Composition providing improved oral bioavailability of drug and method therefor

Abstract

A composition providing improved oral bioavailability of a drug and a method therefor. Also disclosed is the use of a delivery synergist in the improvement of the oral bioavailability of a protein or polypeptide drug. When the delivery synergist is added to the pharmaceutical composition at a certain ratio relative to a delivery agent, the delivery effect of the delivery agent can be maximized, which can not only reduce the use amount of the delivery agent, but can also improve the oral bioavailability of the drug.

Description

Composition and method for improving oral bioavailability of drugs Technical Field

[0001] The present invention relates to the field of biomedicine and specifically relates to a composition and method for improving the oral bioavailability of a drug. Background Art

[0002] Oral administration has long been the preferred route of administration for mainstream therapeutic drugs due to its simplicity, safety, effectiveness, and diverse formulation options. It is favored by patients and enjoys good patient compliance. However, many high-demand drugs are still administered via other routes, such as injection, due to various limitations. For example, most peptide drugs, such as insulin and GLP-1 agonists, are currently administered via injection, which has the disadvantage of low patient compliance, making medication use more difficult and causing long-term pain for patients.

[0003] Oral modification of drugs that are difficult to take orally has always been one of the important directions of drug research. Currently, the mainstream oral administration scheme for drugs that are difficult to take orally (such as protein and peptide drugs) is to use oral delivery agents, such as sodium octanoate (C8Na), sodium decanoate (C10Na), sodium laurate (C12Na), sodium chenodeoxycholate, etc., to prepare oral preparations with active drugs. A relatively successful example of oral drug development is the GLP-1R agonist drug semaglutide tablets developed by Novo Nordisk. It increases the oral absorption and utilization of peptides by adding the delivery agent sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) to GLP-1R agonist tablets. The drug has been approved for marketing in many regions including the United States and Europe. However, the biggest difficulty in the current oral protein or peptide drug technology is still the drug delivery efficiency. The lower delivery efficiency leads to higher raw material costs. This is mainly due to the presence of the gastrointestinal barrier, which makes it difficult for oral protein and peptide drugs to deliver drugs to the body's circulatory system.

[0004] Therefore, improving the oral bioavailability of drugs that are difficult to take orally (such as proteins and peptides), saving drug production costs, and benefiting more patients are urgent issues to be addressed in this field.

[0005] Summary of the Invention

[0006] To achieve the above objectives, this application adopts the following technical solutions:

[0007] The first aspect of the present application provides: the use of a delivery enhancer in improving the oral bioavailability of a protein or polypeptide drug, wherein the protein or polypeptide drug is used in combination with the delivery enhancer, and the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; the protein or polypeptide drug is delivered by the delivery agent.

[0008] In some preferred technical solutions, the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

[0009] In the application provided in the first aspect of the present application, the protein or polypeptide drug can be any type commonly used in the art, including but not limited to hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters and / or antibodies.

[0010] In the application provided in the first aspect of the present application, the protein or polypeptide drug may further include a receptor agonist or antagonist commonly used in the art.

[0011] In some preferred technical solutions, the receptor agonist or antagonist includes a GLP-1 receptor agonist, a GLP-1 receptor antagonist, a GIP receptor agonist, a GIP receptor antagonist and / or an insulin receptor agonist.

[0012] Furthermore, the receptor agonist or antagonist includes a GLP-1 receptor agonist.

[0013] Furthermore, the GLP-1 receptor agonist includes exendin, GLP-1 or its analogs, fragments, derivatives, fusion proteins, conjugates or pharmaceutically acceptable salts thereof.

[0014] In some of the most preferred technical solutions, the structure of the GLP-1 receptor agonist is shown in formula (I):

[0015] In the application provided in the first aspect of the present application, the structure of the delivery agent may be as shown in formula (III):

[0016] In formula (III), L represents a C5-C11 straight chain or branched alkylene group, and M represents Na + , K + or NH4 + .

[0017] Furthermore, L represents a C7-C9 straight or branched alkylene group, and M represents K + .

[0018] Furthermore, L represents a C7-C9 straight chain alkylene group, and M represents K+ .

[0019] In some preferred embodiments, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

[0020] Furthermore, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid includes sodium salt, potassium salt and / or ammonium salt.

[0021] In some of the most preferred technical solutions, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salt, and its structure is shown in formula (II):

[0022] In the application provided in the first aspect of the present application, the structure of the delivery agent may also be as shown in formula (IV): CH3-(CH2)n-COOM, (IV)

[0023] In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + .

[0024] Furthermore, n represents an integer of 6 to 8, and M represents Na + .

[0025] In some preferred embodiments, the delivery agent comprises a salt of caprylic acid, capric acid and / or lauric acid.

[0026] Furthermore, the delivery agent includes sodium, potassium and / or ammonium salts of caprylic acid, capric acid and / or lauric acid.

[0027] In some most preferred embodiments, the delivery agent comprises sodium salts of caprylic acid, capric acid, and / or lauric acid.

[0028] In the application provided in the first aspect of the present application, the delivery agent may further include a salt of chenodeoxycholic acid.

[0029] Furthermore, the delivery agent comprises sodium salt, potassium salt and / or ammonium salt of chenodeoxycholic acid.

[0030] In some preferred technical solutions, the delivery agent includes sodium chenodeoxycholate.

[0031] In the application provided in the first aspect of the present application, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:3.

[0032] In some preferred technical solutions, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:2.

[0033] In the application provided in the first aspect of the present application, the combined use includes using the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; or using them separately in a specific order, for example, using the delivery enhancer first and then the protein or polypeptide drug.

[0034] Furthermore, the combined use is to use the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition.

[0035] In the application provided in the first aspect of the present application, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5-1:150.

[0036] In some preferred technical solutions, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10-1:50, for example, 1:10-1:30.

[0037] In the application provided in the first aspect of the present application, the pharmaceutical composition further includes a pharmaceutically acceptable carrier, which can be any type commonly used in the art, including but not limited to one or more of lubricants, fillers, disintegrants, flavoring agents, colorants, adhesives, excipients, buffers, diluents, solubilizers, tonicity regulators, surfactants, preservatives, isotonic agents, stabilizers, and chelating agents.

[0038] In some preferred technical solutions, the pharmaceutically acceptable carrier includes a lubricant, a filler and a disintegrant.

[0039] Furthermore, the lubricant includes magnesium stearate, glyceryl tribehenate and / or stearic acid.

[0040] In some most preferred technical solutions, the lubricant is selected from magnesium stearate; and / or the filler is selected from mannitol and / or microcrystalline cellulose; and / or the disintegrant is selected from cross-linked carboxymethyl cellulose sodium.

[0041] In the application provided in the first aspect of the present application, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug.

[0042] In some preferred technical solutions, the active pharmaceutical ingredient is selected from antidiabetic agents, antiobesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and conditions caused by or associated with diabetes, and agents for treating and / or preventing complications and conditions caused by or associated with obesity.

[0043] In the application provided in the first aspect of the present application, the dosage form of the pharmaceutical composition can be any dosage form commonly used in the art.

[0044] In some preferred technical solutions, the dosage form of the pharmaceutical composition can be an oral dosage form, including but not limited to one or more of tablets, capsules, emulsions, aqueous suspensions, dispersions, and powders.

[0045] In some most preferred technical solutions, the pharmaceutical composition is in the form of a tablet.

[0046] In some most preferred technical solutions, the tablets can be prepared by dry granulation processes and / or direct mixing processes commonly used in the art.

[0047] In some preferred technical solutions, the tablet hardness is 30-90N.

[0048] The second aspect of the present application provides: a method for improving the oral bioavailability of a protein or polypeptide drug, the method comprising: using the protein or polypeptide drug in combination with a delivery enhancer, the delivery enhancer comprising hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; the protein or polypeptide drug is delivered via a delivery agent.

[0049] In some preferred technical solutions, the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

[0050] In the method provided in the second aspect of the present application, the protein or polypeptide drug is as defined in the first aspect of the present application.

[0051] In the method provided in the second aspect of the present application, the delivery agent is as defined in the first aspect of the present application.

[0052] In the method provided in the second aspect of the present application, the manner of combined use is as defined in the first aspect of the present application.

[0053] In the method provided in the second aspect of the present application, the mass ratio of the delivery agent to the delivery enhancer, and the mass ratio of the protein or polypeptide drug to the delivery agent are as defined in the first aspect of the present application.

[0054] In the method provided in the second aspect of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, which is as defined in the first aspect of the present application.

[0055] In the method provided in the second aspect of the present application, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug, which are as defined in the first aspect of the present application.

[0056] In the method provided in the second aspect of the present application, the dosage form of the pharmaceutical composition and the preparation method thereof can be any dosage form and process commonly used in the art, for example, as defined in the first aspect of the present application.

[0057] The third aspect of the present application provides: a pharmaceutical composition with improved oral bioavailability and containing a protein or polypeptide drug as an active ingredient, the pharmaceutical composition comprising a delivery enhancer, the delivery enhancer comprising hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; the pharmaceutical composition also comprising a delivery agent.

[0058] In some preferred technical solutions, the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

[0059] In the pharmaceutical composition provided in the third aspect of the present application, the protein or polypeptide drug is as defined in the first aspect of the present application.

[0060] In the pharmaceutical composition provided in the third aspect of the present application, the delivery agent is as defined in the first aspect of the present application.

[0061] In the pharmaceutical composition provided in the third aspect of the present application, the mass ratio of the delivery agent to the delivery enhancer, and the mass ratio of the protein or polypeptide drug to the delivery agent are as defined in the first aspect of the present application.

[0062] In the pharmaceutical composition provided in the third aspect of the present application, the protein or polypeptide drug is used in combination with a delivery enhancer, and the manner of the combined use is as defined in the first aspect of the present application.

[0063] In the pharmaceutical composition provided in the third aspect of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, which is as defined in the first aspect of the present application.

[0064] In the pharmaceutical composition provided in the third aspect of the present application, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug, which are as defined in the first aspect of the present application.

[0065] In the pharmaceutical composition provided in the third aspect of the present application, the dosage form and preparation method of the pharmaceutical composition can be any dosage form and process commonly used in the art, for example, as defined in the first aspect of the present application.

[0066] The fourth aspect of the present application provides: the use of the following substances as synergists for drug delivery agents: aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; wherein the delivery agent is as defined in the first aspect of the present application.

[0067] The fifth aspect of the present application provides: a pharmaceutical composition comprising a delivery agent and a delivery enhancer, wherein the delivery agent is as defined in the first aspect of the present application, and the delivery enhancer comprises aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide.

[0068] In some preferred technical solutions, the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

[0069] In the pharmaceutical composition provided in the fifth aspect of the present application, the pharmaceutical composition further comprises a protein or polypeptide drug, which is as defined in the first aspect of the present application.

[0070] In the pharmaceutical composition provided in the fifth aspect of the present application, the mass ratio of the delivery agent to the delivery enhancer, and the mass ratio of the protein or polypeptide drug to the delivery agent are as defined in the first aspect of the present application.

[0071] In the pharmaceutical composition provided in the fifth aspect of the present application, the protein or polypeptide drug is used in combination with a delivery enhancer, and the manner of the combined use is as defined in the first aspect of the present application.

[0072] In the pharmaceutical composition provided in the fifth aspect of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, which is as defined in the first aspect of the present application.

[0073] In the pharmaceutical composition provided in the fifth aspect of the present application, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug, which are as defined in the first aspect of the present application.

[0074] In the pharmaceutical composition provided in the fifth aspect of the present application, the dosage form and preparation method of the pharmaceutical composition can be any dosage form and process commonly used in the art, for example, as defined in the first aspect of the present application.

[0075] The sixth aspect of the present application provides: the use of the pharmaceutical composition described in the third aspect and the fifth aspect of the present application as a medicine (i.e., for treatment).

[0076] The seventh aspect of the present application provides: the use of the pharmaceutical composition described in the third aspect and the fifth aspect of the present application in the preparation of drugs for preventing and / or treating metabolic-related diseases, neurological-related diseases or brain-related diseases.

[0077] The eighth aspect of the present application provides: a method for preventing and / or treating metabolic-related diseases, neurological-related diseases or brain-related diseases, comprising administering a therapeutically effective dose of the pharmaceutical composition described in the third aspect and the fifth aspect of the present application to a patient in need.

[0078] In the seventh and eighth aspects of the present application, the metabolism-related diseases include glucose metabolism disorders and / or fat metabolism disorders.

[0079] In some preferred technical solutions, the glucose metabolism disorder disease includes a disease related to abnormal blood sugar.

[0080] Furthermore, the diseases related to abnormal blood sugar include diabetes, diabetic eye disease, diabetic heart disease, diabetic nephropathy, diabetic neuropathy and distal limb necrosis of the lower limbs, atherosclerosis, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, osteoporosis, hyperlipidemia, hypertension, obesity, fatty liver and / or cirrhosis.

[0081] Furthermore, the diabetes mellitus includes hyperglycemia, type II diabetes, impaired glucose tolerance, type I diabetes, non-insulin-dependent diabetes mellitus, maturity-onset diabetes of the young (MODY) and / or gestational diabetes.

[0082] In some preferred technical solutions, the fat metabolism disorder disease includes a disease related to abnormal body weight.

[0083] Furthermore, the diseases associated with abnormal weight include anemia, gastroptosis, inflammatory bowel disease, indigestion, gastrointestinal ulcers, endocrine disorders, osteoporosis, obesity, hypertension, hyperlipidemia, coronary heart disease, diabetes, fatty liver, joint deformity, pain, cancer, respiratory insufficiency, kidney disease, hyperlipidemia, hypertension, atherosclerosis, cirrhosis, angina pectoris and / or myocardial infarction.

[0084] In the seventh and eighth aspects of the present application, the nerve-related diseases include neurodegenerative diseases.

[0085] Furthermore, the neurodegenerative diseases include brain atrophy, cerebral ischemia, brain injury, epilepsy, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, spinocerebellar ataxia, Pick's disease, bovine spongiform encephalopathy and / or Creutzfeldt-Jakob disease.

[0086] The ninth aspect of the present application provides: a kit comprising the pharmaceutical composition described in the third aspect and the fifth aspect of the present application.

[0087] Advantages and beneficial effects of this application:

[0088] The pharmaceutical composition provided in this application, after adding the delivery enhancer described in this application, can maximize the delivery effect of the delivery agent in a certain ratio with the delivery agent, which not only reduces the amount of delivery agent used, but also increases the oral bioavailability of drugs (for example, protein or polypeptide drugs). BRIEF DESCRIPTION OF THE DRAWINGS

[0089] FIG1 is a graph showing the oral absorption of the GLP-1 receptor agonist after calcium carbonate and aluminum hydroxide are added to the composition in Example 1.

[0090] FIG2 is a graph showing the plasma concentration-time curves of the pharmacokinetic study of each composition in cynomolgus monkeys on Day 7 in Example 3. DETAILED DESCRIPTION

[0091] The following provides definitions of some terms used in this specification. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0092] In this application, "protein or polypeptide drugs" refer to protein or polypeptide compounds contained in oral drugs that have the function of directly acting as active pharmaceutical ingredients in the body or indirectly helping active pharmaceutical ingredients to prevent and / or treat diseases.

[0093] In some embodiments of the present application, the protein or polypeptide drug can be a natural protein or polypeptide compound (such as hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters and antibodies) or an artificially synthesized polypeptide or protein, as well as analogs, derivatives, conjugates or fusion proteins of the above polypeptides or proteins or their pharmaceutically acceptable salts.

[0094] In some embodiments of the present application, the protein or polypeptide drug may be a compound having receptor agonist or antagonist activity. The receptor agonists or antagonists include, but are not limited to, GLP-1 receptor agonists, GLP-1 receptor antagonists, GIP receptor agonists, GIP receptor antagonists, Amylin receptor agonists, heparin receptor agonists, growth hormone receptor agonists, interferon receptor agonists, interleukin receptor agonists, follicle-stimulating hormone receptor agonists, gonadotropin receptor agonists, erythropoietin receptor agonists, PYY (peptide tyrosine) receptor agonists, oxygenomodulin receptor agonists, GLP-2 (glucagon-like peptide-2) receptor agonists, calcitonin receptor agonists, PTH (parathyroid hormone) receptor agonists, ghrelin receptor agonists, endocannabinoid receptor agonists, leptin receptor agonists, serotonin receptor agonists, fibroblast growth factor 21 (FGF21) receptor agonists, cholecystokinin (CCK) receptor agonists, and glucagon receptor agonists.

[0095] In some embodiments of the present application, the protein or polypeptide drug simultaneously includes the active functions of one or more receptor agonists or antagonists.

[0096] In some embodiments of the present application, the protein or polypeptide drug is preferably a GLP-1 receptor agonist; the GLP-1 receptor agonist includes compounds having GLP-1 receptor agonist activity, especially polypeptides / proteins, as well as analogs, derivatives, conjugates or fusion proteins of the above polypeptides / proteins or pharmaceutically acceptable salts thereof.

[0097] In some embodiments of the present application, the GLP-1 receptor agonist includes exendin, exendin analogs, exendin agonists, GLP-1 (7-37), GLP-1 (7-37) analogs or derivatives, conjugates or fusion proteins or pharmaceutically acceptable salts thereof. The GLP-1 receptor agonist compound may be optionally amidated. The terms GLP-1 receptor agonist and GLP-1 receptor agonist compound have the same meaning.

[0098] Among these, exendins include naturally occurring exendins (or synthetic versions of naturally occurring ones) found in the salivary secretions of the Gila monster. Exendins of particular interest include exendin-3 and exendin-4. The exendins, exendin analogs, and exendin agonists used in this application may optionally be amidated and may also exist in the acid form, pharmaceutically acceptable salt form, or any other physiologically active form of the molecule.

[0099] GLP-1 (7-37) analogs refer to peptides that elicit biological activity similar to that of GLP-1 (7-37) when assessed by measurement methods known in the art, such as receptor binding assays or in vivo blood glucose assays, e.g., as described in Hargrove et al., Regulatory Peptides, 141: 113-119 (2007), the disclosure of which is incorporated herein by reference. In one embodiment, the term GLP-1 (7-37) analog refers to a peptide having an amino acid sequence that has 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions, insertions, deletions, or a combination of two or more thereof when compared to the amino acid sequence of GLP-1 (7-37). GLP-1 (7-37) analogs include amidated forms, acid forms, and any other physiologically active forms of the molecule.

[0100] As used herein, "agonist" refers to a compound, molecule, or agent that stimulates a biological activity.

[0101] In the present application, "analog" refers to a substance having a similar structure and / or function to the protein or polypeptide of the present application.

[0102] In this application, "pharmaceutically acceptable salt" refers to any adduct between two or more chemical species that are capable of undergoing proton transfer. Thus, pharmaceutically acceptable salts include adducts in which complete proton transfer has occurred; adducts in which partial proton transfer has occurred (e.g., in which an equilibrium mixture of charged and uncharged species is formed); and / or adducts in which proton transfer has not yet occurred, but the chemical species are bound together, for example, by hydrogen bonding. It will be understood that pharmaceutically acceptable salts also encompass adducts in which tight ion pairs exist. It will also be understood that pharmaceutically acceptable salts encompass a continuum of adducts between adducts in which complete proton transfer has occurred to form discrete ions and / or adducts in which two species are bound but no or only partial proton transfer has occurred. See, for example, Childs et al. Mol. Pharmaceutics, 2007, 4(3), pp 323-338. A given pharmaceutically acceptable salt may contain one or more adducts on this continuum.

[0103] Pharmaceutically acceptable salts include salts with acidic or basic groups. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, methanesulfonate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)). Suitable alkali salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.

[0104] In the present application, the mass ratio of the delivery agent to the delivery enhancer can be any mass ratio that can improve the delivery effect, for example, it can be 1:0.3-1:3, including about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2, about 1:2.1, about 1:2.2, about 1:2.3, about 1:2.4, about 1:2.5, about 1:2.6, about 1:2.7, about 1:2.8, about 1:2.9, about 1:3 mass ratios and any mass ratio interval.

[0105] In the present application, the mass ratio of the protein or polypeptide drug to the delivery agent can be any mass ratio that can achieve protein or polypeptide drug delivery, for example, it can be 1:5-1:150, including a mass ratio of about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, about 1:100, about 1:105, about 1:110, about 1:115, about 1:120, about 1:125, about 1:130, about 1:135, about 1:140, about 1:145, about 1:150 and any mass ratio interval.

[0106] In the present application, " bioavailability " refers to the degree and speed at which a substance such as a drug, peptide or hormone can be utilized at a physiologically active site. In the field of pharmacology, the term bioavailability is understood to be the fraction of the dosage of the unchanged medicine, compound or medicine that reaches systemic circulation, and is one of the main pharmacokinetic properties of medicine. According to definition, when a drug is administered intravenously, its bioavailability is 100%. However, when a drug is administered by other approaches (such as oral or intramuscular), its bioavailability is reduced usually due to factors such as incomplete absorption and first-pass metabolism. Due to the difference in, for example, individual metabolism, these factors may vary from patient to patient.

[0107] Standard assays for determining the bioavailability of a drug are known to those skilled in the art and involve, inter alia, measuring the relative area under the curve (AUC) of the concentration of the drug administered orally and intravenously (iv) in the same species.

[0108] In the present application, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be crystalline and / or amorphous, including but not limited to sodium salt, potassium salt and / or ammonium salt.

[0109] In the present application, "pharmaceutically acceptable carrier" refers to a non-toxic material that does not interfere with the effect of the pharmaceutically active ingredient or pharmaceutical composition of the present application or the biological activity of the pharmaceutically active ingredient or pharmaceutical composition of the present application. The use of pharmaceutically acceptable carriers to formulate pharmaceutically active ingredients is known in the art, for example, Remington: The Science and Practice of Pharmacy (e.g., 21st edition (2005), and any subsequent editions). Non-limiting examples of pharmaceutically acceptable carriers include, but are not limited to, salts (e.g., acid salts / anionic salts, basic salts / cationic salts), excipients, buffers, diluents, solubilizers, tonicity regulators, surfactants, preservatives, isotonic agents, flavorings, colorants, stabilizers, binders, disintegrants, fillers, lubricants, and chelating agents. One or more pharmaceutically acceptable carriers can be used to formulate the pharmaceutical composition of the present application.

[0110] In some embodiments of the present application, the pharmaceutically acceptable carrier includes an acid salt / anionic salt. Non-limiting examples of acid salts / anionic salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, p-hydroxyacetamidophenylarsinate, hexylresorcinol salt, hydrazine, hydrobromide, hydrochloride, hydroxynaphthalene

[0014] Examples of the present invention include iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthenate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, triethyl iodide, and combinations thereof.

[0111] In some embodiments of the present application, pharmaceutically acceptable carriers include alkali salts / cationic salts. Non-limiting examples of alkali salts / cationic salts include, but are not limited to, aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethamine, or TRIS), ammonia, benzathine penicillin, tert-butylamine, chloroprocaine, choline, cyclohexylamine, diethanolamine, ethylenediamine, lithium, L-lysine, magnesium, meglumine, N-methyl-D-glucamine, piperidine, potassium, procaine, quinine, sodium, triethanolamine, zinc, and combinations thereof.

[0112] In some embodiments of the present application, the pharmaceutically acceptable carrier comprises a buffer. Non-limiting examples of buffers include, but are not limited to, arginine, aspartic acid, bicine, citrate, disodium hydrogen phosphate, fumaric acid, glycine, glycylglycine, histidine, lysine, maleic acid, malic acid, sodium acetate, sodium carbonate, sodium dihydrogen phosphate, sodium phosphate, succinate, tartaric acid, triazine, and tris(hydroxymethyl)aminomethane, and combinations thereof.

[0113] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a preservative. Non-limiting examples of preservatives include, but are not limited to, benzethonium chloride, benzoic acid, benzyl alcohol, bromonitropropylene glycol, butyl 4-hydroxybenzoate, chlorobutanol, chlorocresol, chlorhexidine, chlorphenesin, o-cresol, m-cresol, p-cresol, ethyl 4-hydroxybenzoate, imidurea, methyl 4-hydroxybenzoate, phenol, 2-phenoxyethanol, 2-phenylethanol, propyl 4-hydroxybenzoate, sodium dehydroacetate, thimerosal, and combinations thereof.

[0114] In some embodiments of the present application, pharmaceutically acceptable carrier includes isotonic agent. Non-limiting examples of isotonic agent include but are not limited to amino acid (such as glycine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan and threonine), sugar alcohol (such as glycerol, 1,2-propylene glycol, propylene glycol), 1,3-propylene glycol and 1,3-butylene glycol), polyethylene glycol (for example, PEG400) and combination thereof. Another example of isotonic agent includes sugar. Non-limiting examples of sugar can be monosaccharide, disaccharide or polysaccharide, or water-soluble glucan, including for example fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, trehalose, glucan, amylopectin, dextrin, cyclodextrin, α and β-HPCD, soluble starch, hydroxyethyl starch, sodium carboxymethyl cellulose and combination thereof. Another example of isotonic agent is sugar alcohol, wherein term " sugar alcohol " is defined as C (4-8) hydrocarbon with at least one -OH group. Non-limiting examples of sugar alcohols include, but are not limited to, mannitol, sorbitol, inositol, galactitol, hexasol, xylitol, arabitol, and combinations thereof. Medicaments comprising each of the isotonic agents listed in this paragraph constitute alternative embodiments of the present application.

[0115] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a chelating agent. Non-limiting examples of chelating agents include, but are not limited to, salts of citric acid, aspartic acid, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0116] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a stabilizer. Non-limiting examples of stabilizers include carboxy- / hydroxycellulose and its derivatives (such as HPC, HPC-SL, HPC-L and HPMC), cyclodextrin, 2-methylthioethanol, polyethylene glycol (such as PEG 3350), polyvinyl alcohol (PVA), polyvinyl pyrrolidone, salts (such as sodium chloride), sulfur-containing substances (such as monothioglycerol or thioglycolic acid) and combinations thereof.

[0117] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a lubricant (also referred to as a "glidant"). Lubricants can be used to prevent the dosage form from adhering to the surfaces of the rollers, dies, and punches and to reduce friction between the particles. Lubricants can also facilitate ejection of the dosage form from the die cavity and improve granulation flow rate during processing. Non-limiting examples of lubricants include, but are not limited to, magnesium stearate, glyceryl behenate, calcium stearate, zinc stearate, stearic acid, silicon dioxide, talc, polyethylene glycol, mineral oil, carnauba wax, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, palmitoyl stearin, myristic acid and hydrogenated vegetable oils and fats, white petrolatum, white beeswax, sodium benzoate, sodium hyaluronate, poloxamer, glyceryl monostearate, dimethicone, mixed fatty acid glycerides (stearin), polyvinyl alcohol, Leucine, light liquid paraffin, hydrogenated soybean oil, sorbitan trioleate (Span 85), glyceryl behenate, cetostearyl alcohol, octyldodecanol, liquid paraffin, stearic acid, magnesium lauryl sulfate, almond oil, rapeseed oil, cetyl esters wax, stearyl palmitate, isopropyl palmitate, light liquid paraffin, sodium stearyl fumarate, glyceryl behenate, potassium benzoate, sterilized corn starch, myristic acid, tricaprylin, lauric acid, magnesium oxide, calcium phosphate, powdered cellulose, magnesium silicate, magnesium trisilicate, calcium phosphate, hydrophobic silica gel and other known lubricants, and / or mixtures of two or more thereof. In one embodiment, if present, the lubricant for raw material granulation is magnesium stearate.

[0118] In some embodiments of the present application, the pharmaceutically acceptable carrier includes one or more surfactants, preferably one surfactant, at least one surfactant, or two different surfactants. Surfactant refers to any molecule or ion composed of a water-soluble portion (hydrophilic) and a fat-soluble portion (lipophilic). For example, the surfactant is selected from: anionic surfactants, cationic surfactants, nonionic surfactants, and / or zwitterionic surfactants, and combinations thereof.

[0119] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a flavoring agent. Flavoring agents can be used to improve the palatability of the pharmaceutical composition. Non-limiting examples of flavoring agents include, but are not limited to, natural and / or synthetic (i.e., artificial) compounds and combinations thereof with corresponding flavors (e.g., mint, spearmint, wintergreen, cinnamon, menthol, cherry, strawberry, watermelon, grape, banana, peach, pineapple, apricot, pear, raspberry, lemon, grapefruit, orange, plum, apple, fruit punch, passion fruit, chocolate (e.g., white chocolate, milk chocolate, dark chocolate), vanilla, caramel, coffee, hazelnut).

[0120] In some embodiments of the present application, a pharmaceutically acceptable carrier includes a colorant. The colorant can be used to color-code the pharmaceutical composition, for example, to indicate the type and dosage of the therapeutic agent therein. Non-limiting examples of colorants include, but are not limited to, natural and / or artificial compounds such as FD&C colorants, natural juice concentrates; dyes such as titanium dioxide, silicon dioxide, and zinc oxide; and combinations thereof.

[0121] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a disintegrant. Non-limiting examples of disintegrants include, but are not limited to, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl methylcellulose, starch, guar gum, magnesium aluminum silicate, alginic acid, sodium alginate, methylcellulose, cross-linked polyvidone, polycrilin potassium, microcrystalline cellulose, anhydrous citric acid, pregelatinized starch, carboxymethyl cellulose calcium, powdered cellulose, sodium carboxymethyl starch, chitosan, calcium alginate, and combinations thereof.

[0122] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a filler. Non-limiting examples of fillers include, but are not limited to, lactose, microcrystalline cellulose, starch, pregelatinized starch, mannitol, kaolin, cellulose acetate, fructose, dextrin, talc, calcium sulfate, sodium chloride, xylitol, glucose, sorbitol, anhydrous lactose, magnesium oxide, zinc oxide, ethyl cellulose, sucrose, anhydrous lactose, dextran, and combinations thereof.

[0123] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a binder. Non-limiting examples of binders include, but are not limited to, low-substituted hydroxypropyl methylcellulose, starch, hydrogenated soybean oil, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, α-lactose, dextran, hydroxypropyl starch, vitamin E polyethylene glycol succinate, gum arabic, alginic acid, methylcellulose, polyacrylic acid resin, povidone, maltodextrin, ethyl hydroxycellulose, zein, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, carob gum, carbomer, povidone, glyceryl behenate, chitosan, liquid glucose, hydroxyethyl methylcellulose, sunflower oil, hydrogenated vegetable oil, inulin, and combinations thereof.

[0124] In the present application, the pharmaceutical composition for oral administration can be any orally acceptable dosage form, including but not limited to capsules, tablets, powders, emulsions and aqueous suspensions, dispersants and solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifier or suspending agent. If desired, certain sweeteners, flavorings or coloring agents can be added. Nasal aerosols or inhalation compositions can be prepared according to techniques well known in the field of pharmaceutical preparations, and can be made into saline solutions, using benzyl alcohol or other suitable preservatives, absorption enhancers, fluorocarbons and / or other solubilizers or dispersants known in the art. The pharmaceutical composition of the present application can also be administered rectally in the form of suppositories.

[0125] If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Any pharmaceutical method can be used to prepare such dosage forms. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then shaping the product into the desired form if necessary.

[0126] In a specific embodiment of the present application, the dosage form of the pharmaceutical composition is a tablet.

[0127] In some embodiments of the present application, the tablet preparation method can be any conventional tablet preparation method familiar to those skilled in the art, for example, it can be prepared using a dry granulation process or a direct mixing process.

[0128] The specific steps of the dry granulation process are as follows: ① Material pretreatment: The protein or polypeptide drug is passed through a 50-200 mesh sieve, preferably a 100 mesh sieve, and can be crushed first and then sieved if necessary. The delivery agent is passed through a 20-100 mesh sieve, preferably a 50 mesh sieve. The material that does not pass through the sieve is ground and sieved again. The delivery enhancer is treated in the same way as the delivery agent. The lubricant is used directly. If present, other pharmaceutically acceptable carriers are all passed through a 20-80 mesh sieve, preferably a 40 mesh sieve. ② First mixing: A certain amount of protein or polypeptide drug, delivery agent, delivery enhancer, part of the lubricant and optional other pharmaceutically acceptable carriers are manually mixed to obtain a mixed powder I. ③ Dry granulation: The above mixed powder I is rolled into a strip-shaped thin sheet with appropriate hardness, and then crushed into particles of appropriate particle size. ④ Re-mixing: The above particles are collected, the remaining lubricant is added again, and manually mixed to obtain a mixed powder I. ⑤ Tableting: Tableting is performed according to a conventional tableting process in the art, and the tablet hardness is controlled within the range of 30-90N.

[0129] The specific steps of the direct mixing process are: 1. Material pretreatment: The protein or polypeptide drug is passed through a 100-mesh sieve, and can be crushed first and then sieved if necessary. The delivery agent is passed through a 50-mesh sieve, and the material that does not pass through the sieve is ground and sieved again. The delivery enhancer is passed through a 20-80 mesh sieve, preferably a 40-mesh sieve. The lubricant is used directly. If present, other pharmaceutically acceptable carriers are passed through a 20-80 mesh sieve, preferably a 40-mesh sieve. 2. Mixing: A certain amount of protein or polypeptide drug, delivery agent, delivery enhancer, lubricant and other optional pharmaceutically acceptable carriers are manually mixed to obtain mixed powder I. 3. Tableting: Tableting is performed according to the conventional tableting process in this field, and the tablet hardness is controlled within the range of 30-90N.

[0130] In a specific embodiment of the present application, tablets are prepared using a direct blending process.

[0131] In a specific embodiment of the present application, the tablet is prepared using a granulation process, preferably dry granulation.

[0132] In the present application, in addition to the pharmaceutical composition, the kit may comprise one or more containers selected from bottles, vials, ampoules, blister packs, and syringes. The kit may further comprise one or more instructions for use, one or more syringes, one or more applicators, or a sterile solution suitable for reconstitution of the pharmaceutical composition of the present application for treating and / or preventing a disease, condition, or disorder.

[0133] In the present application, the active pharmaceutical ingredient for combined use can be any ingredient that is different from the aforementioned protein or polypeptide drug but has the same or similar active function, or that acts together with the aforementioned protein or polypeptide drug to produce active function, for example, it can be selected from antidiabetic agents, antiobesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and diseases caused by or related to diabetes, and agents for treating and / or preventing complications and diseases caused by or related to obesity.Non-limiting examples of such pharmacologically active ingredients include, but are not limited to, insulin, sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV (dipeptidyl peptidase-IV) inhibitors, sodium glucose transporter 2 (SGLT2) inhibitors; canagliflozin, dapagliflozin, empagliflozin, empagliflozin, isogliflozin, togliflozin, lupagliflozin, bexagliflozin, repagliflozin ectoate and sotaglifkozin, in particular dapagliflozin and empagliflozin, inhibitors of liver enzymes involved in stimulating gluconeogenesis and / or glycogenolysis, glucose uptake regulators, compounds that alter lipid metabolism such as antihyperlipidemic agents such as HMG coenzyme A inhibitors (statins), gastric inhibitory polypeptide (GIP analogs), compounds that reduce food intake, RXR agonists and agents that act on ATP-dependent potassium channels of beta cells; cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, Pravastatin, simvastatin, probucol, dextrothyroxine, nateglinide, repaglinide; beta-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, and metoprolol; ACE (angiotensin-converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, fasidotril, quinapril, and ramipril; calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, and Verapamil; and alpha-blockers such as doxazosin, urapidil, prazosin, and terazosin; CART (cocaine amphetamine-regulated transcript) agonists, NPY (neuropeptide Y) antagonists, PYY agonists, Y2 receptor agonists, Y4 receptor agonists, mixed Y2 / Y4 receptor agonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin-releasing factor) agonists, CRF BP (corticotropin-releasing factor binding protein) antagonists, urocortin agonists, β3 agonists, oxyntomodulin and analogs, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, mixed serotonin and norepinephrine compounds, 5HT (5-hydroxytryptamine) agonists, bombesin Agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH (thyrotropin-releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, RXR (retinoid X receptor) modulators, TRβ agonists; histamine H3 antagonists, gastric inhibitory polypeptide agonists or antagonists (GIP analogs), gastrin and gastrin analogs.

[0134] The pharmaceutical composition of the present application can be used to prevent and / or treat diseases, preferably metabolic-related diseases or nerve-related diseases or brain-related diseases, including but not limited to glucose metabolism disorders and / or fat metabolism disorders and / or neurodegenerative diseases.

[0135] In some embodiments of the present application, the glucose metabolism disorder is a disease related to abnormal blood sugar, and the fat metabolism disorder is a disease related to abnormal weight. Wherein, the disease related to abnormal blood sugar refers to a disease / symptom accompanied by abnormal blood sugar or a complication / symptom caused by a disease accompanied by abnormal blood sugar, selected from one or more of the following: diabetes, diabetic eye disease, diabetic heart disease, diabetic nephropathy, diabetic neuropathy and distal limb necrosis of the lower limbs, atherosclerosis, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, osteoporosis, hyperlipidemia, hypertension, obesity, fatty liver, cirrhosis. The diabetes, such as hyperglycemia, type II diabetes, impaired glucose tolerance, type I diabetes, non-insulin-dependent diabetes mellitus, MODY (maturity-onset diabetes of the young), gestational diabetes. The abnormal weight-related diseases refer to diseases / symptoms associated with abnormal weight or complications / symptoms caused by diseases associated with abnormal weight, selected from one or more of the following: anemia, gastroptosis, inflammatory bowel disease, indigestion, gastrointestinal ulcers, endocrine disorders, osteoporosis, obesity, hypertension, hyperlipidemia, coronary heart disease, diabetes, fatty liver, joint deformity, pain, cancer, respiratory insufficiency, kidney disease, hyperlipidemia, hypertension, atherosclerosis, cirrhosis, angina pectoris, and myocardial infarction.

[0136] In some embodiments of the present application, the neurodegenerative disease is selected from one or more of the following: brain atrophy, cerebral ischemia, brain injury, epilepsy, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, spinocerebellar ataxia, Pick's disease, bovine spongiform encephalopathy, and Creutzfeldt-Jakob disease.

[0137] The pharmaceutical composition of the present application can also be used as a therapeutic agent to reduce HbA1C; delay or prevent the progression of diabetes, such as the progression of type 2 diabetes, delay the progression of impaired glucose tolerance (IGT) to type 2 diabetes requiring insulin, and / or delay the progression of type 2 diabetes not requiring insulin to type 2 diabetes requiring insulin; improve β-cell function, such as reducing β-cell apoptosis, improving β-cell function and / or β-cell mass, and / or restoring β-cell glucose sensitivity.

[0138] As used herein, "treat," "treat," "treat," and similar synonyms include alleviating, alleviating, or ameliorating symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing underlying metabolic causes of symptoms, inhibiting a disease or condition, such as arresting the progression of the disease or condition, relieving a disease or condition, causing amelioration of a disease or condition, relieving symptoms caused by a disease or condition, or halting symptoms of a disease or condition, and further, the term encompasses the purpose of prevention. The term also encompasses achieving a therapeutic effect and / or a prophylactic effect.

[0139] In this application, "patient" refers to an individual suffering from a disease, disorder, condition, etc., including mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.

[0140] In the present application, "C5-C11" means that the group has 5 to 11 carbon atoms, that is, the group contains 5 carbon atoms (C5), 6 carbon atoms (C6), 7 carbon atoms (C7), 8 carbon atoms (C8), 9 carbon atoms (C9), 10 carbon atoms (C10) or 11 carbon atoms (C11).

[0141] In this application, a numerical range, such as "4 to 10" or "6 to 8" refers to each integer in the given range, including 4, 5, 6, 7, 8, 9 or 10.

[0142] The present application will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are presented by way of example and are not intended to limit the present application. The main features of the present application may be applied to various embodiments without departing from the scope of the present application.

[0143] The structure of the GLP-1 receptor agonist used in the examples and comparative examples is shown in formula (I), and is named N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide, a glucagon-like peptide-1 receptor (GLP-1R) polypeptide agonist, prepared with reference to WO2019201328A1.

[0144] The PNAC used in the Examples and Comparative Examples is an anhydrous crystalline sample of potassium salt of N-(8-(2-hydroxybenzoyl)amino)octanoate. The structure of PNAC is shown in Formula (II), and it was prepared according to CN 112661663B, i.e., Form I.

[0145] Unless otherwise specified, the experimental animals, experimental instruments, experimental reagents, etc. used in the examples and comparative examples are all common commercially available products.

[0146] The analysis method for the GLP-1 receptor agonist content used in the Examples and Comparative Examples is as follows:

[0147] For the content analysis of the active substance GLP-1 receptor agonist, the HPLC method (General Chapter 0512 of Part IV of the 2020 Chinese Pharmacopoeia) is used. The specific test process is as follows: Take 5 tablets of the composition, weigh the total weight, grind and mix them, weigh an appropriate amount and dissolve them in a diluent (0.01% Tween 20 + 0.05M Na2HPO4), dilute and fix the volume after full dissolution, shake well, and continue to stand for 30 minutes for full extraction. After shaking, the sample is centrifuged (4°C 12000rpm centrifugation for 10 minutes), and the supernatant is taken into an HPLC liquid phase vial of appropriate volume, sampled and analyzed, and detected using a Waters high performance liquid chromatograph. The reversed-phase chromatographic column is a YMC UltraHT Pro C18 column. In addition, electronic balances (one hundred thousandth), ultrasonic instruments, volumetric flasks, reagent bottles, sealing films and other instruments will also be used. Reagents used included distilled water, acetonitrile (HPLC grade), isopropanol (HPLC grade), trifluoroacetic acid (HPLC grade), anhydrous disodium hydrogen phosphate, and Tween 20. Mobile phase A consisted of water:acetonitrile:TFA in a volume ratio of 830:170:2. Mobile phase B consisted of acetonitrile:isopropanol:TFA in a volume ratio of 850:150:2. The content of the GLP-1 receptor agonist in the tablet composition was calculated relative to the peak area of ​​the reference substance.

[0148] Example 1 Pharmacokinetic Study in Beagle Dogs

[0149] 1. Preparation of Composition Tablets

[0150] Tablets with the same amount of GLP-1 receptor agonist were prepared, but the contents of excipients, such as the delivery agent PNAC, delivery enhancer, and other excipients, were different. Tables 1 and 2 provide the contents of the various components in the prepared tablets of different compositions.

[0151] The specific preparation steps of the tablets are as follows: ① Material pretreatment: The GLP-1 receptor agonist is passed through a 100-mesh sieve and can be crushed first and then sieved if necessary. The delivery agent PNAC is passed through a 50-mesh sieve, and the material that does not pass through the sieve is ground and sieved again. The delivery enhancer is treated in the same way as PNAC. The lubricant magnesium stearate is used directly. ② First mixing: A certain amount of GLP-1 receptor agonist, delivery agent, delivery enhancer and an appropriate amount of magnesium stearate are manually mixed to obtain a mixed powder I. ③ Dry granulation: The above-mentioned mixed powder I is rolled into strip-shaped flakes with appropriate hardness, and then crushed into granules. ④ Re-mixing: Collect the above-mentioned granules, add the remaining magnesium stearate again, and mix manually to obtain a uniform mixture. ⑤ Tableting: The tablet hardness is controlled within the range of 30-90N.

[0152] Table 1 Compositions of tablets of different compositions

[0153] Table 2 Composition of calcium carbonate-containing tablets

[0154] 2. Test methods and results

[0155] 2.1 Disintegration test

[0156] According to the disintegration time limit inspection method of Part 4 of the Chinese Pharmacopoeia 2020 Edition, the tablet disintegration test in this embodiment was carried out, and the disintegration time of tablets of different compositions in vitro was recorded. The specific method is as follows: the hanging basket is suspended on the bracket by a stainless steel shaft, immersed in a 1000mL beaker, and the position of the hanging basket is adjusted so that when it drops to the lowest point, the bottom screen is about 25mm from the bottom of the cup. The beaker is filled with purified water at a temperature of 37±1°C. The water level is adjusted so that when the hanging basket rises to the highest point, the screen is 15mm below the water surface, and the top of the hanging basket is not immersed in the solution.

[0157] In this example, the disintegration time was measured using the ZB-1D intelligent disintegration instrument from Tianjin Tianhe Analytical Instrument Co., Ltd. The results were taken as the median value of 3-6 tablets of the composition.

[0158] The results are shown in Table 3. The disintegration time of tablets of different compositions changes with the type or ratio of the delivery enhancer, and increases to varying degrees relative to the reference composition A.

[0159] Table 3 Disintegration time results

[0160] 2.2 Pharmacokinetic studies in beagle dogs

[0161] The beagles used are male dogs, aged approximately 0.5 to 6 years, weighing approximately 9-12 kg. Some of these beagles will undergo repeated pharmacokinetic studies. After the previous round of dosing, an appropriate washout period will be given to assess their mental state, food intake, and weight. Only those that meet these criteria will be eligible for the next round of dosing.

[0162] Dosing requirements: fast overnight (water is not required) before each dose. Dosing is performed in this state. The tablets are washed down with 10 mL of water (quantitative amount) to ensure they are not chewed and remain intact. Food intake is resumed 4 hours after dosing. Blood samples are collected before dosing (0 h) and 0.5 h, 1.5 h, 3 h, 8 h, and 24 h after dosing, and continue until 24 hours after dosing to fully cover the complete plasma concentration-time absorption spectrum of the GLP-1 receptor agonist.

[0163] At each blood collection time point, blood samples were collected. The general preparation process was as follows: approximately 1.5 mL of whole blood was anticoagulated and centrifuged at 5000 × g for 10 minutes at 4°C. Plasma was then separated and collected in EDTA-anticoagulated EP tubes, with a volume of at least 600 μL per tube. The plasma was then stored at -80°C until analysis.

[0164] The active ingredients in the blood samples were detected by liquid chromatography-mass spectrometry (LC-MS), the mass spectrometer was a Thermo Q EXACTIVE instrument, and the high performance liquid chromatography was a Thermo Ultimate 3000 instrument.

[0165] The plasma concentration of GLP-1 receptor agonist was analyzed by LC-MS to obtain a plasma concentration-time curve, and the exposure of GLP-1 receptor agonist from 0 to 3 hours was determined to obtain the AUC (0-3小时) and C max The dose-corrected exposure was obtained by calculating the ratio of (administered dose mg / body weight Kg)*100.

[0166] As shown in Table 4 and Figure 1, at the same delivery agent (PNAC) dosage, oral exposure was observed to beagle dogs with the delivery enhancer-containing tablet composition. When the delivery enhancer was absent, the oral exposure was significantly reduced (Composition A) compared to Composition B, with a reduced delivery agent (PNAC) dosage. By adding the delivery enhancer, oral exposure was significantly improved, and the overall excipient dosage was reduced. These results demonstrate that the delivery enhancer can effectively reduce the amount of delivery agent used and improve the oral bioavailability of the peptide.

[0167] Table 4 Pharmacokinetic studies evaluating in vivo exposure of GLP-1 receptor agonists

[0168] Example 2 Steady-state pharmacokinetic study in beagle dogs

[0169] 1. Preparation of Composition Tablets

[0170] Table 3 provides the content of each component in the different composition tablets (compositions M1-M9) used in this example. The preparation process of the tablets is to directly mix and then tablet, and the specific steps are as follows: ① Material pretreatment: The GLP-1R agonist is passed through a 100-mesh sieve and, if necessary, can be crushed first and then sieved. The delivery agent PNAC is passed through a 50-mesh sieve, and the material that does not pass through the sieve is ground and sieved again. Other excipients are all passed through a 40-mesh sieve. ② Mixing: A certain amount of GLP-1R agonist, delivery agent, delivery enhancer and other excipients are manually mixed to obtain a mixed powder I. ③ Tableting: Tablets are pressed as required, and the tablet hardness is controlled within the range of 30-90N.

[0171] Table 5 Composition tablet components for steady-state pharmacokinetic studies in beagle dogs

[0172] 2. Test methods and results

[0173] A steady-state (multiple-dose) pharmacokinetic study in beagle dogs was conducted to determine the in vivo exposure of the GLP-1R agonist following multiple oral administrations of composition tablets in varying ratios.

[0174] The experimental animals and methods were the same as those in Section 2.2 of Example 1, except that the drug was administered once a day, one tablet each time, for seven consecutive days, and blood samples were collected before administration (0 h), and 0.5 h, 1.5 h, 3 h, 8 h, and 24 h after administration on the seventh day (Day 7).

[0175] The plasma concentration of the GLP-1R agonist was analyzed using LC-MS to obtain a plasma concentration-time curve, and the exposure of the GLP-1R agonist in the animal body from 0 to 24 hours at steady state (Day 7) was obtained, namely AUC (0-24小时) and C max The dose-corrected exposure was obtained by calculating the ratio of (administered dose mg / body weight kg)*100. The experimental results are shown in Table 6.

[0176] Table 6 Steady-state pharmacokinetic study results in beagle dogs

[0177] The results showed that compared with composition B (control group) without delivery enhancer, the compositions M1-M9 in which delivery enhancer was mixed with PNAC at different contents and ratios had a significantly lower oral absorption (AUC) at steady state after multiple oral administration. 0-24h) were improved to varying degrees compared to composition B (control group). On the other hand, compared to composition B (control group) with a PNAC dosage of up to 300 mg, due to the addition of a delivery enhancer, even in the M4 group with a PNAC content of only 50 mg, its oral absorption (AUC 0-24h ) can still be increased to 2 times compared with composition B (control group).

[0178] Example 3 Pharmacokinetic Study in Cynomolgus Monkeys

[0179] 1. Preparation of Composition Tablets

[0180] Table 7 provides the content of each component in the tablets of different compositions (Compositions N1-N3) used in this example. The tablet preparation process was the same as that in Section 1 of Example 1, except that mannitol and croscarmellose sodium were passed through a 40-mesh sieve during the "pretreatment" stage and mixed with the dry granulation granules and remaining magnesium stearate during the "remixing" stage.

[0181] Table 7 Compositions of the pharmacokinetic study composition in cynomolgus monkeys

[0182] 2. Test methods and results

[0183] A pharmacokinetic study of tablets of different dosages of the composition was conducted in cynomolgus monkeys to determine the in vivo exposure of different dosages of the GLP-1R agonist after multiple consecutive oral administration of tablets of different compositions.

[0184] Twelve animals were divided into four groups of three males each, weighing approximately 3-6 kg. Oral administration of Composition N1 (2 mg), Composition N2 and Composition B (7 mg), and Composition N3 (15 mg) was performed. All animals were administered one tablet daily for seven consecutive days. Plasma samples were collected from each group on Day 7 before dosing (0 h), and at 2, 4, 8, and 24 hours after dosing.

[0185] Blood samples were processed according to the experimental method of Example 2 and a pharmacokinetic study was conducted on cynomolgus monkeys with multiple doses. The plasma concentration of the GLP-1R agonist was analyzed and a plasma concentration-time curve was obtained. The exposure of the GLP-1R agonist in the animals at steady state (Day 7) from 0 to 24 hours, i.e., AUC (0-24小时) and C max , and normalized by calculating the ratio of (administered dose mg / body weight Kg)*100 to obtain dose-corrected exposure. The results are shown in Table 8 and Figure 2.

[0186] Table 8 Pharmacokinetic study results in cynomolgus monkeys

[0187] The results showed that after continuous oral administration of compositions N1, N2, and N3 to cynomolgus monkeys for 7 days, the systemic exposure of GLP-1R agonists in cynomolgus monkeys (C max and AUC (0-24h) ) increased with the increase of the dose, and was dose-dependent. The groups administered with compositions N1-N3 showed similar correction C max and corrected AUC 0-24 Compared with the 7 mg / tablet dosage group, the oral absorption of composition B without the addition of a delivery enhancer was significantly lower than that of composition N2 with the addition of a delivery enhancer, and composition N2 showed a significantly higher corrected AUC 0-24h , which indicates that the composition containing the delivery enhancer has better oral absorption.

[0188] Example 4 Comparative study of different delivery agents

[0189] 1. Preparation of Composition Tablets

[0190] To further validate the oral synergistic effect of delivery enhancers on oral delivery agents, the oral efficacy of different oral delivery agents (sodium octanoate (C8Na), sodium caprate (C10Na), sodium laurate (C12Na), and sodium chenodeoxycholate) combined with delivery enhancers (compositions J1-J4) was investigated. The composition of these compositions is shown in Table 9. Tablets were prepared using the same method as in Example 2, i.e., direct mixing followed by tableting.

[0191] Table 9 Compositions of different delivery agents for comparative study

[0192] 2. Test methods and results

[0193] The pharmacokinetic study in beagle dogs was conducted according to the experimental method of Example 2.

[0194] Table 10 Comparative study results of different delivery agents

[0195] Oral absorption (AUC 0-24h The results are shown in Table 10. Compared to the control group, Compositions J2-J4 showed varying degrees of reduced exposure, but their oral delivery agent content was reduced by as much as two-thirds. Surprisingly, compared to Composition B, despite a reduced delivery agent content, Composition J1, like Composition M1, showed an increase in oral exposure. This demonstrates that the delivery enhancer calcium carbonate also has a good synergistic effect on other delivery agents (e.g., sodium caprylate, sodium caprate, sodium laurate, sodium chenodeoxycholate, etc.).

[0196] Comparative study of different carrier reagents

[0197] 1. Preparation of Composition Tablets

[0198] The oral efficacy of several other agents with potential delivery enhancement effects combined with the delivery agent PNAC (compositions F1-F7) was investigated. The composition of the compositions is shown in Table 11. The tablets were prepared using the same method as in Example 1.

[0199] Table 11 Compositions of the comparative example compositions

[0200] 2. Test methods and results

[0201] The pharmacokinetic test in beagle dogs was carried out according to the test method of Example 1. The results are shown in Table 12.

[0202] Table 12 Comparative pharmacokinetic study evaluating in vivo exposure results of GLP-1 receptor agonists

[0203] The results showed that, when the delivery enhancer was not present, the amount of delivery agent (PNAC) in Composition A was reduced compared to Composition B, and oral exposure was significantly reduced. At the same delivery agent (PNAC) dosage, several candidate enhancers from this comparative example were selected and combined with the delivery agent to form a composition tablet, which reduced exposure in beagle dogs after oral administration. The results indicate that, although some structural features are similar to the delivery enhancers of the present application, oral administration of the composition tablet containing several candidate enhancers from this comparative example did not increase drug exposure, but rather reduced it. This indicates that not all similar carrier agents commonly used in the pharmaceutical field can reduce the amount of delivery agent used and improve the bioavailability of the polypeptide.

[0204] The description of the above embodiments is only for understanding the method and core concept of the present application. It should be noted that, for those skilled in the art, without departing from the principles of the present application, several improvements and modifications can be made to the present application, and such improvements and modifications will also fall within the scope of protection of the claims of the present application.

Claims

1. Application of a delivery enhancer in improving the oral bioavailability of a protein or polypeptide drug, characterized in that: The protein or polypeptide drug is used in combination with a delivery enhancer, wherein the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; The protein or polypeptide drug is delivered via a delivery agent; Preferably, the delivery enhancer comprises hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

2. The use according to claim 1, characterized in that: The protein or polypeptide drugs include hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters and / or antibodies.

3. The use according to claim 1, characterized in that: The protein or polypeptide drugs include receptor agonists or antagonists; Preferably, the receptor agonist or antagonist includes a GLP-1 receptor agonist, a GLP-1 receptor antagonist, a GIP receptor agonist, a GIP receptor antagonist and / or an insulin receptor agonist; Preferably, the receptor agonist or antagonist comprises a GLP-1 receptor agonist; Preferably, the GLP-1 receptor agonist comprises exendin, GLP-1 or its analogs, fragments, derivatives, fusion proteins, conjugates or pharmaceutically acceptable salts thereof; Preferably, the structure of the GLP-1 receptor agonist is as shown in formula (I):

4. The use according to any one of claims 1 to 3, characterized in that: The structure of the delivery agent is shown in formula (III): In formula (III), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Preferably, L represents a C7-C9 straight or branched alkylene group, and M represents K + ; Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises sodium salt, potassium salt and / or ammonium salt; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salt, and its structure is shown in formula (II): Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2)n-COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + ; Preferably, n represents an integer of 6 to 8, and M represents Na + ; Preferably, the delivery agent comprises a salt of caprylic acid, capric acid and / or lauric acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of caprylic acid, capric acid and / or lauric acid; Alternatively, the delivery agent comprises a salt of chenodeoxycholic acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of chenodeoxycholic acid; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:3; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:2; Preferably, the combined use includes using the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; or using them separately in sequence; Preferably, the combined use is to use the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5-1:150; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10-1:50; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutically acceptable carrier comprises a lubricant, a filler, a disintegrant, a flavoring agent, a colorant, a binder, an excipient, a buffer, a diluent, a solubilizer, a tonicity regulator, a surfactant, a preservative, an isotonic agent, a stabilizer and / or a chelating agent; Preferably, the pharmaceutically acceptable carrier comprises a lubricant, a filler and a disintegrant; Preferably, the lubricant comprises magnesium stearate, glyceryl tribehenate and / or stearic acid; Preferably, the lubricant is selected from magnesium stearate; Preferably, the filler is selected from mannitol and / or microcrystalline cellulose; Preferably, the disintegrant is selected from cross-linked carboxymethyl cellulose sodium; Preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug; Preferably, the active pharmaceutical ingredient is selected from antidiabetic agents, antiobesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and conditions caused by or associated with diabetes, and agents for treating and / or preventing complications and conditions caused by or associated with obesity; Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersions or powders; Preferably, the dosage form of the pharmaceutical composition is a tablet; Preferably, the tablet is prepared by a dry granulation process and / or a direct mixing process; Preferably, the tablet hardness is 30-90N.

5. A method for improving the oral bioavailability of protein or polypeptide drugs, characterized in that: The method comprises: using a protein or polypeptide drug in combination with a delivery enhancer, wherein the delivery enhancer comprises hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; The protein or polypeptide drug is delivered via a delivery agent; Preferably, the delivery enhancer comprises hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

6. The method according to claim 5, characterized in that The protein or polypeptide drugs include hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters and / or antibodies.

7. The method according to claim 5, characterized in that The protein or polypeptide drugs include receptor agonists or antagonists; Preferably, the receptor agonist or antagonist includes a GLP-1 receptor agonist, a GLP-1 receptor antagonist, a GIP receptor agonist, a GIP receptor antagonist and / or an insulin receptor agonist; Preferably, the receptor agonist or antagonist comprises a GLP-1 receptor agonist; Preferably, the GLP-1 receptor agonist comprises exendin, GLP-1 or its analogs, fragments, derivatives, fusion proteins, conjugates or pharmaceutically acceptable salts thereof; Preferably, the structure of the GLP-1 receptor agonist is as shown in formula (I):

8. The method according to any one of claims 5 to 7, characterized in that: The combined use includes using the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; or using them separately in sequence; Preferably, the combined use is to use the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersions or powders; Preferably, the dosage form of the pharmaceutical composition is a tablet; Preferably, the tablet is prepared by a dry granulation process and / or a direct mixing process; Preferably, the tablet hardness is 30-90N.

9. The method according to any one of claims 5 to 8, characterized in that: The structure of the delivery agent is shown in formula (III): In formula (III), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Preferably, L represents a C7-C9 straight or branched alkylene group, and M represents K + ; Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises sodium salt, potassium salt and / or ammonium salt; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salt, and its structure is shown in formula (II): Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2)n-COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + ; Preferably, n represents an integer of 6 to 8, and M represents Na + ; Preferably, the delivery agent comprises a salt of caprylic acid, capric acid and / or lauric acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of caprylic acid, capric acid and / or lauric acid; Alternatively, the delivery agent comprises a salt of chenodeoxycholic acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of chenodeoxycholic acid; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:3; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:2; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5-1:150; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10-1:

50.

10. The method according to claim 8, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutically acceptable carrier comprises a lubricant, a filler, a disintegrant, a flavoring agent, a colorant, a binder, an excipient, a buffer, a diluent, a solubilizer, a tonicity regulator, a surfactant, a preservative, an isotonic agent, a stabilizer and / or a chelating agent; Preferably, the pharmaceutically acceptable carrier comprises a lubricant, a filler and a disintegrant; Preferably, the lubricant comprises magnesium stearate, glyceryl tribehenate and / or stearic acid; Preferably, the lubricant is selected from magnesium stearate; Preferably, the filler is selected from mannitol and / or microcrystalline cellulose; Preferably, the disintegrant is selected from cross-linked carboxymethyl cellulose sodium; Preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug; Preferably, the active pharmaceutical ingredient is selected from antidiabetic agents, antiobesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and conditions caused by or associated with diabetes, and agents for treating and / or preventing complications and conditions caused by or associated with obesity.

11. A pharmaceutical composition with improved oral bioavailability and containing a protein or polypeptide drug as an active ingredient, characterized in that: The pharmaceutical composition includes a delivery enhancer, and the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; The pharmaceutical composition further comprises a delivery agent; Preferably, the delivery enhancer comprises hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate; Preferably, the protein or polypeptide drugs include hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters and / or antibodies; Alternatively, the protein or polypeptide drug includes a receptor agonist or antagonist; Preferably, the receptor agonist or antagonist includes a GLP-1 receptor agonist, a GLP-1 receptor antagonist, a GIP receptor agonist, a GIP receptor antagonist and / or an insulin receptor agonist; Preferably, the receptor agonist or antagonist comprises a GLP-1 receptor agonist; Preferably, the GLP-1 receptor agonist comprises exendin, GLP-1 or its analogs, fragments, derivatives, fusion proteins, conjugates or pharmaceutically acceptable salts thereof; Preferably, the structure of the GLP-1 receptor agonist is as shown in formula (I): Preferably, the structure of the delivery agent is as shown in formula (III): In formula (III), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Preferably, L represents a C7-C9 straight or branched alkylene group, and M represents K + ; Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises sodium salt, potassium salt and / or ammonium salt; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salt, and its structure is shown in formula (II): Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2)n-COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + ; Preferably, n represents an integer of 6 to 8, and M represents Na + ; Preferably, the delivery agent comprises a salt of caprylic acid, capric acid and / or lauric acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of caprylic acid, capric acid and / or lauric acid; Alternatively, the delivery agent comprises a salt of chenodeoxycholic acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of chenodeoxycholic acid; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:3; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:2; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5-1:150; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10-1:50; Preferably, the protein or polypeptide drug is used in combination with a delivery enhancer; Preferably, the combined use includes using the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; or using them separately in sequence; Preferably, the combined use is to use the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition.

12. The pharmaceutical composition according to claim 11, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutically acceptable carrier comprises a lubricant, a filler, a disintegrant, a flavoring agent, a colorant, a binder, an excipient, a buffer, a diluent, a solubilizer, a tonicity regulator, a surfactant, a preservative, an isotonic agent, a stabilizer and / or a chelating agent; Preferably, the pharmaceutically acceptable carrier comprises a lubricant, a filler and a disintegrant; Preferably, the lubricant comprises magnesium stearate, glyceryl tribehenate and / or stearic acid; Preferably, the lubricant is selected from magnesium stearate; Preferably, the filler is selected from mannitol and / or microcrystalline cellulose; Preferably, the disintegrant is selected from cross-linked carboxymethyl cellulose sodium; Preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug; Preferably, the active pharmaceutical ingredient is selected from antidiabetic agents, antiobesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and conditions caused by or associated with diabetes, and agents for treating and / or preventing complications and conditions caused by or associated with obesity; Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersions or powders; Preferably, the dosage form of the pharmaceutical composition is a tablet; Preferably, the tablet is prepared by a dry granulation process and / or a direct mixing process; Preferably, the tablet hardness is 30-90N.

13. Use of the following substances as synergists for drug delivery agents: hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; in, The structure of the delivery agent is shown in formula (III): In formula (III), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Preferably, L represents a C7-C9 straight or branched alkylene group, and M represents K + ; Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises sodium salt, potassium salt and / or ammonium salt; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salt, and its structure is shown in formula (II): Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2)n-COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + ; Preferably, n represents an integer of 6 to 8, and M represents Na + ; Preferably, the delivery agent comprises a salt of caprylic acid, capric acid and / or lauric acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of caprylic acid, capric acid and / or lauric acid; Alternatively, the delivery agent comprises a salt of chenodeoxycholic acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of chenodeoxycholic acid.

14. A pharmaceutical composition comprising a delivery agent and a delivery enhancer, wherein: The structure of the delivery agent is shown in formula (III): In formula (III), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Preferably, L represents a C7-C9 straight or branched alkylene group, and M represents K + ; Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises sodium salt, potassium salt and / or ammonium salt; Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salt, and its structure is shown in formula (II): Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2)n-COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + ; Preferably, n represents an integer of 6 to 8, and M represents Na + ; Preferably, the delivery agent comprises a salt of caprylic acid, capric acid and / or lauric acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of caprylic acid, capric acid and / or lauric acid; Alternatively, the delivery agent comprises a salt of chenodeoxycholic acid; Preferably, the delivery agent comprises sodium, potassium and / or ammonium salts of chenodeoxycholic acid; The delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; Preferably, the delivery enhancer comprises hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:3; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:

2.

15. The pharmaceutical composition according to claim 14, wherein The pharmaceutical composition further comprises a protein or polypeptide drug, wherein the protein or polypeptide drug comprises a hormone, a growth factor, a cytokine, an analgesic peptide, an enzyme, a coagulation factor, a peptide neurotransmitter and / or an antibody; Alternatively, the protein or polypeptide drug includes a receptor agonist or antagonist; Preferably, the receptor agonist or antagonist includes a GLP-1 receptor agonist, a GLP-1 receptor antagonist, a GIP receptor agonist, a GIP receptor antagonist and / or an insulin receptor agonist; Preferably, the receptor agonist or antagonist comprises a GLP-1 receptor agonist; Preferably, the GLP-1 receptor agonist comprises exendin, GLP-1 or its analogs, fragments, derivatives, fusion proteins, conjugates or pharmaceutically acceptable salts thereof; Preferably, the structure of the GLP-1 receptor agonist is as shown in formula (I): Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5-1:150; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10-1:50; Preferably, the protein or polypeptide drug is used in combination with a delivery enhancer; Preferably, the combined use includes using the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; or using them separately in sequence; Preferably, the combined use is to use the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutically acceptable carrier comprises a lubricant, a filler, a disintegrant, a flavoring agent, a colorant, a binder, an excipient, a buffer, a diluent, a solubilizer, a tonicity regulator, a surfactant, a preservative, an isotonic agent, a stabilizer and / or a chelating agent; Preferably, the pharmaceutically acceptable carrier comprises a lubricant, a filler and a disintegrant; Preferably, the lubricant comprises magnesium stearate, glyceryl tribehenate and / or stearic acid; Preferably, the lubricant is selected from magnesium stearate; Preferably, the filler is selected from mannitol and / or microcrystalline cellulose; Preferably, the disintegrant is selected from cross-linked carboxymethyl cellulose sodium; Preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug; Preferably, the active pharmaceutical ingredient is selected from antidiabetic agents, antiobesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and conditions caused by or associated with diabetes, and agents for treating and / or preventing complications and conditions caused by or associated with obesity; Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersions or powders; Preferably, the dosage form of the pharmaceutical composition is a tablet; Preferably, the tablet is prepared by a dry granulation process and / or a direct mixing process; Preferably, the tablet hardness is 30-90N.

16. Use of the pharmaceutical composition according to any one of claims 11, 12, 14 or 15 in the preparation of a medicament for preventing and / or treating metabolic-related diseases, nerve-related diseases or brain-related diseases; Preferably, the metabolism-related diseases include glucose metabolism disorders and / or fat metabolism disorders; Preferably, the glucose metabolism disorder disease includes diseases related to abnormal blood sugar; Preferably, the abnormal blood sugar related diseases include diabetes, diabetic eye disease, diabetic heart disease, diabetic nephropathy, diabetic neuropathy and distal limb necrosis of lower limbs, atherosclerosis, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, osteoporosis, hyperlipidemia, hypertension, obesity, fatty liver and / or cirrhosis; Preferably, the diabetes mellitus includes hyperglycemia, type II diabetes, impaired glucose tolerance, type I diabetes, non-insulin-dependent diabetes mellitus, maturity-onset diabetes of the young (MODY) and / or gestational diabetes; Preferably, the fat metabolism disorder disease includes a disease related to abnormal body weight; Preferably, the abnormal weight-related diseases include anemia, gastroptosis, inflammatory bowel disease, indigestion, gastrointestinal ulcers, endocrine disorders, osteoporosis, obesity, hypertension, hyperlipidemia, coronary heart disease, diabetes, fatty liver, joint deformity, pain, cancer, respiratory insufficiency, kidney disease, hyperlipidemia, hypertension, atherosclerosis, cirrhosis, angina pectoris and / or myocardial infarction; Preferably, the nerve-related diseases include neurodegenerative diseases; Preferably, the neurodegenerative disease comprises brain atrophy, cerebral ischemia, brain injury, epilepsy, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, spinocerebellar ataxia, Pick's disease, bovine spongiform encephalopathy and / or Creutzfeldt-Jakob disease.

17. A kit comprising the pharmaceutical composition of any one of claims 11, 12, 14 or 15.

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