of the peptide targeting both GIP and GLP-1 receptors;

[0683] Approximately 10-200 parts by weight of nicotinamide;

[0684] Arginine: approximately 10-500 parts by weight;

[0685] Sodium decanoate, approximately 100-500 parts by weight; and

[0686] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0687] The filler is approximately 10-80 parts by weight;

[0688] Lubricant approximately 1-15 parts by weight; and

[0689] The disintegrant is approximately 1-30 parts by weight.

[0690] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0691] Approximately 20-30 parts by weight of the peptide targeting both GIP and GLP-1 receptors;

[0692] Approximately 30-70 parts by weight of nicotinamide;

[0693] Arginine: approximately 30-70 parts by weight;

[0694] Sodium decanoate, approximately 130-180 parts by weight; and

[0695] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 130-180 parts by weight;

[0696] The filler is approximately 10-80 parts by weight;

[0697] Lubricant approximately 1-15 parts by weight; and

[0698] The disintegrant is approximately 1-30 parts by weight.

[0699] In one technical solution disclosed herein, the oral pharmaceutical composition is in solid dosage form.

[0700] In one technical solution of this disclosure, the oral pharmaceutical composition is a tablet, capsule, granule, powder, powder, drop pill, or pill.

[0701] In one technical solution of this disclosure, the oral pharmaceutical composition is a tablet.

[0702] In one technical solution of this disclosure, the tablets are in the form of 1-50 mg, for example, 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 or 10 mg.

[0703] In one embodiment of this disclosure, the tablets are approximately 1-40 mg in size.

[0704] In one embodiment of this disclosure, the tablets are approximately 1-30 mg in size.

[0705] In one embodiment of this disclosure, the tablets are approximately 5-10 mg in size.

[0706] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0707] telpolide 7±10% mg;

[0708] Nicotinamide 50±10% mg;

[0709] Arginine 50±10% mg;

[0710] Sodium decanoate 150±10% mg; and

[0711] N-(8-[2-hydroxybenzoyl]amino)octanoic acid sodium salt (SNAC) 150±10% mg; and

[0712] Excipients 53±10% mg.

[0713] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0714] telpoeptide 7mg;

[0715] Nicotinamide 50mg;

[0716] Arginine 50mg;

[0717] Sodium decanoate 150mg; and

[0718] N-(8-[2-hydroxybenzoyl]amino)octanoic acid sodium salt (SNAC) 150 mg; and

[0719] Excipient 53mg.

[0720] In one technical solution disclosed herein, the oral pharmaceutical composition is a single-ingredient preparation or a compound preparation.

[0721] In one technical solution of this disclosure, the compound preparation contains at least two active ingredients, wherein the active ingredients include a polypeptide targeting both GIP and GLP-1 receptors, and the active ingredients further include those selected from sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, insulin, statins, ACE inhibitors or ARBs, antidiabetic small molecule drugs (e.g., metformin, sulfonylureas), and GLP-1 receptor agonists (e.g., semaglutide).

[0722] In another aspect, this disclosure relates to the use of an oral pharmaceutical composition comprising a polypeptide targeting both GIP and GLP-1 receptors for (i) treating diseases associated with GLP-1 receptor and / or GIP receptor activating; and / or (ii) preparing a medicament for diseases associated with GLP-1 and / or GIP receptor activating.

[0723] The pharmaceutical composition comprises: a polypeptide targeting both GIP and GLP-1 receptors, a complexing molecule, a compound containing a nitrogen-containing functional group, a medium-chain fatty acid or a salt thereof, and N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof; wherein the complexing molecule is a C-chain compound containing a hydrophilic group. 6- C 10 Aromatic rings or 5-10 membered heteroaromatic rings; the nitrogen-containing functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of the substituent groups selected from -S(O)2OH and -OH.

[0724] In one technical solution of this disclosure, the diseases related to GLP-1 and / or GIP receptor agonism are selected from at least one of type 2 diabetes, obesity, weight loss indications, cardiovascular disease, non-alcoholic fatty liver disease, neurodegenerative diseases, cancer, chronic kidney disease, and musculoskeletal inflammation.

[0725] In another aspect, this disclosure relates to an oral pharmaceutical composition containing a polypeptide targeting a parathyroid hormone (PTH) receptor, wherein the pharmaceutical composition comprises: a polypeptide targeting a parathyroid hormone (PTH) receptor, a coordinating molecule, a compound containing a nitrogen-containing functional group, a medium-chain fatty acid or a salt thereof, and N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof; wherein the coordinating molecule is a C-chain compound containing a hydrophilic group. 6- C 10Aromatic rings or 5-10 membered heteroaromatic rings; the nitrogen-containing functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of the substituent groups selected from -S(O)2OH and -OH.

[0726] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a polypeptide targeting the parathyroid hormone (PTH) receptor at a rate of not less than about 0.5% w / w.

[0727] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a polypeptide targeting the parathyroid hormone (PTH) receptor at a concentration of not less than about 0.5% w / w and not more than about 5.0% w / w.

[0728] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w of medium-chain fatty acids or their salts.

[0729] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 25% w / w of medium-chain fatty acids or their salts.

[0730] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30% w / w of medium-chain fatty acids or their salts.

[0731] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0732] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 45% w / w of medium-chain fatty acids or their salts.

[0733] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 40% w / w of medium-chain fatty acids or their salts.

[0734] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50.0% w / w of medium-chain fatty acids or their salts.

[0735] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30.0% w / w and not more than about 40% w / w of medium-chain fatty acids or their salts.

[0736] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0737] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 25% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0738] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0739] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 50.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0740] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 45% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0741] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 40% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0742] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50% w / w N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0743] In one embodiment of this disclosure, the oral pharmaceutical composition comprises not less than about 30.0% w / w and not more than about 40% w / w N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0744] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 5.0% w / w of a compound containing a nitrogen-atom functional group.

[0745] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 7.0% w / w of a compound containing a nitrogen-atom functional group.

[0746] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 8.0% w / w of a compound containing a nitrogen-containing functional group.

[0747] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 9.0% w / w of a compound containing a nitrogen-containing functional group.

[0748] In one aspect of this disclosure, the oral pharmaceutical composition comprises not less than about 10.0% w / w of a compound containing a nitrogen-containing functional group.

[0749] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a rate not exceeding about 30.0 w / w.

[0750] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 25% w / w of a compound containing a nitrogen-containing functional group.

[0751] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 20% w / w of a compound containing a nitrogen-containing functional group.

[0752] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 18.0% of a compound containing a nitrogen-atom functional group. In another embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 16.0% of a compound containing a nitrogen-atom functional group.

[0753] In one aspect of this disclosure, the oral pharmaceutical composition comprises no more than about 15.0% of a compound containing a nitrogen-containing functional group.

[0754] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 5.0% w / w and not more than about 30.0 w / w.

[0755] In one aspect of this disclosure, the oral pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 10.0% w / w and not more than about 15.0 w / w.

[0756] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 5.0% w / w.

[0757] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 7.0% w / w.

[0758] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 8.0% w / w.

[0759] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 9.0% w / w.

[0760] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule of not less than about 10.0% w / w.

[0761] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule at a concentration of no more than about 20.0 w / w.

[0762] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 18.0% of a coordinating molecule.

[0763] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 16.0% of a coordinating molecule.

[0764] In one embodiment of this disclosure, the oral pharmaceutical composition comprises no more than about 15.0% of a coordinating molecule.

[0765] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule comprising not less than about 5.0% w / w and not more than about 20.0 w / w.

[0766] In one embodiment of this disclosure, the oral pharmaceutical composition comprises a complexing molecule comprising not less than about 10.0% w / w and not more than about 15.0% w / w.

[0767] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 1-50 parts by weight of a polypeptide that targets the parathyroid hormone (PTH) receptor.

[0768] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 1-20 parts by weight of a polypeptide that targets the parathyroid hormone (PTH) receptor.

[0769] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 10-200 parts by weight of a complexing molecule.

[0770] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 10-100 parts by weight of a complexing molecule.

[0771] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-500 parts by weight of a compound containing a nitrogen-atom functional group.

[0772] In one aspect of this disclosure, the oral pharmaceutical composition comprises about 10-100 parts by weight of a compound containing a nitrogen-atom functional group.

[0773] In one embodiment of this disclosure, the oral pharmaceutical composition comprises 100-500 parts by weight of medium-chain fatty acids or their salts.

[0774] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-300 parts by weight of medium-chain fatty acids or their salts.

[0775] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-500 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0776] In one embodiment of this disclosure, the oral pharmaceutical composition comprises about 100-300 parts by weight of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0777] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 1-50 mg of a polypeptide that targets the parathyroid hormone (PTH) receptor.

[0778] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 1-20 mg of a polypeptide that targets the parathyroid hormone (PTH) receptor.

[0779] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 10-200 mg of a complexing molecule.

[0780] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 10-100 mg of a complexing molecule.

[0781] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 30-70 mg of a complexing molecule.

[0782] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-500 mg of a compound containing a nitrogen-containing functional group.

[0783] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 10-100 mg of a compound containing a nitrogen-containing functional group.

[0784] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 30-70 mg of a compound containing a nitrogen-containing functional group.

[0785] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-500 mg of medium-chain fatty acids or their salts.

[0786] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 100-300 mg of medium-chain fatty acids or their salts.

[0787] In one embodiment of this disclosure, the pharmaceutical composition in a unit dosage form comprises about 130-180 mg of medium-chain fatty acids or their salts.

[0788] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 100-500 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0789] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 100-300 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0790] In one embodiment of this disclosure, the pharmaceutical composition in a unit formulation comprises about 130-180 mg of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

[0791] In one embodiment of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group in the pharmaceutical composition is approximately 1:(0.8-1.2).

[0792] In one embodiment of this disclosure, the mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group in the pharmaceutical composition is approximately 1:1.

[0793] In one embodiment of this disclosure, the oral pharmaceutical composition comprises, by mass percentage, the polypeptide targeting the parathyroid hormone (PTH) receptor, the ligand, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt, approximately (1-10):(10-100):(10-100):(100-500):(100-500).

[0794] In one embodiment of this disclosure, the oral pharmaceutical composition comprises, by mass percentage, the polypeptide targeting the parathyroid hormone (PTH) receptor, the coordinating molecule, the compound containing a nitrogen-containing functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or its salt, approximately (1-10):(10-100):(10-100):(100-300):(100-300); more preferably (4-10):(30-80):(30-80):(100-200):(100-200); for example, 7:50:50:150:150.

[0795] In one technical solution of this disclosure, the compound containing a nitrogen-atom functional group contains an amino group and -C(O)OH, an amino group and -C(O)OH; or contains an amino group and -S(O)2OH, an amino group and -S(O)2OH; or contains a quaternary ammonium group and -C(O)O -It may contain quaternary ammonium groups and -OH; or it may contain quaternary ammonium groups and -C(O)O. - and -OH.

[0796] In one technical solution disclosed herein, the molecular weight of the compound containing nitrogen-atom functional groups ranges from 50 to 250 g / mol, wherein the molecular weight of the compound containing nitrogen-atom functional groups is in free form.

[0797] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is C. 1-8 Compounds containing amino, amine, or quaternary ammonium functional groups.

[0798] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of amino acids, L-carnitine, taurine, betaine, choline, choline chloride, and carnitine. The amino acids are selected from natural amino acids or synthetic amino acids.

[0799] In one technical solution disclosed herein, the amino acid is selected from at least one of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, asparagine, glutamine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, sarcosine, γ-aminobutyric acid, ornithine, and citrulline.

[0800] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, and γ-aminobutyric acid.

[0801] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0802] In one technical solution disclosed herein, the compound containing the nitrogen-atom functional group is an amino acid.

[0803] In one technical solution disclosed herein, the compound containing a nitrogen-atom functional group is arginine, lysine, or citrulline; arginine is preferred.

[0804] In one technical solution disclosed herein, the coordinating molecule is a C containing a hydrophilic group. 6- C 10 Aromatic rings or 5-10 membered heteroaromatic rings.

[0805] In one technical solution disclosed herein, the coordination molecule does not contain a ribose structure.

[0806] In one technical solution disclosed herein, the coordinating molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0807] In one technical solution disclosed herein, the coordinating molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide; preferably nicotinamide.

[0808] In one technical solution disclosed herein, the polypeptide or protein targeting the parathyroid hormone (PTH) receptor is targeting parathyroid hormone receptor 1 (PTHR1).

[0809] In one technical solution disclosed herein, the polypeptide or protein targeting the parathyroid hormone (PTH) receptor is a parathyroid hormone analog.

[0810] In one technical solution disclosed herein, the polypeptide or protein targeting the parathyroid hormone (PTH) receptor is a parathyroid hormone receptor agonist.

[0811] In one technical solution disclosed herein, the polypeptide targeting the parathyroid hormone (PTH) receptor is teriparatide or its pharmaceutically acceptable salt, ester, amide, or prodrug.

[0812] In one technical solution of this disclosure, the molecular weight of the polypeptide targeting the parathyroid hormone (PTH) receptor is approximately 1000-50000 Da, such as 1000 Da, 2000 Da, 3000 Da, 3500 Da, 4000 Da, 4500 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, 10000 Da, 11000 Da, 12000 Da, 13000 Da, 14000 Da, or 15000 Da.

[0813] In one technical solution disclosed herein, the molecular weight of the polypeptide targeting the parathyroid hormone (PTH) receptor is approximately 2000-20000 Da.

[0814] In one technical solution disclosed herein, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is a sodium salt, potassium salt, or amine salt.

[0815] In one technical solution of this disclosure, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC).

[0816] In one technical solution of this disclosure, the medium-chain fatty acid or its salt is C 6- C 14 Carboxylic acid or C 6- C14 Carboxylates.

[0817] In one technical solution of this disclosure, the medium-chain fatty acid or its salt is C 8- C 14 Carboxylic acid or C 8- C 14 Carboxylates.

[0818] In one technical solution disclosed herein, the medium-chain fatty acid or its salt is a saturated C 8- C 12 Straight-chain carboxylic acids or their salts.

[0819] In one technical solution disclosed herein, the medium-chain fatty acid is selected from octanoic acid (C8) and decanoic acid (C9). 10 ), n-Undecanoic acid (C 11 ) and n-dodecanoic acid (C 12 ).

[0820] In one technical solution disclosed herein, the medium-chain fatty acid is decanoic acid (C10-C10-C10). 10 ).

[0821] In one technical solution disclosed herein, the medium-chain fatty acid salt is a sodium salt, potassium salt, or ammonium salt.

[0822] In one technical solution disclosed herein, the medium-chain fatty acid salt is a sodium salt.

[0823] In one technical solution disclosed herein, the medium-chain fatty acid salt is sodium decanoate (SD).

[0824] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0825] Approximately 1-50 parts by weight of a polypeptide targeting the parathyroid hormone (PTH) receptor;

[0826] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0827] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0828] Sodium decanoate, approximately 100-500 parts by weight; and

[0829] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0830] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0831] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0832] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient, the content of which is not higher than 20% w / w.

[0833] In one embodiment of this disclosure, the pharmaceutical composition further includes an excipient, the content of which is not higher than 15% w / w.

[0834] In one technical solution disclosed herein, the excipient is selected from one or more of fillers, disintegrants, and lubricants.

[0835] 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.

[0836] In one technical solution disclosed herein, the filler is microcrystalline cellulose.

[0837] 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.

[0838] In one technical solution disclosed herein, the lubricant is sodium dodecyl sulfate.

[0839] 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.

[0840] In one technical solution disclosed herein, the disintegrant is sodium carboxymethyl starch.

[0841] In one technical solution of this disclosure, the content of the filler is not higher than about 15.0 w / w; for example, 14.6 w / w, 14.5 w / w, 14.0 w / w, 13.5 w / w, 13.0 w / w, 12.7 w / w, 12.5 w / w, 12.0 w / w, 11.8 w / w, 11.6 w / w, 10.0 w / w, 9.6 w / w, 9.5 w / w, 9.3 w / w, 9.2 w / w, 9.0 w / w, 8.9 w / w, 8.8 w / w, 8.5 w / w, 8.3 w / w, 7.5 w / w, 7.3 w / w, or 7.0 w / w.

[0842] In one technical solution disclosed herein, the content of the lubricant is not higher than about 3.0 w / w; for example, 2.7 w / w, 2.4 w / w, 2.5 w / w, 2.2 w / w, 2.0, 1.9 w / w, 1.7 w / w, 1.6 w / w, 1.4 w / w, 1.3 w / w, 1.2 w / w, 1.1 w / w, or 1.0 w / w.

[0843] In one technical solution of this disclosure, the content of the disintegrant is not higher than about 5.0 w / w; for example, 5.0 w / w, 4.9 w / w, 4.7 w / w, 4.5 w / w, 4.1 w / w, 4.0 w / w, 3.8 w / w, 3.3 w / w, 3.2 w / w, 3.0 w / w, 2.7 w / w, 2.6 w / w, 2.4 w / w, 2.3 w / w, 2.2 w / w, 2.1 w / w, 2.0 w / w, 1.8 w / w, 1.9 w / w, 1.6 w / w, or 1.5 w / w.

[0844] In one technical solution disclosed herein, the excipients include microcrystalline cellulose, sodium dodecyl sulfate, and sodium carboxymethyl starch.

[0845] In one embodiment of this disclosure, the excipient comprises microcrystalline cellulose at a concentration of not less than about 5.0% w / w and not more than about 15.0 w / w.

[0846] 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.

[0847] 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.

[0848] In one embodiment of this disclosure, the excipients comprise about 5.0-10.0% 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.

[0849] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0850] Approximately 1-50 parts by weight of a polypeptide targeting the parathyroid hormone (PTH) receptor;

[0851] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0852] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0853] Sodium decanoate, approximately 100-500 parts by weight; and

[0854] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0855] Excipients: approximately 12-150 parts by weight;

[0856] The liganding molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide.

[0857] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, and γ-aminobutyric acid.

[0858] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0859] Approximately 1-50 parts by weight of a polypeptide targeting the parathyroid hormone (PTH) receptor;

[0860] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0861] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0862] Sodium decanoate, approximately 100-500 parts by weight; and

[0863] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0864] Excipients: approximately 12-150 parts by weight;

[0865] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0866] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0867] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0868] Approximately 1-50 parts by weight of a polypeptide targeting the parathyroid hormone (PTH) receptor;

[0869] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0870] The amount of compounds containing nitrogen-containing functional groups is approximately 10-500 parts by weight;

[0871] Sodium decanoate, approximately 100-500 parts by weight; and

[0872] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0873] The filler is approximately 10-80 parts by weight;

[0874] Lubricant approximately 1-15 parts by weight; and

[0875] The disintegrant is approximately 1-30 parts by weight;

[0876] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0877] The compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, and carnitine.

[0878] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0879] Approximately 1-50 parts by weight of a polypeptide targeting the parathyroid hormone (PTH) receptor;

[0880] The amount of the compounding molecule is approximately 10-200 parts by weight;

[0881] Approximately 10-500 parts by weight of amino acids;

[0882] Sodium decanoate, approximately 100-500 parts by weight; and

[0883] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0884] The filler is approximately 10-80 parts by weight;

[0885] Lubricant approximately 1-15 parts by weight; and

[0886] The disintegrant is approximately 1-30 parts by weight;

[0887] The synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide;

[0888] The amino acid is selected from at least one of arginine, citrulline, and lysine.

[0889] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0890] Approximately 1-50 parts by weight of a polypeptide targeting the parathyroid hormone (PTH) receptor;

[0891] Approximately 10-200 parts by weight of nicotinamide;

[0892] Arginine: approximately 10-500 parts by weight;

[0893] Sodium decanoate, approximately 100-500 parts by weight; and

[0894] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 100-500 parts by weight;

[0895] The filler is approximately 10-80 parts by weight;

[0896] Lubricant approximately 1-15 parts by weight; and

[0897] The disintegrant is approximately 1-30 parts by weight.

[0898] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0899] Approximately 20-30 parts by weight of a polypeptide targeting the parathyroid hormone (PTH) receptor;

[0900] Approximately 30-70 parts by weight of nicotinamide;

[0901] Arginine: approximately 30-70 parts by weight;

[0902] Sodium decanoate, approximately 130-180 parts by weight; and

[0903] Sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) approximately 130-180 parts by weight;

[0904] The filler is approximately 10-80 parts by weight;

[0905] Lubricant approximately 1-15 parts by weight; and

[0906] The disintegrant is approximately 1-30 parts by weight.

[0907] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0908] Teriparatide 7±10% mg;

[0909] Nicotinamide 50±10% mg;

[0910] Arginine 50±10% mg;

[0911] Sodium decanoate 150±10% mg; and

[0912] N-(8-[2-hydroxybenzoyl]amino)octanoic acid sodium salt (SNAC) 150±10% mg; and

[0913] Excipients 53±10% mg.

[0914] In one embodiment of this disclosure, the oral pharmaceutical composition comprises:

[0915] Teriparatide 7mg;

[0916] Nicotinamide 50mg;

[0917] Arginine 50mg;

[0918] Sodium decanoate 150mg; and

[0919] N-(8-[2-hydroxybenzoyl]amino)octanoic acid sodium salt (SNAC) 150 mg; and

[0920] Excipient 53mg.

[0921] In one technical solution disclosed herein, the oral pharmaceutical composition is in solid dosage form.

[0922] In one technical solution of this disclosure, the oral pharmaceutical composition is a tablet, capsule, granule, powder, powder, drop pill, or pill.

[0923] In one technical solution of this disclosure, the oral pharmaceutical composition is a tablet.

[0924] In one technical solution of this disclosure, the tablets are in the form of 1-50 mg, for example, 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 or 10 mg.

[0925] In one embodiment of this disclosure, the tablets are approximately 1-40 mg in size.

[0926] In one embodiment of this disclosure, the tablets are approximately 1-30 mg in size.

[0927] In one embodiment of this disclosure, the tablets are approximately 5-10 mg in size.

[0928] In one technical solution disclosed herein, the oral pharmaceutical composition is a single-ingredient preparation or a compound preparation.

[0929] In one technical solution of this disclosure, the compound preparation contains at least two active ingredients, wherein the active ingredients include a polypeptide that targets the parathyroid hormone (PTH) receptor, and the active ingredients also include at least one selected from zoledronic acid or denosumab, calcitonin drugs (e.g., calcitonin injection, salmon calcitonin injection) and alendronate sodium.

[0930] In another aspect, this disclosure relates to the use of oral pharmaceutical compositions containing peptides that target parathyroid hormone (PTH) receptors for (i) treating diseases associated with parathyroid hormone deficiency; and / or (ii) preparing medicaments for diseases associated with parathyroid hormone deficiency.

[0931] The pharmaceutical composition comprises: a polypeptide targeting the parathyroid hormone (PTH) receptor, a complexing molecule, a compound containing a nitrogen-containing functional group, a medium-chain fatty acid or a salt thereof, and N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof; wherein the complexing molecule is a C-chain compound containing a hydrophilic group. 6- C 10 Aromatic rings or 5-10 membered heteroaromatic rings; the nitrogen-containing functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of -S(O)2OH and -OH groups.

[0932] In one of the technical solutions disclosed herein, the disease associated with parathyroid hormone deficiency is osteoporosis.

[0933] In one technical solution of this disclosure, the osteoporosis is selected from at least one of glucocorticoid-induced osteoporosis, male osteoporosis, and postmenopausal female osteoporosis.

[0934] On the other hand, this disclosure relates to an oral pharmaceutical composition containing a polypeptide targeting the somatostatin receptor (SSTR), wherein the pharmaceutical composition comprises: a polypeptide targeting the somatostatin receptor, a coordinating molecule, a compound containing a nitrogen-containing functional group, a medium-chain fatty acid or a salt thereof, and N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or a salt thereof; wherein the coordinating molecule is a C-chain compound containing a hydrophilic group. 6- C 10 Aromatic rings or 5-10 membered heteroaromatic rings; the nitrogen-containing functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of the substituent groups selected from -S(O)2OH and -OH.

[0935] In one technical solution disclosed herein, the polypeptide targeting the somatostatin receptor (SSTR) is a somatostatin analogue.

[0936] In one technical solution disclosed herein, the polypeptide targeting the somatostatin receptor (SSTR) is a somatostatin receptor agonist.

[0937] In one technical solution disclosed herein, the polypeptide targeting the somatostatin receptor is octreotide.

[0938] In another respect, this disclosure relates to the use of oral pharmaceutical compositions containing peptide analogs that target the somatostatin receptor for (i) treating diseases associated with the somatostatin receptor; and / or (ii) preparing medicaments for diseases associated with the somatostatin receptor.

[0939] In the oral formulation system disclosed herein, molecules containing amino, amine, or quaternary ammonium groups and molecules with aromatic rings and excellent water solubility are introduced as coordinating factors. Through electrostatic interactions, cation-π interactions, and π-π stacking, the binding affinity between drug molecules and penetration enhancers is increased, constructing a multi-component reversible complex. This maintains solubility and microscopic stability during the release phase and increases the local concentration and residence time of peptide drug molecules and penetration enhancers, thereby promoting membrane phase partitioning and transmembrane flux.

[0940] The oral pharmaceutical compositions disclosed herein can significantly improve the oral bioavailability of peptides or proteins through the synergistic effects of peptides or proteins, complexing molecules, compounds containing nitrogen-containing functional groups, medium-chain fatty acids or their salts, and NAC or their salts.

[0941] The oral pharmaceutical composition disclosed herein, through the combined action of compounds containing nitrogen-containing functional groups and coordinating molecules, significantly improves oral bioavailability compared to pharmaceutical compositions lacking compounds or coordinating molecules containing nitrogen-containing functional groups in their formulation.

[0942] The tablets made from the oral pharmaceutical compositions disclosed herein exhibit high dissolution and good stability. Detailed Implementation

[0943] 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.

[0944] I. Definition

[0945] 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.

[0946] 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.

[0947] The term "about" means approximately, close to, roughly, or roughly. When the term "about" is used in conjunction with a numerical range, it is modified by 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 given value.

[0948] The term "heteroaromatic ring" refers to a monocyclic or bicyclic aromatic ring containing at least one heteroatom selected from N, O, and S. Examples of heteroaromatic rings include, but are not limited to, pyrrole rings, isoxazole rings, isothiazole rings, pyrazole rings, pyridine rings, oxazole rings, oxadiazole rings, thiadiazole rings, thiazazole rings, imidazole rings, triazole rings, tetraazole rings, furan rings, triazine rings, thiophene rings, pyrimidine rings, pyridazine rings, pyrazine rings, benzoxazole rings, benzothiazole rings, benzimidazole rings, benzofuran rings, benzothiophene rings, furano[2,3-b]pyridine rings, quinoline rings, indole rings, isoquinoline rings, etc.

[0949] The term "aromatic ring" refers to a monocyclic or bicyclic aromatic hydrocarbon consisting only of carbon atoms. "Fused analogues of aromatic rings" refer to compounds formed by fusion of an aromatic ring with a monocyclic cycloalkyl or monocyclic heterocyclic group, with the fusion point located at the aryl moiety. Examples of aromatic rings and their fused ring analogues include, but are not limited to, benzene rings, naphthalene rings, indene rings, tetrahydronaphthalene rings, 2,3-dihydrobenzofuran, dihydrobenzopyran, and 1,4-benzodioxane.

[0950] Pharmaceutical Composition

[0951] The terms “pharmaceutical acceptable” or “medicinal” refer 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.

[0952] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound as a free acid or base without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0953] The term "pharmaceutically acceptable ester" refers to an ester that retains the biological potency of the original specific compound without any adverse biological effects. Ester groups are typically introduced via organic acids and alcohol hydroxyl groups. In some embodiments, peptides are linked to fatty acids or derivatives thereof via ester bonds to obtain pharmaceutically acceptable esters.

[0954] The term "pharmaceutically acceptable amide" refers to an amide or derivative containing an amide structure that retains the biological efficacy of the original specific compound without any adverse biological effects.

[0955] The term "prodrug" refers to a compound that can be converted into an active drug substance in the body and exert its therapeutic effect. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. In embodiments of this disclosure, the prodrug may be an ester.

[0956] The terms "polypeptide" and "peptide" are used interchangeably to refer to a compound comprising a series of amino acids linked together by amide (or peptide) bonds. The term "medicinalizable peptide" refers to those peptide-based compounds suitable for use in human and animal tissue contact without, to the extent reasonably medically permissible, excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio. Medicinalizable peptides typically contain at least 20 amino acid residues. In some embodiments, medicinalizable peptides contain at least 30, at least 40, or at least 50 amino acid residues. In some embodiments, medicinalizable peptides contain 20-500 amino acid residues. In some embodiments, one or more modified amino acid residues and / or non-protein amino acid residues are included.

[0957] In some embodiments, the pharmaceutically acceptable peptide is a GLP-1 analog or a peptide targeting GLP-1 (e.g., smegglutide), a peptide targeting both GIP and GLP-1 receptors (e.g., telpolide), a peptide targeting the GIP receptor, a parathyroid hormone analog (e.g., teriparatide), a peptide targeting the parathyroid hormone (PTH) receptor (e.g., teriparatide), a somatostatin analog (e.g., octreotide), or a peptide targeting the somatostatin receptor (e.g., octreotide).

[0958] The terms "GLP-1 analog" or "GLP-1 analogue" refer to peptides or compounds that are variants of human glucagon-like peptide-1 (GLP-1(7-37)). GLP-1(7-37) has the sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1). The term "variant" refers to a peptide or compound comprising one or more amino acid substitutions, deletions, additions, and / or insertions, and variants also include peptides or compounds resulting from chemical modifications of the original peptide. In one embodiment, the chemical modification is carried out by introducing a fatty acid chain onto one or more amino acids of the peptide chain, an example of a fatty acid in the fatty acid chain being C. 12 -C 22 Straight-chain fatty acids, such as C 18 Linear fatty acids; linear fatty acids may be optionally acylated, for example, C 18 Straight-chain fatty acids. The aforementioned fatty acid chains can be linked to peptide chains via glutamic acid and PEG-type linkers. Examples of PEG-type linkers include, but are not limited to, H-AEEA, AEEA-AEEA, and AEEA-AEEA-AEEA.

[0959] In one embodiment, the pharmaceutically acceptable peptide is semaglutide.

[0960] In one embodiment, the pharmaceutically acceptable peptide is Tirzepatide.

[0961] In one embodiment, the pharmaceutically acceptable peptide is teriparatide.

[0962] In one embodiment, the pharmaceutically acceptable peptide is octreotide.

[0963] In one embodiment, the pharmaceutically usable peptide has a molecular weight of 1000-50000 Da.

[0964] The term "coordination molecule" refers to a molecule containing a hydrophilic group (C₁, C₂, C₃). 6- C 10 Aromatic ring or C 5-10 Heteroaromatic ring (5-10 membered heteroaromatic ring) compounds, wherein a heteroaromatic ring compound refers to an aromatic ring compound containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The heteroaromatic ring can be monocyclic or polycyclic, such as bicyclic, wherein two or more rings exist in the form of fused rings, bridged rings, or spirocyclic rings, and at least one ring contains one or more heteroatoms. Specific examples of heteroaromatic ring compounds include, but are not limited to, pyridine, thiophene, imidazole, pyrimidine, furan, pyrazine, thiazole, quinoline, isoquinoline, indole, benzimidazole, imidazopyridine, benzofuran, pyridazine, isoindole, and pyridinone. In some embodiments, the coordinating molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. In some preferred embodiments, the coordinating molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide. In some preferred embodiments, the coordinating molecule is nicotinamide.

[0965] The term "hydrophilic group" refers to a group of atoms or functional groups in a molecule that can form hydrogen bonds with water molecules, thereby making the molecule readily soluble in water. These groups are typically polar or ionic and can form hydrogen bonds with polar oxygen atoms in water molecules, thus giving the molecule hydrophilicity. Examples of hydrophilic groups in this disclosure include, but are not limited to, hydroxyl, carboxyl, amino, sulfonic acid, phosphate, amide, ribosyl (or deoxyribosyl), and carboxyl groups.

[0966] The term "amino" refers to a compound consisting of one nitrogen atom (N) and two hydrogen atoms (H), which is often combined with other groups or molecular structures to form more complex compounds.

[0967] The term "amine group" is a broad chemical functional group that refers to a structure containing a nitrogen atom that can be attached to one or more hydrocarbon groups (such as methyl, ethyl, etc.). The amine group is the basis of amine compounds.

[0968] Primary amines: An amino group is attached to a hydrocarbon group (e.g., methylamine: CH3NH2).

[0969] Secondary amines: An amino group is attached to two hydrocarbon groups (e.g., dimethylamine: CH3NHCH3).

[0970] Tertiary amines: An amino group is attached to three hydrocarbon groups (e.g., trimethylamine: N(CH3)3).

[0971] The term "quaternary ammonium group" refers to -N + (R)3, wherein each R is independently a straight-chain or branched alkyl group, with an exemplary quaternary ammonium group being -N. + (CH3)3、-N + (CH2CH3)3.

[0972] In some embodiments, the compound containing the nitrogen-functional group is an amino acid, such as glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, asparagine, glutamine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, sarcosine, γ-aminobutyric acid, ornithine, and citrulline. In some preferred embodiments, the compound containing the nitrogen-functional group is a basic amino acid. In some preferred embodiments, the compound containing the nitrogen-functional group is an amino acid that carries a positive charge at physiological pH. In some embodiments, the compound containing the nitrogen-functional group is a quaternary ammonium cation complex, such as carnitine, L-carnitine, choline, choline chloride, and betaine. In some embodiments, the compound containing the nitrogen-functional group is taurine.

[0973] In some embodiments, the compound containing the nitrogen-containing functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, monosodium glutamate, leucine, and γ-aminobutyric acid; preferably at least one of arginine, citrulline, lysine, choline, choline chloride, monosodium glutamate, leucine, and carnitine.

[0974] The term "excipient" refers to a substance added to a pharmaceutical composition to impart a certain shape, size, or physical properties 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 are selected based on factors such as the properties, type, route of administration, and therapeutic purpose of the drug. In some embodiments, the excipients are fillers, disintegrants, and lubricants.

[0975] 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.

[0976] 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.

[0977] 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.

[0978] 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.

[0979] 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.

[0980] The term "specification" or "drug specification" refers to the amount of drug ingredient contained in a unit dosage form of a drug, usually expressed as the weight or content per tablet, capsule, or vial, etc., and includes indicators such as the content, potency, or fill volume of the active ingredient. In some embodiments of this disclosure, the tablet specifications are 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, or 10 mg.

[0981] 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, 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.

[0982] The term "single-drug formulation" refers to a single dosage form in which a prescription contains only one drug or active ingredient.

[0983] The term "compound preparation" refers to a dosage form in which two or more drugs or active ingredients are combined in a fixed dose in one dosage form.

[0984] The term "treatment" includes the suppression, relief, prevention, or elimination of one or more symptoms or side effects associated with the disease, condition, or disorder being treated. The term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, suppress, or reduce one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effect. Precise dosages will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, 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.

[0985] II. Examples

[0986] 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.

[0987] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0988] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0989] Example 1: Preparation of Smegglutide Tablets

[0990] 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).

[0991] The pharmaceutical composition containing semaglutide is formulated as follows: 1.52% w / w semaglutide, 10.87% w / w arginine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% 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:nicotinamide is 7:150:150:50:50.

[0992] 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 7mg of smegglutinin.

[0993] Example 2: Preparation of Smegglutide tablets

[0994] 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).

[0995] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.52% w / w semaglutide, 10.87% w / w lysine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:lysine:nicotinamide is 7:150:150:50:50.

[0996] 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 7mg of smegglutinin.

[0997] Comparative Example 1: Preparation of Smegglutide Tablets

[0998] 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).

[0999] The formulation of the pharmaceutical composition containing smegglutide is as follows: 1.52% w / w smegglutide, 10.87% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 19.39% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1000] Smegglutide: SNAC: Sodium decanoate: Arginine = 7:150:150:50

[1001] 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 7mg of smegglutinin.

[1002] Comparative Example 2: Preparation of Smegglutide Tablets

[1003] 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).

[1004] The formulation of the pharmaceutical composition containing semaglutide is as follows: 1.52% w / w semaglutide, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 19.39% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of semaglutide:SNAC:sodium decanoate:nicotinamide is 7:150:150:50.

[1005] 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 7mg of smegglutinin.

[1006] Test Example 1

[1007] The absorption of the prepared semaglutide tablets in beagle dogs after oral administration was tested. Specifically, 1 ml of blank blood was collected using an EDTA-K2 blood collection tube before administration as the zero-point blood sample. The tablets prepared in Example 1 were administered to beagle dogs via gavage, with four dogs per group. 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. Whole blood from the beagle dogs was collected and centrifuged. The supernatant plasma sample was then frozen at -20°C for subsequent mass spectrometry analysis. Mass spectrometry analysis was performed according to the method described in the published literature "Quantitative Analysis of Semaglutide and Tirzepatide in Rat Plasma by SCIEX LC-MS / MS System".

[1008] The absorption test results of the above-mentioned smegglutide tablets in beagle dogs after oral administration are shown in Table 1 below.

[1009] Table 1

[1010] Compared with Comparative Examples 1 and 2, the blood concentration C of semaglutide in Examples 1 and 2 was significantly lower. max The significant increase indicates that the formulations of Examples 1 and 2 significantly improved the oral absorption of smegglutinin in beagle dogs.

[1011] Example 3: Preparation of telpopritide tablets

[1012] 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).

[1013] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide:SNAC:sodium decanoate:arginine:nicotinamide is 7:150:150:50:50.

[1014] 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 7mg of telpolide.

[1015] Example 4: Preparation of telpopritide tablets

[1016] 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).

[1017] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w lysine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide:SNAC:sodium decanoate:lysine:nicotinamide is 7:150:150:50:50.

[1018] 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 7mg of telpolide.

[1019] Example 5: Preparation of telpopritide tablets

[1020] 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).

[1021] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w citrulline, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide:SNAC:sodium decanoate:citrulline:nicotinamide is 7:150:150:50:50.

[1022] 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 7mg of telpolide.

[1023] Example 6: Preparation of telpopritide tablets

[1024] 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).

[1025] The formulation of the pharmaceutical composition containing telpotetide is as follows: 1.52% w / w telpotetide, 10.87% w / w choline chloride, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpotetide:SNAC:sodium decanoate:choline chloride:nicotinamide is 7:150:150:50:50.

[1026] 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 7mg of telpolide.

[1027] Example 7: Preparation of telpopritide tablets

[1028] 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).

[1029] The formulation of the pharmaceutical composition containing telpotetide is as follows: 1.52% w / w telpotetide, 10.87% w / w L-carnitine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpotetide:SNAC:sodium decanoate:carnitine:nicotinamide is 7:150:150:50:50.

[1030] 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 7mg of telpolide.

[1031] Example 8: Preparation of telpopritide tablets

[1032] 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).

[1033] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w salicylamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide:SNAC:sodium decanoate:arginine:salicylamide is 7:150:150:50:50.

[1034] 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 7mg of telpolide.

[1035] Example 9: Preparation of telpopritide tablets

[1036] 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).

[1037] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w adenosine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide:SNAC:sodium decanoate:arginine:adenosine is 7:150:150:50:50.

[1038] 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 7mg of telpolide.

[1039] Example 10: Preparation of telpopritide tablets

[1040] 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).

[1041] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w trigonelline, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide:SNAC:sodium decanoate:arginine:trigonelline is 7:150:150:50:50.

[1042] 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 7mg of telpolide.

[1043] Example 11: Preparation of telpopritide tablets

[1044] 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).

[1045] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w monosodium glutamate, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1046] Telpoeptide: SNAC: Sodium decanoate: Monosodium glutamate: Nicotinamide = 7:150:150:50:50.

[1047] 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 7mg of telpolide.

[1048] Example 12: Preparation of telpopritide tablets

[1049] 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).

[1050] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w leucine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1051] Telpoeptide: SNAC: Sodium decanoate: Leucine: Nicotinamide = 7:150:150:50:50.

[1052] 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 7mg of telpolide.

[1053] Example 13: Preparation of telpopritide tablets

[1054] 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).

[1055] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w adenine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1056] Telpoeptide: SNAC: Sodium decanoate: Arginine: Adenine = 7:150:150:50:50.

[1057] 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 7mg of telpolide.

[1058] Example 14: Preparation of telpopritide tablets

[1059] 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).

[1060] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w cytosine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1061] Telpoeptide: SNAC: Sodium decanoate: Arginine: Cytosine = 7:150:150:50:50.

[1062] 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 7mg of telpolide.

[1063] Example 15: Preparation of telpopritide tablets

[1064] 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).

[1065] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.37% w / w telpolide, 19.61% w / w arginine, 9.80% w / w nicotinamide, 29.41% w / w SNAC, 29.41% w / w sodium decanoate, 7.69% w / w microcrystalline cellulose, 0.90% w / w sodium dodecyl sulfate, and 1.80% w / w sodium carboxymethyl starch.

[1066] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:150:150:100:50.

[1067] 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 7mg of telpolide.

[1068] Example 16: Preparation of telpopritide tablets

[1069] 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).

[1070] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w nicotinamide, 21.74% w / w SNAC, 43.48% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1071] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:100:200:50:50.

[1072] 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 7mg of telpolide.

[1073] Example 17: Preparation of telpopritide tablets

[1074] 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).

[1075] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w nicotinamide, 10.87% w / w SNAC, 54.35% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1076] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:50:250:50:50.

[1077] 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 7mg of telpolide.

[1078] Example 18: Preparation of telpopritide tablets

[1079] 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).

[1080] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w nicotinamide, 43.48% w / w SNAC, 21.74% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1081] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:200:100:50:50.

[1082] 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 7mg of telpolide.

[1083] Example 19: Preparation of telpopritide tablets

[1084] 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).

[1085] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 10.87% w / w nicotinamide, 48.92% w / w SNAC, 16.30% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1086] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:225:75:50:50.

[1087] 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 7mg of telpolide.

[1088] Example 20: Preparation of telpopritide tablets

[1089] 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).

[1090] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 5.43% w / w arginine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 13.96% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1091] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:150:150:25:50.

[1092] 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 7mg of telpolide.

[1093] Example 21: Preparation of telpopritide tablets

[1094] 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).

[1095] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 5.43% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 13.96% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1096] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:150:150:50:25.

[1097] 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 7mg of telpolide.

[1098] Example 22: Preparation of telpopritide tablets

[1099] 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).

[1100] The formulation of the pharmaceutical composition containing telpolide is as follows: 2.27% w / w telpolide, 10.70% w / w arginine, 10.70% w / w nicotinamide, 32.43% w / w SNAC, 32.43% w / w sodium decanoate, 8.46% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1101] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:100:100:33:33.

[1102] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 308.34mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 7mg of telpolide.

[1103] Example 23: Preparation of telpopritide tablets

[1104] 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).

[1105] The formulation of the pharmaceutical composition containing telpolide is as follows: 3.00% w / w telpolide, 10.70% w / w arginine, 10.70% w / w nicotinamide, 32.11% w / w SNAC, 32.11% w / w sodium decanoate, 8.39% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1106] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:75:75:25:25.

[1107] 2) Tableting: After mixing, the material is compressed into tablets using a 10mm diameter flat die. Each tablet contains 233.6mg of material. The tablet is then removed from the die to obtain a 10mm round flat tablet containing 7mg of telpolide.

[1108] Example 24: Preparation of telpopritide tablets

[1109] 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).

[1110] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.27% w / w telpolide, 27.27% w / w arginine, 9.09% w / w nicotinamide, 27.27% w / w SNAC, 27.27% w / w sodium decanoate, 4.82% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1111] Telpoeptide: SNAC: Sodium decanoate: Arginine: Nicotinamide = 7:150:150:150:50.

[1112] 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 7mg of telpolide.

[1113] Comparative Example 3: Preparation of telpopritide tablets

[1114] 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).

[1115] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 65.22% w / w SNAC, 30.26% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide to SNAC is 7:300.

[1116] 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 7mg of telpolide.

[1117] Comparative Example 4: Preparation of telpolide tablets

[1118] 1) Mixing: Prepare the drug formulation system powder from the raw materials. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass ratio shown below. After weighing, mix using a three-dimensional mixer (50 rpm, 300 s). The formulation of the drug composition containing telpolide is as follows: 1.52% w / w telpolide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 30.26% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1119] Telpoeptide: SNAC: Sodium decanoate = 7:150:150

[1120] 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 7mg of telpolide.

[1121] Comparative Example 5: Preparation of telpolide tablets

[1122] 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).

[1123] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 19.39% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide:SNAC:sodium decanoate:arginine is 7:150:150:50.

[1124] 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 7mg of telpolide.

[1125] Comparative Example 6: Preparation of telpolide tablets

[1126] 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).

[1127] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 19.39% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch, wherein the ratio of telpolide:SNAC:sodium decanoate:nicotinamide is 7:150:150:50.

[1128] 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 7mg of telpolide.

[1129] Comparative Example 7: Preparation of telpopritide tablets

[1130] 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).

[1131] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 84.61% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide to arginine is 7:50.

[1132] 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 7mg of telpolide.

[1133] Comparative Example 8: Preparation of telpopritide tablets

[1134] 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).

[1135] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w nicotinamide, 84.61% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of telpolide to nicotinamide is 7:50.

[1136] 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 7mg of telpolide.

[1137] Comparative Example 9

[1138] 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).

[1139] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w arginine, 65.22% w / w sodium decanoate, 19.39% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1140] Telpoeptide: Sodium decanoate: Arginine = 7:300:50.

[1141] 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 7mg of telpolide.

[1142] Comparative Example 10

[1143] 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).

[1144] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% w / w nicotinamide, 65.22% w / w sodium decanoate, 19.39% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1145] Telpoeptide: Sodium decanoate: Nicotinamide = 7:300:50.

[1146] 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 7mg of telpolide.

[1147] Comparative Example 11

[1148] 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).

[1149] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 95.48% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1150] 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 7mg of telpolide.

[1151] Comparative Example 12

[1152] 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).

[1153] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% arginine, 10.87% w / w nicotinamide, 65.22% w / w SNAC, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1154] Telpoeptide:SNAC:Arginine:Nicotinamide = 7:300:50:50.

[1155] 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 7mg of telpolide.

[1156] Comparative Example 13

[1157] 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).

[1158] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 10.87% arginine, 10.87% w / w nicotinamide, 65.22% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1159] Telpoeptide: Sodium decanoate: Arginine: Nicotinamide = 7:300:50:50.

[1160] 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 7mg of telpolide.

[1161] Comparative Example 14

[1162] 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).

[1163] The formulation of the pharmaceutical composition containing telpolide is as follows: 1.52% w / w telpolide, 65.22% w / w sodium decanoate, 30.26% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, and 2% w / w sodium carboxymethyl starch.

[1164] Telpoeptide: Sodium decanoate = 7:300.

[1165] 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 7mg of telpolide.

[1166] Test Example 2

[1167] The absorption of the prepared telpolide tablets in beagles after oral administration was tested. Specifically, 1 ml of blank blood was collected using an EDTA-K2 blood collection tube before administration as the zero-point blood sample. The tablets prepared in Example 5 were administered to beagles via gavage, with 3 dogs per group. Subsequently, blood was collected from the forearm vein of the beagles 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 was centrifuged, and the supernatant plasma sample was collected and stored at -20°C for subsequent mass spectrometry analysis.

[1168] Mass spectrometry analysis was performed according to the method described in the published literature "Quantitative Analysis of Semaglutide and Tirzepatide in Rat Plasma by SCIEX LC-MS / MS System". The absorption test results of the above-mentioned tirzepatide tablets after oral administration in beagle dogs are shown in Table 2 below.

[1169] Table 2 * Blood drug concentrations were all below the lower limit of dosage.

[1170] Example 3-24 C max The mean values ​​were generally higher than those of Comparative Examples 3-14, indicating that the formulations of Examples 3-24 significantly improved the oral absorption of telpotriol in beagle dogs.

[1171] Example 25: Preparation of a pharmaceutical composition containing teriparatide

[1172] 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).

[1173] The formulation of the pharmaceutical composition containing teriparatide is as follows: 1.52% w / w teriparatide, 10.87% w / w arginine, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 8.52% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of teriparatide:SNAC:sodium decanoate:arginine:nicotinamide is 7:150:150:50:50.

[1174] 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 7mg of teriparatide.

[1175] Comparative Example 15: Preparation of a pharmaceutical composition containing teriparatide

[1176] 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).

[1177] The formulation of the pharmaceutical composition containing teriparatide is as follows: 1.52% w / w teriparatide, 10.87% w / w arginine, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 19.39% w / w microcrystalline cellulose, 1% w / w sodium lauryl sulfate, and 2% w / w sodium carboxymethyl starch. The ratio of teriparatide:SNAC:sodium decanoate:nicotinamide is 7:150:150:50.

[1178] 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 7mg of teriparatide.

[1179] Comparative Example 16: Preparation of a pharmaceutical composition containing teriparatide

[1180] 1) Mixing: Prepare the drug formulation system powder from the raw materials. After passing each component powder through a 40-mesh sieve, accurately weigh each component according to the mass ratio shown below. After weighing, mix using a three-dimensional mixer (50 rpm, 300 s). The formulation of the drug composition containing teriparatide is as follows: 1.52% w / w teriparatide, 10.87% w / w nicotinamide, 32.61% w / w SNAC, 32.61% w / w sodium decanoate, 19.39% w / w microcrystalline cellulose, 1% w / w sodium dodecyl sulfate, 2% w / w sodium carboxymethyl starch. The ratio of teriparatide:SNAC:sodium decanoate:arginine is 7:150:150:50.

[1181] 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 7mg of teriparatide.

[1182] Test Example 3

[1183] The absorption of the teriparatide tablets prepared above was tested in beagle dogs after oral administration. Specifically, 1 ml of blank blood was collected using an EDTA-K2 blood collection tube before administration as the zero-point blood sample. The tablets prepared in Example 5 were administered to beagle dogs via gavage, with 5 dogs per group. 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.

[1184] Mass spectrometry analysis was performed according to the method described in EE Chambers et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2013 Nov 1:938:96-104.

[1185] The absorption test results of the above-mentioned teriparatide tablets after oral administration in beagle dogs are shown in Table 3 below.

[1186] Table 3

[1187] Example 25 C max The mean values ​​were higher than those of Comparative Examples 15 and 16, indicating that the formulation of Example 25 improved the oral absorption of teriparatide in beagle dogs.

Claims

1. An oral pharmaceutical composition, wherein, The pharmaceutical composition comprises: (i) Medicinal polypeptides or proteins; (ii) Coordinating molecules; (iii) Compounds containing nitrogen-containing functional groups; (iv) medium-chain fatty acids or their salts; and (v) N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof; Wherein, the coordinating molecule is a C containing a hydrophilic group. 6- C 10 Aromatic ring or C 5-10 Heteroaromatic compounds; The compound containing a nitrogen-atom functional group contains an amino, amine, or quaternary ammonium group, and contains a group selected from -C(O)OH, -C(O)O - At least one of the substituent groups selected from -S(O)2OH and -OH.

2. The pharmaceutical composition of claim 1, wherein, Both the coordinating molecule and the compound containing the nitrogen-atom functional group are small molecule compounds with a molecular weight of less than 900 Da, preferably less than 500 Da.

3. The pharmaceutical composition of claim 1, wherein, The coordination molecule is: Where ring A is C 6- C 10 Aromatic ring or 5-10 membered heteroaryl ring, the ring being divided by one or more R 1 and one or more R 2 Replace, each R 1 Each R is an independent hydrophilic group. 2 It can be hydrogen, methyl, ethyl, halogen, or oxo (=O) independently.

4. The pharmaceutical composition of claim 3, wherein, Each R 1 It can be independently a hydroxyl, carboxyl, amino, sulfonic acid, phosphate, amide, ribose, or carboxylate group.

5. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises not less than about 0.5% w / w of a pharmaceutically acceptable polypeptide or protein.

6. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises a pharmaceutically acceptable polypeptide or protein in an amount of not less than about 0.5% w / w and not more than 10.0% w / w.

7. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises not less than about 20.0% w / w of medium-chain fatty acids or their salts.

8. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50.0% w / w of medium-chain fatty acids or their salts.

9. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises not less than about 20.0% w / w of N-(8-[2-hydroxybenzoyl]amino)octanoic acid (NAC) or a salt thereof.

10. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises not less than about 20.0% w / w and not more than about 50.0% w / w of medium-chain fatty acids or their salts.

11. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises not less than about 5.0% w / w of a compound containing a nitrogen-containing functional group.

12. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises a compound containing a nitrogen-containing functional group at a concentration of not less than about 5.0% w / w and not more than about 30.0 w / w.

13. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises a complexing molecule of not less than about 5.0% w / w.

14. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises a complexing molecule of not less than about 5.0% w / w and not more than about 20.0 w / w.

15. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises:

16. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises:

17. The pharmaceutical composition of claim 1, wherein, The oral pharmaceutical composition comprises:

18. The pharmaceutical composition of claim 1, wherein, The mass percentage ratio of the coordinating molecule to the compound containing the nitrogen-atom functional group is 1:(0.5-4).

19. The pharmaceutical composition of claim 1, wherein, The mass percentage ratio of the pharmaceutically acceptable polypeptide or protein to the complexing molecule is approximately 1:(3-10).

20. The pharmaceutical composition of claim 1, wherein, The mass percentage ratio of the medium-chain fatty acid or its salt to the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is approximately 1:(0.8-1.2).

21. The pharmaceutical composition of claim 1, wherein, The mass percentage ratio of the complexing molecule, the compound containing the nitrogen functional group, the medium-chain fatty acid or its salt, and the N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) or its salt is (0.8-1.2):(0.8-1.2):(2.5-3.5):(2.5-3.5).

22. The pharmaceutical composition according to any one of claims 1-21, wherein, The salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is a sodium salt, potassium salt, or amine salt. Preferably, the salt of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid (NAC) is sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC).

23. The pharmaceutical composition according to any one of claims 1-21, wherein, The medium-chain fatty acid or its salt is C 6- C 14 Carboxylic acid or C 6- C 14 Carboxylate; preferably C 8- C 14 Carboxylic acid or C 8- C 14 Carboxylates.

24. The pharmaceutical composition of claim 23, wherein, The medium-chain fatty acid is selected from caprylic acid (C8) and decanoic acid (C8). 10 ), n-Undecanoic acid (C 11 ) and n-dodecanoic acid (C 12 Preferred to be decanoic acid (C); 10 ).

25. The pharmaceutical composition of claim 23, wherein, The medium-chain fatty acid salt is a sodium salt, potassium salt, or ammonium salt; preferably a sodium salt.

26. The pharmaceutical composition of claim 25, wherein, The medium-chain fatty acid salt is sodium decanoate (SD).

27. The pharmaceutical composition according to any one of claims 1-21, wherein, The compound containing a nitrogen-containing functional group is selected from at least one of amino acids or their salts, L-carnitine, taurine, betaine, choline, choline chloride, and carnitine, wherein the amino acid is selected from natural amino acids or synthetic amino acids.

28. The pharmaceutical composition of claim 27, wherein, The amino acid is selected from at least one of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, asparagine, glutamine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, sarcosine, and γ-aminobutyric acid.

29. The pharmaceutical composition according to any one of claims 1-21, wherein, The compound containing a nitrogen-containing functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, γ-aminobutyric acid, ornithine, citrulline, monosodium glutamate, and leucine. Preferably, the compound containing a nitrogen-containing functional group is selected from at least one of arginine, citrulline, lysine, choline, choline chloride, carnitine, monosodium glutamate, and leucine.

30. The pharmaceutical composition according to any one of claims 1-21, wherein, The compound containing the nitrogen-atom functional group is an amino acid or its salt.

31. The pharmaceutical composition of claim 30, wherein, The compound containing a nitrogen-containing functional group is arginine, lysine, citrulline, leucine, or monosodium glutamate; arginine is preferred.

32. The pharmaceutical composition according to any one of claims 1-21, wherein, The synergistic molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide; preferably, the synergistic molecule is selected from at least one of nicotinamide, adenosine, trigonelline, and salicylamide.

33. The pharmaceutical composition of claim 32, wherein, The coordinating molecule is nicotinamide.

34. The pharmaceutical composition according to any one of claims 1-21, wherein, The molecular weight of the pharmaceutically usable polypeptide or protein is 1000-50000 Da.

35. The pharmaceutical composition according to any one of claims 1-34, wherein, The pharmaceutical composition further includes excipients, the content of which is not higher than 20% w / w.

36. The pharmaceutical composition of claim 35, wherein, The pharmaceutical composition comprises: The liganding molecule is selected from at least one of nicotinamide, adenosine, adenine, guanine, cytosine, trigonelline, and salicylamide. The compound containing a nitrogen-containing functional group is selected from at least one of arginine, lysine, ornithine, citrulline, L-carnitine, taurine, betaine, choline, choline chloride, carnitine, sarcosine, γ-aminobutyric acid, leucine, and monosodium glutamate.

37. The pharmaceutical composition of claim 36, wherein, The excipient is selected from one or more of fillers, disintegrants, and lubricants.

38. The pharmaceutical composition of claim 37, wherein, The excipients comprise not less than about 5.0% w / w and not more than about 15.0 w / w of microcrystalline cellulose; and / or The excipients comprise sodium dodecyl sulfate at a rate of not less than about 0.01% w / w and not more than about 3.0% w / w; and / or The excipients include sodium carboxymethyl starch at a concentration of not less than about 0.1% w / w and not more than about 5.0% w / w.

39. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises:

40. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises:

41. The pharmaceutical composition according to any one of claims 1-40, wherein, The pharmaceutical composition is in solid dosage form.

42. The pharmaceutical composition of claim 41, wherein, The pharmaceutical composition is in the form of tablets, capsules, granules, powders, films, pills, or powders.

43. The pharmaceutical composition according to any one of claims 42, wherein, The pharmaceutical composition is in the form of tablets.

44. The pharmaceutical composition of claim 43, wherein, The tablets are available in strengths of approximately 1-50 mg.

45. The pharmaceutical composition according to any one of claims 1-43, wherein, The tablets weigh approximately 100-1000 mg, preferably approximately 100-600 mg.

46. ​​The pharmaceutical composition according to any one of claims 1-45, wherein, The pharmaceutical composition is a single-ingredient preparation.

47. The method for preparing the pharmaceutical composition according to any one of claims 1-46, wherein, The method includes the step of mixing the materials.

48. An oral pharmaceutical composition comprising:

49. A method for treating GLP-1 receptor-related diseases, the method comprising the step of administering a therapeutically effective amount of the pharmaceutical composition of claim 48 to a subject in need, wherein the GLP-1 receptor-related disease is selected from at least one of type 2 diabetes, obesity, cardiovascular disease, non-alcoholic fatty liver disease, neurodegenerative diseases, cancer, chronic kidney disease, and musculoskeletal inflammation.

50. An oral pharmaceutical composition comprising:

51. A method for treating a disease associated with GLP-1 and / or GIP receptor agonism, the method comprising the step of administering to a subject in need a therapeutically effective amount of the pharmaceutical composition of claim 50, wherein the disease associated with GLP-1 and / or GIP receptor agonism is selected from at least one of type 2 diabetes, obesity, weight loss indications, cardiovascular disease, non-alcoholic fatty liver disease, neurodegenerative diseases, cancer, chronic kidney disease, and musculoskeletal inflammation.

52. An oral pharmaceutical composition comprising:

53. A method for treating a disease associated with parathyroid hormone deficiency, the method comprising the step of administering a therapeutically effective amount of the pharmaceutical composition of claim 52 to a subject in need, wherein the osteoporosis is selected from at least one of glucocorticoid-induced osteoporosis, male osteoporosis, and postmenopausal female osteoporosis.

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