Composition and method for obtaining improved oral bioavailability of a drug

Abstract

A composition and method for having improved oral bioavailability of a drug is disclosed, further comprising the use of a delivery enhancer in improving the oral bioavailability of a protein or polypeptide drug. After adding the delivery enhancer, the pharmaceutical composition can maximize the delivery effect of the delivery agent in a certain ratio with the delivery agent, thereby reducing the amount of delivery agent used and simultaneously increasing the oral bioavailability of the drug.

Description

[Technical Field]

[0001] This application belongs to the field of biopharmaceuticals and specifically relates to compositions and methods for producing drugs with improved oral bioavailability. [Background technology]

[0002] Oral administration has long been the preferred method of administering therapeutic drugs due to its ease of use, safety, effectiveness, and the variety of formulations that can be developed. It is preferred by patients and enjoys good patient compliance. However, many high-demand drugs are still administered by other methods, such as injection, due to various factors. For example, many polypeptide drugs, such as insulin and GLP-1 agonists, are currently administered by injection, which has the disadvantage of being less adaptable to patients, making administration more difficult and causing long-term discomfort.

[0003] Improving the oral administration of drugs that are difficult to administer orally is one of the important directions in drug research. Currently, the mainstream oral administration regimen for drugs that are difficult to administer orally (e.g., protein and polypeptide drugs) involves producing the active drug and oral formulation using oral delivery agents such as sodium octanoate (C8Na), sodium caprate (C10Na), sodium laurate (C12Na), and sodium chenodeoxycholate. A relatively successful example of oral drug development is semaglutide tablets (Rybelsus®), a GLP-1R agonist drug developed by Novo Nordisk. This method increases the oral absorption utilization rate of polypeptides by adding the delivery agent N-(8-(2-hydroxybenzoyl)amino) sodium octanoate (SNAC) to GLP-1R agonist tablets, and this drug has already been approved and marketed in many regions, including the United States and Europe. However, the biggest challenge in oral protein or polypeptide drug technology today remains the efficiency of drug delivery, and relatively low delivery efficiency leads to relatively high raw material costs. This is primarily because the presence of the gastrointestinal barrier makes it difficult for oral protein and polypeptide drugs to be delivered to the body's circulatory system.

[0004] Therefore, improving the oral bioavailability of drugs that are difficult to administer orally (e.g., protein and polypeptide drugs), saving on drug production costs, and benefiting more patients are urgent issues that need to be addressed in this field. [Overview of the Initiative]

[0005] To achieve the above objective, this application adopts the following technical solution.

[0006] A 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, the delivery enhancer comprising magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide, and the protein or polypeptide drug is delivered by the delivery enhancer.

[0007] In several preferred technical proposals, the delivery enhancer comprises magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, and / or sucralfate.

[0008] In the uses provided in the first aspect of this application, the protein or polypeptide drug may be any type commonly found in the art and includes, but is not limited to, hormones, growth factors, cytokines, analgesic peptides, enzymes, blood coagulation factors, peptide neurotransmitters and / or antibodies.

[0009] In the use provided in the first aspect of this application, the protein or polypeptide drug may further comprise a receptor agonist or antagonist commonly found in the art.

[0010] In several preferred technical proposals, 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.

[0011] Furthermore, the above-mentioned receptor agonists or antagonists include GLP-1 receptor agonists.

[0012] Furthermore, the GLP-1 receptor agonist includes exendin, GLP-1 or its analogs, fragments, derivatives, fusion proteins, conjugates or pharmaceutically acceptable salts of these molecules.

[0013] In some of the most preferred technical solutions, the structure of the GLP-1 receptor agonist is shown in formula (I).

[0014]

Chemical formula

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

[0016]

Chemical formula

[0017] In formula (III), L represents a linear or branched alkylene group having from 5 to 11 carbon atoms, and M represents Na <{0000107}>,<{0000105}>,<{0000103}>,<{0000106}>,<{0000104}>, K + or NH4 + . <000009�> Furthermore, L represents a linear or branched alkylene group having from 7 to 9 carbon atoms, and M represents K + .

[0019] Furthermore still, L represents a linear alkylene group having from 7 to 9 carbon atoms, and M represents K + .

[0020] In some preferred technical solutions, the delivery agent includes a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

[0021] [[ID=5३]] Furthermore, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid includes a sodium salt, a potassium salt and / or an ammonium salt.

[0022] In some of the most preferred technical solutions, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salts, and its structure is shown in formula (II).

[0023]

Chemical formula

[0033] In several preferred technical proposals, the delivery agent comprises sodium chenodeoxycholate.

[0034] In the use provided by the first aspect of this application, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3 to 1:3.

[0035] In several preferred technical proposals, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3 to 1:2.

[0036] In the use provided in the first aspect of the present application, the above combination includes using a protein or polypeptide drug and a delivery enhancer simultaneously in the form of a pharmaceutical composition, or using them sequentially in a specific order, such as first using the delivery enhancer and then using the protein or polypeptide drug.

[0037] Furthermore, the above combination involves the simultaneous use of a protein or polypeptide-based drug and a delivery enhancer in the form of a pharmaceutical composition.

[0038] In the use provided by the first aspect of this application, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5 to 1:150.

[0039] In several preferred technical proposals, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10 to 1:50, and may be, for example, 1:10 to 1:30.

[0040] In the use provided in the first aspect of this application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, which may be any type commonly found in the art, and includes, but is not limited to, one or more of the following: lubricants, fillers, disintegrants, flavorings, colorants, binders, excipients, buffers, diluents, solubilizers, tension modifiers, surfactants, preservatives, isotonic agents, stabilizers, and chelating agents.

[0041] In several preferred technical proposals, the above-mentioned pharmaceutically acceptable carrier includes a lubricant, a filler, and a disintegrant.

[0042] Furthermore, the above lubricant comprises magnesium stearate, glyceryl tribehenate, and / or stearic acid.

[0043] In some of the most preferred technical proposals, 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 carboxymethylcellulose sodium.

[0044] In the use provided in the first aspect of this application, the pharmaceutical composition further comprises one or more active drug components for use in combination with the protein or polypeptide drug.

[0045] In several preferred technical proposals, the active drug component is selected from antidiabetic agents, anti-obesity 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.

[0046] In the use provided in the first aspect of this application, the dosage form of the pharmaceutical composition may be any dosage form commonly found in the art.

[0047] In several preferred technical proposals, the dosage form of the pharmaceutical composition may be an oral dosage form and may include, but is not limited to, one or more of the following: tablets, capsules, emulsions, aqueous suspensions, dispersants, and powders.

[0048] In some of the most preferred technical designs, the dosage form of the pharmaceutical composition is a tablet.

[0049] In some of the most preferred technical applications, the tablets can be manufactured by dry granulation processes and / or direct mixing processes commonly found in the art.

[0050] In several preferred technical proposals, the hardness of the above-mentioned tablets is 30 to 90 N.

[0051] A 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 magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide, and the protein or polypeptide drug is delivered by the delivery enhancer.

[0052] In several preferred technical proposals, the delivery enhancer comprises magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, and / or sucralfate.

[0053] In the method provided in the second aspect of this application, the protein or polypeptide drug is as defined in the first aspect of this application.

[0054] In the method provided by the second aspect of the present application, the delivery agent is as defined in the first aspect of the present application.

[0055] In the method provided by the second aspect of this application, the above-mentioned combined method is as defined in the first aspect of this application.

[0056] In the method provided by the second aspect of this 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 both as defined in the first aspect of this application.

[0057] In the method provided in a second aspect of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier as defined in the first aspect of the present application.

[0058] In the method provided in a second aspect of the present application, the pharmaceutical composition further comprises one or more active drug components for use in combination with the protein or polypeptide drug, as defined in the first aspect of the present application.

[0059] In the method provided by a second aspect of this application, the dosage form of the pharmaceutical composition and the method for producing the same may be any dosage form and process commonly found in the art, for example, as defined in the first aspect of this application.

[0060] A third aspect of the present application provides a pharmaceutical composition comprising a protein or polypeptide drug with improved oral bioavailability as an active ingredient, wherein the pharmaceutical composition comprises a delivery enhancer, the delivery enhancer comprising magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide, and the pharmaceutical composition further comprises a delivery agent.

[0061] In several preferred technical proposals, the delivery enhancer comprises magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, and / or sucralfate.

[0062] In the pharmaceutical composition provided by the third aspect of this application, the protein or polypeptide drug is as defined in the first aspect of this application.

[0063] In the pharmaceutical composition provided by the third aspect of this application, the delivery agent is as defined in the first aspect of this application.

[0064] In the pharmaceutical composition provided by the third aspect of this 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 both as defined in the first aspect of this application.

[0065] In the pharmaceutical composition provided by the third aspect of this application, the protein or polypeptide drug is used in combination with a delivery enhancer, the manner of such combination is as defined in the first aspect of this application.

[0066] A pharmaceutical composition provided in a third aspect of the present application further comprises a pharmaceutically acceptable carrier as defined in the first aspect of the present application.

[0067] A pharmaceutical composition provided in a third aspect of the present application further comprises one or more active drug components for use in combination with the protein or polypeptide drug, as defined in the first aspect of the present application.

[0068] In a pharmaceutical composition provided by a third aspect of the present application, the dosage form of the pharmaceutical composition and the method of manufacturing the same may be any dosage form and process commonly found in the art, for example, as defined in the first aspect of the present application.

[0069] A fourth aspect of the present application provides the use of the following substances as enhancers for drug delivery agents: magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide, of which the delivery agent is as defined in the first aspect of the present application.

[0070] A 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 magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide.

[0071] In several preferred technical proposals, the delivery enhancer comprises magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, and / or sucralfate.

[0072] A pharmaceutical composition provided in a fifth aspect of the present application further comprises a protein or polypeptide drug as defined in the first aspect of the present application.

[0073] In the pharmaceutical composition provided by the fifth aspect of this 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 both as defined in the first aspect of this application.

[0074] In the pharmaceutical composition provided by the fifth aspect of this application, the protein or polypeptide drug is used in combination with a delivery enhancer, the manner of such combination is as defined in the first aspect of this application.

[0075] A pharmaceutical composition provided in a fifth aspect of the present application further comprises a pharmaceutically acceptable carrier as defined in the first aspect of the present application.

[0076] A pharmaceutical composition provided in a fifth aspect of the present application further comprises one or more active drug components for use in combination with the protein or polypeptide drug, as defined in the first aspect of the present application.

[0077] In a pharmaceutical composition provided by a fifth aspect of the present application, the dosage form of the pharmaceutical composition and the method of manufacturing the same may be any dosage form and process commonly found in the art, for example, as defined in the first aspect of the present application.

[0078] A sixth aspect of the present application provides a use as a drug (i.e., a use for therapeutic purposes) of the pharmaceutical composition described in either the third aspect or the fifth aspect of the present application.

[0079] A seventh aspect of the present application provides the use of a pharmaceutical composition according to either the third or fifth aspect of the present application in the manufacture of a drug for the prevention and / or treatment of metabolic disorders, neurological disorders or brain disorders.

[0080] The eighth aspect of the present application provides a method for preventing and / or treating a metabolic, neurological, or brain-related disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition described in either the third or fifth aspect of the present application.

[0081] In the seventh and eighth aspects of this application, the metabolic-related diseases include glucose metabolism disorders and / or lipid metabolism disorders.

[0082] In some preferred technical proposals, the above-mentioned glucose metabolism disorders include blood glucose abnormality-related diseases.

[0083] Furthermore, the above-mentioned blood glucose-related diseases include diabetes mellitus, diabetic eye disease, diabetic heart disease, diabetic kidney disease, diabetic neuropathy and distal limb necrosis, atherosclerosis, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, osteoporosis, hyperlipidemia, hypertension, obesity, fatty liver and / or cirrhosis.

[0084] Furthermore, the above-mentioned diabetes includes hyperglycemia, type II diabetes, impaired glucose tolerance, type I diabetes, non-insulin-dependent diabetes, juvenile-onset diabetes (MODY), and / or gestational diabetes.

[0085] In some preferred technical proposals, the above-mentioned lipid metabolism disorders include weight abnormality-related disorders.

[0086] Furthermore, the above-mentioned weight-abnormality-related diseases include anemia, gastroptosis, inflammatory bowel disease, indigestion, gastrointestinal ulcers, endocrine disorders, osteoporosis, obesity, hypertension, hyperlipidemia, coronary heart disease, diabetes mellitus, fatty liver, joint deformities, pain, cancer, respiratory failure, kidney disease, hyperlipidemia, atherosclerosis, cirrhosis, angina pectoris, and / or myocardial infarction.

[0087] In the seventh and eighth aspects of this application, the neurological disease includes neurodegenerative diseases.

[0088] Furthermore, the neurodegenerative diseases mentioned above include cerebral 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.

[0089] A ninth aspect of the present application provides a reagent kit comprising a pharmaceutical composition described in either a third aspect of the present application or a fifth aspect of the present application.

[0090] Advantages and beneficial effects of this application: The pharmaceutical composition provided in this application, after adding the delivery enhancer described herein, can maximize the delivery effect of the delivery agent in a certain ratio with the delivery agent, thereby reducing the amount of delivery agent used and simultaneously increasing the oral bioavailability of the drug (e.g., protein or polypeptide-based drugs). [Brief explanation of the drawing]

[0091] [Figure 1] This is a diagram of the oral absorption curve of the GLP-1 receptor agonist after adding calcium carbonate and aluminum hydroxide to the composition in Example 1, respectively. [Figure 2] This is a plasma concentration-time curve diagram of the pharmacokinetic study of each composition in cynomolgus monkeys on Day 7 of Example 3. [Modes for carrying out the invention]

[0092] The following definitions of some terms used herein are provided. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as they are generally understood by those skilled in the art.

[0093] In this application, "protein or polypeptide-based drug" refers to a protein or polypeptide-based compound contained in an oral drug that either directly acts as a drug-active component in the body or indirectly assists the drug-active component in exerting disease-preventive and / or therapeutic functions.

[0094] In some embodiments of the present application, the protein or polypeptide drug may be a natural protein or polypeptide compound (e.g., hormones, growth factors, cytokines, analgesic peptides, enzymes, blood coagulation factors, peptide neurotransmitters, and antibodies) or a synthetically synthesized polypeptide or protein, or an analog, derivative, conjugate or fusion protein of the polypeptide or protein, or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments of the present application, the protein or polypeptide drug may be a compound having receptor agonist or antagonist activity. The receptor agonist or antagonist may be a GLP-1 receptor agonist, a GLP-1 receptor antagonist, a GIP receptor agonist, a GIP receptor antagonist, an Amylin receptor agonist, a heparin receptor agonist, a growth hormone receptor agonist, an interferon receptor agonist, an interleukin receptor agonist, a follicle-stimulating hormone receptor agonist, a gonadotropin receptor agonist, an erythropoietin receptor agonist, a PYY (peptide tyrosine tyrosine) receptor agonist, or an oxygen receptor agonist. This includes, but is not limited to, synzygogenic 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.

[0096] In some embodiments of the present application, the protein or polypeptide drug simultaneously includes the activity of one or more receptor agonists or antagonists.

[0097] In some embodiments of the present application, the protein or polypeptide drug is preferably a GLP-1 receptor agonist, the GLP-1 receptor agonist comprising compounds having GLP-1 receptor agonist activity, particularly polypeptides / proteins, and analogs, derivatives, conjugates or fusion proteins of the polypeptide / protein or pharmaceutically acceptable salts thereof.

[0098] In some embodiments of the present application, the GLP-1 receptor agonist comprises exendins, exendin analogs, exendin agonists, GLP-1(7-37), GLP-1(7-37) analogs or derivatives thereof, 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.

[0099] Among these, exendins include naturally occurring exendins (or synthetic versions of naturally occurring ones) found in the saliva secretion of Gila monsters. Exendins of particular interest include exendin-3 and exendin-4. The exendins, exendin analogs, and exendin agonists used in this application may be optionally amidated and may exist in the form of an acidic molecule, a pharmaceutically acceptable salt, or any other physiologically active form.

[0100] GLP-1(7-37) analogs refer to peptides that can produce biological activity similar to that of GLP-1(7-37) when evaluated by known assay methods in the art (e.g., receptor-binding assays or endogenous blood glucose assays, e.g., those described in Hargrove et al., Regulatory Peptides, 141:113-119 (2007) (the disclosure thereof is incorporated herein by reference)). In one embodiment, the term GLP-1(7-37) analog refers to a peptide having an amino acid sequence having 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions, insertions, deletions, or combinations thereof of two or more of these compared to the amino acid sequence of GLP-1(7-37). GLP-1(7-37) analogs include the amidated form, acid form, and any other physiologically active form of the above molecule.

[0101] In this application, "agonist" refers to a compound, molecule, or reagent that can stimulate biological activity.

[0102] In this application, “analog” means a substance having a structure and / or function similar to the protein or polypeptide of this application.

[0103] In this application, “pharmaceutically acceptable salt” refers to any adduct between two or more chemical substances capable of proton transfer. Therefore, a pharmaceutically acceptable salt includes adducts where complete proton transfer occurs, adducts where partial proton transfer occurs (e.g., where an equilibrium mixture of charged and uncharged substances is formed), and / or adducts where no proton transfer occurs but the chemical substances are bonded, for example, by hydrogen bonding. It should be understood that a pharmaceutically acceptable salt also includes adducts where tight ion pairs exist. Furthermore, it should be understood that a pharmaceutically acceptable salt also includes a continuum of adducts between the following adducts: adducts where complete proton transfer occurs to form discrete ions, and / or adducts where two substances are bonded but no or only partial proton transfer occurs. 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 in the continuum.

[0104] Pharmacopoecitable salts include salts having an acidic or basic group. Pharmacopoecitable acid addition salts include, but are not limited to, hydrochlorides, hydrobroms, hydroiodides, nitrates, methanesulfons, sulfates, bisulfates, phosphates, acidic phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, hydrogen tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucurons, sucroses, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoates)). Suitable basic salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.

[0105] In this application, the mass ratio of the delivery agent and the delivery enhancer may be any mass ratio that can improve the delivery effect, for example, 1:0.3 to 1:3, and includes mass ratios of 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 and any arbitrary mass ratio interval.

[0106] In this application, the mass ratio of the protein or polypeptide drug to the delivery agent may be any mass ratio that enables the delivery of the protein or polypeptide drug, for example, 1:5 to 1:150, and includes mass ratios of approximately 1:5, approximately 1:10, approximately 1:15, approximately 1:20, approximately 1:25, approximately 1:30, approximately 1:35, approximately 1:40, approximately 1:45, approximately 1:50, approximately 1:55, approximately 1:60, approximately 1:65, approximately 1:70, approximately 1:75, approximately 1:80, approximately 1:85, approximately 1:90, approximately 1:95, approximately 1:100, approximately 1:105, approximately 1:110, approximately 1:115, approximately 1:120, approximately 1:125, approximately 1:130, approximately 1:135, approximately 1:140, approximately 1:145, approximately 1:150 and any arbitrary mass ratio intervals.

[0107] In this application, "bioavailability" refers to the extent and rate to which a substance, such as a drug, peptide, or hormone, is available at its physiologically active site. In the field of pharmacology, the term bioavailability is understood as a score of the dose of an unchanged drug, compound, or drug that reaches systemic circulation and is one of the primary pharmacokinetic properties of a drug. By definition, when a drug is administered intravenously, its bioavailability is 100%. However, when a drug is administered via other routes (e.g., orally or intramuscularly), its bioavailability is usually reduced due to factors such as incomplete absorption and first-pass metabolism. For example, these factors may differ from patient to patient due to differences in individual metabolism.

[0108] Standard tests for measuring the bioavailability of a drug are known to those skilled in the art and, in particular, include measuring the area under the relative curve (AUC) of the concentrations of the drug administered orally and intravenously (iv) in the same class.

[0109] In this application, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid may be crystalline and / or amorphous, and includes, but is not limited to, sodium salts, potassium salts and / or ammonium salts.

[0110] In this application, “pharmaceutically acceptable carrier” refers to a non-toxic material that does not interfere with the effect of the pharmacoactive ingredient or pharmaceutical composition of this application, or with the biological activity of the pharmacoactive ingredient or pharmaceutical composition of this application. Methods for preparing pharmacoactive ingredients using pharmaceutically acceptable carriers are known in the art; see, 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., acidic salts / anionic salts, basic salts / cationic salts), excipients, buffers, diluents, solubilizers, tonicity modifiers, surfactants, preservatives, isotonic agents, flavorings, colorants, stabilizers, binders, disintegrants, fillers, lubricants, and chelating agents. One or more pharmaceutically acceptable carriers may be used in the preparation of the pharmaceutical compositions of this application.

[0111] In some embodiments of the present application, pharmaceutically acceptable carriers include acidic salts / anionic salts. Non-limiting examples of acidic salts / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphor sulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estrate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, p-hydroxyacetamidephenylarsoneate, hexylresorcinolate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, and iodide. This includes, but is not limited to, substances, hydroxyethyl sulfonates, lactates, lactobionates, malates, maleates, mandelates, methanesulfons, methyl bromides, methyl nitrates, methyl sulfates, mucoates, naphthalene sulfons, nitrates, pamoates, pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, hypoacetates, succinates, sulfates, tannates, tartrates, theoclates, tosylates, triethyl iodide, and combinations thereof.

[0112] In some embodiments of the present application, pharmaceutically acceptable carriers include basic salts / cationic salts. Non-limiting examples of basic salts / cationic salts include, but are not limited to, aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, trometamol, or TRIS), ammonia, benzathine benzylpenicillin, tert-butylamine, chloroprocaine, choline, cyclohexylamine, diethanolamine, ethylenediamine, lithium, L-lysine, magnesium, meglumine, N-methyl-D-glucosamine, piperidine, potassium, procaine, quinine, sodium, triethanolamine, zinc, and combinations thereof.

[0113] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a buffer. Non-limiting examples of buffers include, but are not limited to, arginine, aspartic acid, dihydroxyethylglycine, 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.

[0114] In some embodiments of the present application, pharmaceutically acceptable carriers include preservatives. Non-limiting examples of preservatives include, but are not limited to, benzethonium chloride, benzoic acid, benzyl alcohol, bromonitropropylene glycol, butyl 4-hydroxybenzoate, chlorobutanol, chlorocresol, chlorohexidine, chlorophenesin, o-cresol, m-cresol, p-cresol, ethyl 4-hydroxybenzoate, imidourea, methyl 4-hydroxybenzoate, phenol, 2-phenoxyethanol, 2-phenylethanol, propyl 4-hydroxybenzoate, sodium dehydroacetate, thimerosal, and combinations thereof.

[0115] In some embodiments of the present application, pharmaceutically acceptable carriers include isotonic agents. Non-limiting examples of isotonic agents include, but are not limited to, amino acids (e.g., glycine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, and threonine), sugar alcohols (e.g., glycerin, 1,2-propylene glycol, propylene glycol, 1,3-propylene glycol, and 1,3-butylene glycol), polyethylene glycol (e.g., PEG400), and combinations thereof. Another example of an isotonic agent is a sugar. Non-limiting examples of sugars may be monosaccharides, disaccharides or polysaccharides, or water-soluble glucans, and include, for example, fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, trehalose, dextran, amylopectin, dextrin, cyclodextrin, α and β-HPCD, soluble starch, hydroxyethyl starch, sodium carboxymethylcellulose, and combinations thereof. Another example of isotonic agents is sugar alcohols, where the term “sugar alcohol” is defined as a C(4-8) hydrocarbon having at least one -OH group. Non-limiting examples of sugar alcohols include, but are not limited to, mannitol, sorbitol, inositol, galactitol, hexanehexol, xylitol, arabitol, and combinations thereof. Drugs comprising each of the isotonic agents listed in this paragraph constitute selectable embodiments of the present invention.

[0116] 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, citric acid, aspartic acid, ethylenediaminetetraacetic acid (EDTA) salts, and combinations thereof.

[0117] In some embodiments of the present application, pharmaceutically acceptable carriers include stabilizers. 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), polyvinylpyrrolidone, salts (such as sodium chloride), sulfur-containing substances (such as thioglycerol or mercaptoacetic acid), and combinations thereof.

[0118] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a lubricant (also called a “flow enhancer”). The lubricant can be used to prevent the formulation from adhering to the surfaces of rolls, dies, and punches and to reduce friction between fine particles. The lubricant can also facilitate the extrusion of the formulation from the mold groove and improve the granulation flow rate during processing. Non-exclusive examples of lubricants include magnesium stearate, glyceryl behenate, calcium stearate, zinc stearate, stearic acid, silica, talc, polyethylene glycol, mineral oil, carnauba wax, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl palmitate stearate, myristic acid, hydrogenated vegetable oil, fat, 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), and behenic acid. This includes, but is not limited to, glyceryl, cetostearyl alcohol, octyldodecanol, liquid paraffin, stearic acid, magnesium lauryl sulfate, almond oil, low erucic acid rapeseed oil, cetyl ester wax, glyceryl palmitate stearate, isopropyl palmitate, light liquid paraffin, sodium stearyl fumarate, glyceryl behenate, potassium benzoate, sterile corn starch, myristic acid, glyceryl tricaprylate, 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 of these. In one embodiment, if present, the lubricant for raw material granulation is magnesium stearate.

[0119] In some embodiments of the present application, the pharmaceutically acceptable carrier comprises one or more surfactants, preferably one surfactant, at least one surfactant, or two different surfactants. A surfactant refers to any molecule or ion consisting of a water-soluble (hydrophilic) portion and a lipid-soluble (lipophilic) portion. For example, the surfactant is selected from anionic surfactants, cationic surfactants, nonionic surfactants and / or amphoteric surfactants and combinations thereof.

[0120] In some embodiments of the present application, pharmaceutically acceptable carriers include flavorings. Flavorings can be used to improve the palatability of pharmaceutical compositions. Non-limiting examples of flavorings include, but are not limited to, natural or synthetic (i.e., artificial) compounds and combinations thereof having corresponding flavors (e.g., mint, spearmint, holly, 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).

[0121] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a colorant. The colorant can be used to color and code a pharmaceutical composition, for example, to indicate the type and dosage of a therapeutic agent therein. Non-limiting examples of colorants include, but are not limited to, FD&C colorants, natural and / or artificial compounds such as natural fruit juice concentrates, dyes such as titanium dioxide, silica and zinc oxide, and combinations thereof.

[0122] 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 polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropyl methylcellulose, starch, guar gum, magnesium aluminum silicate, alginic acid, sodium alginate, methylcellulose, cross-linked povidone, potassium polariphosphate, microcrystalline cellulose, anhydrous citric acid, pregelatinized starch, calcium carboxymethylcellulose, powdered cellulose, sodium carboxymethyl starch, chitosan, calcium alginate, and combinations thereof.

[0123] 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, ethylcellulose, sucrose, anhydrous lactose, dextran, and combinations thereof.

[0124] In some embodiments of the present application, pharmaceutically acceptable carriers include binders. 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, acacia gum, alginic acid, methylcellulose, polyacrylic acid resin, povidone, maltodextrin, ethyl hydroxycellulose, zein, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, locust bean gum, carbomer, povidone, glyceryl behenate, chitosan, liquid glucose, hydroxyethyl methylcellulose, sunflower oil, hydrogenated vegetable oil, inulin, and combinations thereof.

[0125] In this application, pharmaceutical compositions for oral administration may be in any orally administrative dosage form, including but not limited to capsules, tablets, powders, emulsions, and aqueous suspensions, dispersants, and solutions. When tablets are administered orally, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. Diluents useful for oral administration in capsule form include lactose and dried 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. Sweeteners, flavorings, or colorants may be added as desired. Nasal aerosols or inhalation compositions can be manufactured according to known techniques in the pharmaceutical field and can be prepared as saline aqueous solutions using benzyl alcohol or other suitable preservatives, absorption enhancers, fluorocarbons, and / or other solvents or dispersants known in the art. The pharmaceutical compositions of this application may also be administered rectally in the form of suppositories.

[0126] If necessary, tablets can be coated with standard water or non-aqueous techniques. Such dosage forms can be manufactured using any pharmaceutical method. Generally, pharmaceutical compositions and dosage forms are manufactured by uniformly and tightly mixing the active ingredient with a liquid carrier, a fragmented solid carrier, or both, and, if necessary, shaping the product into the desired form.

[0127] In a specific embodiment of this application, the dosage form of the pharmaceutical composition is a tablet.

[0128] In some embodiments of the present application, the tablets may be manufactured using any conventional method of manufacturing tablets that is well known to those skilled in the art, for example, by a dry granulation process or by a direct mixing process.

[0129] The specific steps of the dry granulation process described above are as follows: (1) Material pretreatment: Protein or polypeptide drugs are sieved through a 50-200 mesh sieve, preferably a 100 mesh sieve, and can be sieved again after grinding as needed. Delivery agents are sieved through a 20-100 mesh sieve, preferably a 50 mesh sieve, and any material that does not pass through the sieve is polished and then sieved again. The treatment of delivery enhancers is the same as that of delivery agents. Lubricants are used directly. If present, other pharmaceutically acceptable carriers are sieved through a 20-80 mesh sieve, preferably a 40 mesh sieve. (2) Initial mixing: A certain amount of protein or polypeptide drugs, delivery agents, delivery enhancers, some lubricants and other selectable pharmaceutically acceptable carriers are manually and uniformly mixed to obtain mixed powder I. (3) Dry granulation: The mixed powder I is rolled into a strip sheet of appropriate hardness and then ground into particles of appropriate size. (4) Remixing: Collect the above particles, add the remaining lubricant again, and mix uniformly by hand. (5) Tableting: Tablets are compressed according to the normal tableting process in this field, and the hardness of the tablets is controlled within the range of 30 to 90 N.

[0130] The specific steps of the direct mixing process described above are as follows: (1) Pretreatment of materials: Protein or polypeptide drugs are sieved through a 100-mesh sieve, and if necessary, can be crushed and then sieved again. The delivery agent is sieved through a 50-mesh sieve, and any material that does not pass through the sieve is polished and then sieved again. The delivery enhancer is sieved through a 20-80 mesh sieve, preferably a 40-mesh sieve. The lubricant is used directly. If present, other pharmaceutically acceptable carriers are sieved through a 20-80 mesh sieve, preferably a 40-mesh sieve. (2) Mixing: A certain amount of protein or polypeptide drugs, delivery agents, delivery enhancers, lubricants and other selectable pharmaceutically acceptable carriers are mixed by hand to obtain mixed powder I. (3) Tableting: Tablets are compressed according to the usual tableting process in this art, and the hardness of the tablets is controlled to be within the range of 30-90 N.

[0131] In specific embodiments of the present application, the tablets are manufactured using a direct mixing process.

[0132] In a specific embodiment of the present invention, the tablets are manufactured using a granulation process, preferably a dry granulation process.

[0133] In this application, in addition to the pharmaceutical composition, the reagent kit may include one or more containers selected from bottles, vials, ampoules, blister packs, and syringes. The reagent kit may further include one or more instructions for use for treating and / or preventing a disease, symptom, or disorder, one or more syringes, one or more applicators, or a sterile solution suitable for reconstituting the pharmaceutical composition of this application.

[0134] In this application, the active drug component used in combination may be of a different type from the above-mentioned protein or polypeptide drug, but may have the same or similar active function, or may be any component that acts in conjunction with the above-mentioned protein or polypeptide drug to produce an active function. For example, it may be selected from antidiabetic agents, anti-obesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and symptoms caused by or related to diabetes, and agents for treating and / or preventing complications and symptoms caused by or related to obesity. Non-exclusive examples of these pharmacologically active drug components include insulin, sulfonylurea, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV (dipeptidyl peptidase-IV) inhibitors, sodium glucose cotransporter 2 (SGLT2) inhibitors; canagliflozin, dapagliflozin, empagliflozin, erzgliflozin, ipragliflozin, tofogliflozin, luseogliflozin, bexagliflozin, remogliflozin etavonate, and sotaglifkozin, particularly dapagliflozin and empagliflozin; inhibitors of hepatic enzymes involved in stimulating glycogen disogenesis and / or glycogen breakdown; glucose uptake regulators; compounds that alter lipid metabolism, such as antihyperlipidemic agents, such as HMG coenzymes. A inhibitors (statins), gastric suppressant polypeptides (GIP analogs), compounds that reduce food uptake, RXR agonists, and drugs that act on ATP-dependent potassium channels in β-cells; cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol, dextrothyroxine, nateglinide, repaglinide; β-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;Also, α-blockers such as doxazosin, urapidil, prazosin and terazosin; CART (cocaine amphetamine regulatory 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, oxytomodulin and analogs, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, 5-hydroxytryptamine reuptake inhibitors, 5-hydroxytryptamine and norepinephrine reuptake inhibitors, mixed 5-hydroxytryptamine and norepinephrine agonistic compounds, 5HT (5-hydroxytryptamine) agonists, Bombesi This includes, but is not limited to, agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH (thyroid-stimulating hormone-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 suppressor polypeptide agonists or antagonists (GIP analogs), gastrin, and gastrin analogs.

[0135] The pharmaceutical composition of this application can be used for the prevention and / or treatment of diseases, preferably metabolic diseases, neurological diseases, or brain-related diseases, including but not limited to glucose metabolism disorders and / or lipid metabolism disorders and / or neurodegenerative diseases.

[0136] In some embodiments of the present application, the glucose metabolism disorder is a blood glucose abnormality-related disease, and the lipid metabolism disorder is a weight abnormality-related disease. Of these, the blood glucose abnormality-related disease refers to a disease / symptom accompanied by a blood glucose abnormality or a complication / symptom caused by a disease accompanied by a blood glucose abnormality, and is one or more selected from diabetes mellitus, diabetic eye disease, diabetic heart disease, diabetic kidney disease, diabetic neuropathy and distal limb necrosis, atherosclerosis, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, osteoporosis, hyperlipidemia, hypertension, obesity, fatty liver, and cirrhosis. The diabetes mellitus includes, for example, hyperglycemia, type II diabetes mellitus, impaired glucose tolerance, type I diabetes mellitus, non-insulin-dependent diabetes mellitus, MODY (young-onset diabetes mellitus), and gestational diabetes mellitus. The above-mentioned weight-abnormality-related diseases refer to diseases / symptoms accompanied by weight abnormalities or complications / symptoms caused by diseases accompanied by weight abnormalities, and include one or more selected from anemia, gastroptosis, inflammatory bowel disease, indigestion, gastrointestinal ulcers, endocrine disorders, osteoporosis, obesity, hypertension, hyperlipidemia, coronary heart disease, diabetes mellitus, fatty liver, joint deformities, pain, cancer, respiratory failure, kidney disease, hyperlipidemia, atherosclerosis, cirrhosis, angina pectoris, and myocardial infarction.

[0137] In some embodiments of the present application, the neurodegenerative disease is one or more selected from cerebral 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.

[0138] The pharmaceutical compositions of the present invention can also be used as therapeutic agents to reduce HbA1c, delay or prevent the progression of diabetes, for example, the progression of type 2 diabetes, delay the progression of impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delay the progression of insulin-free type 2 diabetes to insulin-requiring type 2 diabetes, improve β-cell function, for example, reduce β-cell apoptosis, improve β-cell function and / or β-cell mass, and / or restore β-cell glucose sensitivity.

[0139] In this application, “treatment” and other similar synonyms include the alleviation, reduction, or improvement of symptoms of a disease or illness; the prevention of other symptoms; the improvement or prevention of potential metabolic causes that lead to symptoms; the suppression of a disease or illness, such as the cessation of the progression of a disease or illness; the alleviation of a disease or illness; the recovery from the progression of a disease or illness; the alleviation of symptoms caused by a disease or illness; or the cessation of symptoms of a disease or illness; and the term also includes the purpose of prevention. The term further includes obtaining therapeutic and / or preventive effects.

[0140] In this application, "patient" refers to an individual suffering from a disease, illness, or condition, and includes mammals. Examples of mammals include, but are not limited to, humans, non-human primates (e.g., chimpanzees and other apes and monkeys), livestock such as cattle, horses, sheep, goats, and pigs, pet animals such as rabbits, dogs, and cats, and laboratory animals such as rodents such as rats, mice, and guinea pigs, which are any member of the class Mammalia.

[0141] In this application, "C5~C11" refers to a group having 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).

[0142] In this application, the range of numbers, for example, "4-10" or "6-8", refers to each integer within the specified range, including 4, 5, 6, 7, 8, 9, or 10.

[0143] The present application will be further described below in accordance with specific embodiments. The specific embodiments described herein are shown in an exemplary manner and should be understood not as limiting the present application. The main features of the present application are applicable to various embodiments without departing from the scope of the present application.

[0144] The GLP-1 receptor agonists used in the examples and comparative examples have the structure shown in formula (I), and are N-ε 30-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutyrylamino]ethoxy)ethoxy]acetamide)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 Named the -GLP-1(7-37)) peptide, it is a glucagon-like peptide-1 receptor (GLP-1R) polypeptide agonist and is manufactured by reference to WO2019201328A1.

[0145] [ka]

[0146] The PNAC used in the examples and comparative examples is an anhydrous crystalline sample of potassium N-(8-(2-hydroxybenzoyl)amino)octanoate, and the PNAC has the structure shown in formula (II) and is prepared with reference to CN 112661663B, i.e., crystalline form I.

[0147] [ka]

[0148] Unless otherwise specified, the test animals, test equipment, and test reagents used in the examples and comparative examples are all commonly available commercially.

[0149] The analytical method for determining the content of GLP-1 receptor agonists used in the examples and comparative examples is as follows.

[0150] For the analysis of the active substance GLP-1 receptor agonist content, the HPLC method (Chinese Pharmacopoeia 2020 Edition, General Rules for Four Sections 0512) was adopted, and the specific test procedure was as follows: Five composition tablets were taken, weighed to determine the total weight, finely polished, and uniformly mixed. An appropriate amount was weighed and dissolved in the diluent (0.01% Tween 20 + 0.05M Na2HPO4). After complete dissolution, the solution was diluted to the desired volume, shaken uniformly, and allowed to stand for 30 minutes to allow for sufficient extraction. After uniform shaking, the sample was centrifuged (4°C, 12000 rpm for 10 minutes), the supernatant was taken and placed in an appropriate volume of HPLC liquid phase vial, the sample was injected and analyzed, and detection was performed using Waters high-performance liquid chromatography. The reverse-phase chromatography column used was a YMC UltraHT Pro C18 column. In addition, instruments such as an electronic balance (1 / 100,000), an ultrasonic device, a volumetric flask, reagent bottles, and sealing film were also used. The reagents used include distilled water, acetonitrile (HPLC grade), isopropanol (HPLC grade), trifluoroacetic acid (HPLC grade), anhydrous disodium hydrogen phosphate, and Tween 20. Mobile phase A is water:acetonitrile:TFA in a volume ratio of 830:170:2. Mobile phase B is acetonitrile:isopropanol:TFA in a volume ratio of 850:150:2. The content of each component in the composition tablet is calculated relative to the peak area of ​​the GLP-1 receptor agonist control.

[0151] Example 1: Pharmacokinetic study in Beagle dogs 1. Manufacturing of composition tablets Tablets with the same amount of GLP-1 receptor agonist were manufactured, but the content of adjuvants, such as the delivery agent PNAC, delivery enhancers, and other adjuvants, differed. Tables 1 and 2 provide the content of each component in the different composition tablets manufactured.

[0152] The specific manufacturing steps for the tablets were as follows: (1) Material pretreatment: The GLP-1 receptor agonist was sieved through a 100-mesh sieve, and if necessary, it could be crushed and then sieved again. The delivery agent PNAC was sieved through a 50-mesh sieve, and any material that did not pass through the sieve was polished and then sieved again. The treatment of the delivery enhancer was the same as for PNAC. Magnesium stearate was used directly as a lubricant. (2) Initial mixing: A fixed amount of GLP-1 receptor agonist, delivery agent, delivery enhancer, and an appropriate amount of magnesium stearate were mixed uniformly by hand to obtain mixed powder I. (3) Dry granulation: The above mixed powder I was rolled into a strip sheet of appropriate hardness and then crushed into particles. (4) Remixing: The above particles were collected, the remaining magnesium stearate was added again, and the mixture was mixed uniformly by hand. (5) Tableting: The hardness of the tablets was controlled within the range of 30-90N.

[0153] [Table 1]

[0154] [Table 2]

[0155] 2. Test Methods and Results 2.1 Collapse Test In accordance with the disintegration time test method described in General Rule 0921 of the Four Sections of the "Chinese Pharmacopoeia 2020 Edition," a tablet disintegration test was conducted in this embodiment, and the in vitro disintegration time of tablets of different compositions was recorded. The specific method was as follows: A basket was suspended from a bracket by a stainless steel shaft and immersed in a 1000 mL beaker. The position of the basket was adjusted so that when it was lowered to its lowest point, the sieve at the bottom was approximately 25 mm away from the bottom of the cup. The beaker was filled with purified water at a temperature of 37 ± 1 °C. The water level was adjusted so that when the basket was raised to its highest point, the sieve was 15 mm below the water surface, and the top of the basket was not immersed in the solution.

[0156] In this example, the disintegration time was measured according to the method described above using the ZB-1D intelligent disintegration device from Tianjin Tianhe Analytical Instruments Co., Ltd. The results were taken as the median value for 3 to 6 composition tablets.

[0157] As shown in Table 3, the disintegration times of the tablets of different compositions varied with the type or proportion of the delivery enhancer, and each increased to a different degree compared to reference composition A.

[0158] [Table 3]

[0159] 2.2 Pharmacokinetic studies in Beagle dogs The beagle dogs used were male, approximately 0.5 to 6 years old, and weighed approximately 9 to 12 kg. Pharmacokinetic studies were repeatedly conducted on some of these beagle dogs. After the previous dose, an appropriate washout period was given to each beagle dog. During this period, their condition, such as mental state, feeding status / amount, and weight, was evaluated. If they passed the evaluation, they could proceed to the next dose experiment group.

[0160] The administration requirements were as follows: The patient was fasted overnight before each administration (without withholding water), administered under these conditions, and given a tablet with 10 mL of water (determined amount) at the time of administration, ensuring that the tablet was not chewed and remained intact, and given food 4 hours after administration. Blood samples were taken before administration (0h) and at 0.5h, 1.5h, 3h, 8h, and 24h after administration, and continued for up to 24 hours after administration to adequately cover the complete plasma concentration-time absorption spectrum of the GLP-1 receptor agonist.

[0161] Blood samples were collected at each blood collection point, and the general preparation process was as follows: Approximately 1.5 mL of whole blood was anticoagulated, then centrifuged at 5000 × g for 10 minutes under conditions of 4°C, and the resulting plasma was extracted and separated. The plasma was collected in EDTA anticoagulant EP tubes, at a volume of 600 μL or more per tube. It was stored in a refrigerator at -80°C until detection analysis.

[0162] Active components in blood samples were detected using liquid chromatography-mass spectrometry (LC-MS), with a Thermo Q EXACTIVE mass spectrometer and a Thermo Ultimate 3000 high-performance liquid chromatograph.

[0163] LC-MS was used to analyze the plasma concentration of GLP-1 receptor agonists, obtain plasma concentration-time curves, and determine the GLP-1 receptor agonist exposure status within 0-3 hours, and AUC. (0~3時間) and C max The exposure was obtained by obtaining the result and normalizing it by calculating the ratio (dose mg / body weight kg) * 100 to obtain the dose-corrected exposure.

[0164] As shown in Table 4 and Figure 1, with the same amount of delivery agent (PNAC) used, the composition tablets containing the delivery enhancer showed increased exposure in beagle dogs after oral administration. When the delivery enhancer was not included, the amount of delivery agent (PNAC) used was reduced compared to composition B, and post-oral exposure was significantly reduced (composition A). Increasing the amount of delivery enhancer significantly improved post-oral exposure and reduced the overall amount of adjuvant used. As is clear from the results, the delivery enhancer can effectively reduce the amount of delivery agent used and improve the oral bioavailability of the polypeptide.

[0165] [Table 4]

[0166] Example 2: Steady-state pharmacokinetic studies in Beagle dogs 1. Manufacturing of composition tablets Table 5 provides the content of each component in different composition tablets (compositions M1 to M9) used in this embodiment. The tablet manufacturing process involved direct mixing followed by tableting, and the specific steps were as follows: (1) Material pretreatment: The GLP-1R agonist was sieved through a 100-mesh sieve and, if necessary, crushed and then sieved again. The delivery agent PNAC was sieved through a 50-mesh sieve, and any material that did not pass through the sieve was polished and then sieved again. All other auxiliary agents were sieved through a 40-mesh sieve. (2) Mixing: A fixed amount of GLP-1R agonist, delivery agent, delivery enhancer and other auxiliary agents were manually mixed uniformly to obtain mixed powder I. (3) Tableting: Tablets were compressed as required, and the hardness of the tablets was controlled within the range of 30 to 90 N.

[0167] [Table 5]

[0168] 2. Test Methods and Results We conducted steady-state (multiple-dose) pharmacokinetic studies in beagle dogs to determine the exposure status of GLP-1R agonists in the body after multiple consecutive oral administrations of tablets with different proportions of the composition.

[0169] The test animals and methods were the same as in Section 2.2 of Example 1, the only difference being that one tablet was administered once daily for seven consecutive days, and blood samples were collected on Day 7 (0h) before administration, and at 0.5h, 1.5h, 3h, 8h, and 24h after administration.

[0170] Using LC-MS, plasma concentrations of GLP-1R agonists were analyzed to obtain a blood drug concentration-time curve, which represents the exposure to GLP-1R agonists in animals within 0-24 hours at steady state (Day 7), i.e., AUC. (0~24時間) and C max The exposure was obtained by obtaining the result and normalizing it by calculating the ratio of (dose mg / body weight kg)*100. The results of the study are shown in Table 6.

[0171] [Table 6]

[0172] The results showed that, compared to composition B (control group) which did not contain a delivery enhancer, compositions M1 to M9, each mixed with PNAC in different amounts and proportions of delivery enhancers, were administered orally multiple times, and their oral absorption (AUC) at steady state was significantly better. 0~24h ) was shown to be improved to varying degrees compared to composition B (control group). On the other hand, compared to composition B (control group), in which the maximum amount of PNAC used was 300 mg, the delivery enhancer was increased, and even in group M4, which contained only 50 mg of PNAC, its oral absorption (AUC) was improved. 0~24h ) still showed a twofold improvement compared to composition B (control group).

[0173] Example 3: Pharmacokinetic studies in cynomolgus monkeys 1. Manufacturing of composition tablets Table 7 shows the content of each component in the different composition tablets (compositions N1 to N3) used in this example. The tablet manufacturing process was the same as in Section 1 of Example 1, the difference being that mannitol and cross-linked carboxymethylcellulose sodium were sieved through a 40-mesh sieve in the "pretreatment" stage, and then mixed with the particles obtained by dry granulation and the remaining magnesium stearate in the "remixing" stage.

[0174] [Table 7]

[0175] 2. Test Methods and Results Pharmacokinetic studies of different doses of composition tablets were conducted using cynomolgus monkeys, thereby determining the exposure status of different doses of GLP-1R agonists in the body after multiple consecutive oral administrations of the different composition tablets.

[0176] A total of 12 animals were used in the study, divided into 4 groups of 3 animals each. All were male and weighed approximately 3-6 kg. Oral administration consisted of composition N1 (2 mg), composition N2 and composition B (7 mg), and composition N3 (15 mg). All were administered multiple times, once a day, one tablet each time, for 7 consecutive days. Plasma samples were collected from each group before administration (0h) and at 2h, 4h, 8h, and 24h after administration on Day 7.

[0177] Pharmacokinetic studies were conducted by processing blood samples according to the test method of Example 2 and administering them multiple times to cynomolgus monkeys. Plasma concentrations of the GLP-1R agonist were analyzed to obtain plasma concentration-time curves, which showed the exposure status of the GLP-1R agonist in the animal body within 0 to 24 hours at steady state (Day 7), i.e., AUC. (0~24時間) and C max The dose-corrected exposure was obtained by obtaining the result and normalizing it by calculating the ratio of (dose mg / body weight kg)*100, and the results are shown in Table 8 and Figure 2.

[0178] [Table 8]

[0179] The results showed that after oral administration of compositions N1, N2, and N3 to cynomolgus monkeys for 7 consecutive days, the system exposure level (C) of the GLP-1R agonist in the cynomolgus monkeys was measured. max and AUC (0~24h) ) was shown to increase with increasing dose, indicating a dose-dependent relationship. Compositions N1-N3 dose groups showed similar corrected C max and corrected AUC 0~24 The values ​​were observed and were clearly higher than those of composition B. Compared to the 7 mg / tablet dose group, composition B without the delivery enhancer had a clearly lower oral absorption than composition N2 with the delivery enhancer, and composition N2 had a clearly higher corrected AUC. 0~24h This indicates that compositions containing delivery enhancers have superior oral absorption.

[0180] Example 4: Comparative study of different delivery agents 1. Manufacturing of composition tablets To further investigate the oral efficacy-enhancing effect of delivery enhancers on oral delivery agents, the oral effects of different oral delivery agents with sodium octanoate (C8Na), sodium caprate (C10Na), sodium laurate (C12Na), sodium chenodeoxycholate, and delivery enhancer compositions (compositions J1-J4) were examined. The compositional components of the compositions are shown in Table 9. The method for manufacturing the tablets was the same as in Example 2, i.e., the ingredients were directly mixed and then compressed into tablets.

[0181] [Table 9]

[0182] 2. Test Methods and Results Pharmacokinetic studies were conducted in beagle dogs according to the test method of Example 2.

[0183] [Table 10]

[0184] Oral absorption (AUC) 0~24h The results are shown in Table 10. Compared to the control group of composition B, the exposure levels of compositions J2 to J4 were reduced to varying degrees, but the reduction in the content of the oral delivery agent reached up to two-thirds. Surprisingly, when the content of the delivery agent was reduced compared to composition B, composition J1 showed an improvement in oral exposure, similar to composition M1. This indicates that calcium carbonate, as a delivery enhancer, also has a good potency-enhancing effect on other delivery agents (e.g., sodium octanoate, sodium caprate, sodium laurate, sodium chenodeoxycholate, etc.).

[0185] Comparative study of different carrier reagents 1. Manufacturing of composition tablets The oral effects of compositional tablets (compositions F1-F7) containing the delivery agent PNAC along with several other reagents having potential delivery-enhancing effects were investigated. The compositional components of the compositions are shown in Table 11. The method for manufacturing the tablets was the same as in Example 1.

[0186] [Table 11]

[0187] 2. Test Methods and Results A pharmacokinetic study was conducted in beagle dogs according to the test method of Example 1, and the results are shown in Table 12.

[0188] [Table 12]

[0189] The results showed that, when no delivery enhancer was included, the amount of delivery agent (PNAC) used in composition A was reduced compared to composition B, and oral exposure was significantly reduced. When the same amount of delivery agent (PNAC) was used, several candidate enhancers from this comparative example were selected to form the delivery agent and composition tablets, and exposure in beagle dogs after oral administration was reduced. As is clear from the results, although there are similarities with the delivery enhancer of the present application in several structural features, after oral administration of composition tablets containing several candidate enhancers from this comparative example, the amount of drug exposure was not improved, but rather reduced. This indicates that not all similar carrier reagents commonly found in the pharmaceutical field can reduce the amount of delivery agent used and improve the bioavailability of polypeptides.

[0190] The above description of the embodiments is merely for the purpose of understanding the method and its core concept. Those skilled in the art will be able to make various improvements and modifications to the present invention without departing from its principles, and these improvements and modifications will also fall within the scope of the claims of the present invention.

Claims

1. 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 comprises magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide. The aforementioned protein or polypeptide-based drug is delivered by a delivery agent. Preferably, the delivery enhancer is characterized by comprising magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate. use.

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

3. The aforementioned 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 includes a GLP-1 receptor agonist. Preferably, the GLP-1 receptor agonist comprises an exendin, GLP-1 or its analogues, fragments, derivatives, fusion proteins, conjugates, or pharmaceutically acceptable salts thereof. Preferably, the structure of the GLP-1 receptor agonist is characterized by being shown in formula (I), 【Chemistry 1】 The use described in claim 1.

4. The structure of the delivery agent is shown in formula (III), 【Chemistry 2】 In formula (III), L represents a linear or branched alkylene group of C5 to C11, and M is Na ＋ _K ＋ or NH ４ ＋ Show, Preferably, L represents a linear or branched alkylene group of C7 to C9, and M represents K ＋ Show, Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid includes a sodium salt, a potassium salt and / or an ammonium salt. Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salts, and its structure is shown in formula (II). 【Transformation 3】 Alternatively, the structure of the delivery agent is shown in formula (IV), 【Chemistry 4】 In formula (IV), n represents an integer from 4 to 10, and M is Na ＋ , K ＋ or NH ４ ＋ and represents Preferably, n is an integer between 6 and 8, and M is Na ＋ Show, Preferably, the delivery agent comprises a salt of octanoic acid, capric acid and / or lauric acid. Preferably, the delivery agent comprises octanoic acid, capric acid and / or lauric acid sodium salts, potassium salts and / or ammonium salts, Alternatively, the delivery agent contains a salt of chenodeoxycholic acid, Preferably, the delivery agent comprises a sodium salt, potassium salt, and / or ammonium salt of chenodeoxycholic acid. Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3 to 1:

3. Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3 to 1:

2. Preferably, the combination includes using a protein or polypeptide drug and a delivery enhancer simultaneously in the form of a pharmaceutical composition, or using them sequentially in a specific order. Preferably, the combination involves using a protein or polypeptide-based drug and a 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 to 1:

150. Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10 to 1:

50. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, Preferably, the pharmaceutically acceptable carrier comprises a lubricant, filler, disintegrant, flavoring agent, coloring agent, binder, excipient, buffer, diluent, solubilizer, tension modifier, surfactant, preservative, isotonic agent, stabilizer and / or 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 carboxymethylcellulose sodium. Preferably, the pharmaceutical composition further comprises one or more active drug components for use in combination with the protein or polypeptide drug, Preferably, the active drug component is selected from antidiabetic agents, anti-obesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and symptoms caused by or associated with diabetes, and agents for treating and / or preventing complications and symptoms caused by or associated with obesity. Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersants, or powders. Preferably, the dosage form of the pharmaceutical composition is a tablet. Preferably, the tablets are manufactured by a dry granulation process and / or a direct mixing process. Preferably, the hardness of the tablet is 30 to 90 N. The use described in any one of claims 1 to 3.

5. 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 aluminum magnesium carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide, The aforementioned protein or polypeptide-based drug is delivered by a delivery agent. Preferably, the delivery enhancer is characterized by comprising magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate. method.

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

7. The aforementioned 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 includes a GLP-1 receptor agonist. Preferably, the GLP-1 receptor agonist comprises an exendin, GLP-1 or its analogues, fragments, derivatives, fusion proteins, conjugates, or pharmaceutically acceptable salts thereof. Preferably, the structure of the GLP-1 receptor agonist is characterized by being shown in formula (I), 【Transformation 5】 The method according to claim 5.

8. The aforementioned combination includes using a protein or polypeptide-based drug and a delivery enhancer simultaneously in the form of a pharmaceutical composition, or using them sequentially in a specified order. Preferably, the combination involves using a protein or polypeptide-based drug and a delivery enhancer simultaneously in the form of a pharmaceutical composition. Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersants, or powders. Preferably, the dosage form of the pharmaceutical composition is a tablet. Preferably, the tablets are manufactured by a dry granulation process and / or a direct mixing process. Preferably, the hardness of the tablet is 30 to 90 N. The method according to any one of claims 5 to 7.

9. The structure of the delivery agent is shown in formula (III), 【Transformation 6】 In formula (III), L represents a linear or branched alkylene group of C5 to C11, and M is Na ＋ _K ＋ or NH ４ ＋ Show, Preferably, L represents a linear or branched alkylene group of C7 to C9, and M represents K ＋ Show, Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid includes a sodium salt, a potassium salt and / or an ammonium salt. Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salts, and its structure is shown in formula (II). 【Transformation 7】 Alternatively, the structure of the delivery agent is shown in formula (IV), 【Transformation 8】 In equation (IV), n is an integer between 4 and 10, and M is Na ＋ _K ＋ or NH ４ ＋ Show, Preferably, n is an integer between 6 and 8, and M is Na ＋ Show, Preferably, the delivery agent comprises a salt of octanoic acid, capric acid and / or lauric acid. Preferably, the delivery agent comprises octanoic acid, capric acid and / or lauric acid sodium salts, potassium salts and / or ammonium salts, Alternatively, the delivery agent contains a salt of chenodeoxycholic acid, Preferably, the delivery agent comprises a sodium salt, potassium salt, and / or ammonium salt of chenodeoxycholic acid. Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3 to 1:

3. Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3 to 1:

2. Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5 to 1:

150. Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10 to 1:

50. The method according to any one of claims 5 to 8.

10. The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, Preferably, the pharmaceutically acceptable carrier comprises a lubricant, filler, disintegrant, flavoring agent, coloring agent, binder, excipient, buffer, diluent, solubilizer, tension modifier, surfactant, preservative, isotonic agent, stabilizer and / or 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 carboxymethylcellulose sodium. Preferably, the pharmaceutical composition further comprises one or more active drug components for use in combination with the protein or polypeptide drug, Preferably, the active drug component is selected from antidiabetic agents, anti-obesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and symptoms caused by or related to diabetes, and agents for treating and / or preventing complications and symptoms caused by or related to obesity. The method according to claim 8.

11. A pharmaceutical composition comprising a protein or polypeptide drug with improved oral bioavailability as an active ingredient, wherein the pharmaceutical composition comprises a delivery enhancer, and the delivery enhancer comprises aluminum magnesium carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide. The aforementioned pharmaceutical composition further comprises a delivery agent, Preferably, the delivery enhancer comprises magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate. Preferably, the protein or polypeptide drug includes hormones, growth factors, cytokines, analgesic peptides, enzymes, blood coagulation factors, peptide neurotransmitters and / or antibodies. Alternatively, the protein or polypeptide drug may include 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 includes a GLP-1 receptor agonist. Preferably, the GLP-1 receptor agonist comprises an exendin, GLP-1 or its analogues, fragments, derivatives, fusion proteins, conjugates, or pharmaceutically acceptable salts thereof. Preferably, the structure of the GLP-1 receptor agonist is shown in formula (I), 【Chemistry 9】 Preferably, the structure of the delivery agent is shown in formula (III), 【Chemistry 10】 In formula (III), L represents a linear or branched alkylene group of C5 to C11, and M is Na ＋ _K ＋ or NH ４ ＋ Show, Preferably, L represents a linear or branched alkylene group of C7 to C9, and M represents K ＋ Show, Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid includes a sodium salt, a potassium salt and / or an ammonium salt. Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salts, and its structure is shown in formula (II). 【Chemistry 11】 Alternatively, the structure of the delivery agent is shown in formula (IV), 【Chemistry 12】 In equation (IV), n is an integer between 4 and 10, and M is Na ＋ _K ＋ or NH ４ ＋ Show, Preferably, n is an integer between 6 and 8, and M is Na ＋ Show, Preferably, the delivery agent comprises a salt of octanoic acid, capric acid and / or lauric acid. Preferably, the delivery agent comprises octanoic acid, capric acid and / or lauric acid sodium salts, potassium salts and / or ammonium salts, Alternatively, the delivery agent contains a salt of chenodeoxycholic acid, Preferably, the delivery agent comprises a sodium salt, potassium salt, and / or ammonium salt of chenodeoxycholic acid. Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3 to 1:

3. Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3 to 1:

2. Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5 to 1:

150. Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10 to 1:

50. Preferably, the protein or polypeptide drug is used in combination with a delivery enhancer. Preferably, the combination includes using a protein or polypeptide drug and a delivery enhancer simultaneously in the form of a pharmaceutical composition, or using them sequentially in a specific order. Preferably, the combination is characterized by the simultaneous use of a protein or polypeptide-based drug and a delivery enhancer in the form of a pharmaceutical composition. Pharmaceutical composition.

12. The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, Preferably, the pharmaceutically acceptable carrier comprises a lubricant, filler, disintegrant, flavoring agent, coloring agent, binder, excipient, buffer, diluent, solubilizer, tension modifier, surfactant, preservative, isotonic agent, stabilizer and / or 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 carboxymethylcellulose sodium. Preferably, the pharmaceutical composition further comprises one or more active drug components for use in combination with the protein or polypeptide drug, Preferably, the active drug component is selected from antidiabetic agents, anti-obesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and symptoms caused by or associated with diabetes, and agents for treating and / or preventing complications and symptoms caused by or associated with obesity. Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersants, or powders. Preferably, the dosage form of the pharmaceutical composition is a tablet. Preferably, the tablets are manufactured by a dry granulation process and / or a direct mixing process. Preferably, the hardness of the tablet is 30 to 90 N. The pharmaceutical composition according to claim 11.

13. The use of substances such as magnesium aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide as enhancers for drug delivery agents, The structure of the delivery agent is shown in formula (III), 【Chemistry 13】 In formula (III), L represents a linear or branched alkylene group of C5 to C11, and M is Na ＋ _K ＋ or NH ４ ＋ Show, Preferably, L represents a linear or branched alkylene group of C7 to C9, and M represents K ＋ Show, Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid includes a sodium salt, a potassium salt and / or an ammonium salt. Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salts, and its structure is shown in formula (II). 【Chemistry 14】 Alternatively, the structure of the delivery agent is shown in formula (IV), 【Chemistry 15】 In equation (IV), n is an integer between 4 and 10, and M is Na ＋ _K ＋ or NH ４ ＋ Show, Preferably, n is an integer between 6 and 8, and M is Na ＋ Show, Preferably, the delivery agent comprises a salt of octanoic acid, capric acid and / or lauric acid. Preferably, the delivery agent comprises octanoic acid, capric acid and / or lauric acid sodium salts, potassium salts and / or ammonium salts, Alternatively, the delivery agent contains a salt of chenodeoxycholic acid, Preferably, the delivery agent comprises a sodium salt, potassium salt, and / or ammonium salt of chenodeoxycholic acid. use.

14. A pharmaceutical composition comprising a delivery agent and a delivery enhancer, wherein the structure of the delivery agent is shown in formula (III), 【Chemistry 16】 In formula (III), L represents a linear or branched alkylene group of C5 to C11, and M is Na ＋ _K ＋ or NH ４ ＋ Show, Preferably, L represents a linear or branched alkylene group of C7 to C9, and M represents K ＋ Show, Preferably, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid includes a sodium salt, a potassium salt and / or an ammonium salt. Preferably, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salts, and its structure is shown in formula (II). 【Chemistry 17】 Alternatively, the structure of the delivery agent is shown in formula (IV), [Chemistry 18] In equation (IV), n is an integer between 4 and 10, and M is Na ＋ _K ＋ or NH ４ ＋ Show, Preferably, n is an integer between 6 and 8, and M is Na ＋ Show, Preferably, the delivery agent comprises a salt of octanoic acid, capric acid and / or lauric acid. Preferably, the delivery agent comprises octanoic acid, capric acid and / or lauric acid sodium salts, potassium salts and / or ammonium salts, Alternatively, the delivery agent contains a salt of chenodeoxycholic acid, Preferably, the delivery agent comprises a sodium salt, potassium salt, and / or ammonium salt of chenodeoxycholic acid. The delivery enhancer comprises aluminum magnesium carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide. Preferably, the delivery enhancer comprises magnesium aluminum carbonate, 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 to 1:

3. Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3 to 1:

2. Pharmaceutical composition.

15. The pharmaceutical composition further comprises a protein or polypeptide drug, the protein or polypeptide drug comprising a hormone, growth factor, cytokine, analgesic peptide, enzyme, blood coagulation factor, peptide neurotransmitter and / or antibody, Alternatively, the protein or polypeptide drug may include 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 includes a GLP-1 receptor agonist. Preferably, the GLP-1 receptor agonist comprises an exendin, GLP-1 or its analogues, fragments, derivatives, fusion proteins, conjugates, or pharmaceutically acceptable salts thereof. Preferably, the structure of the GLP-1 receptor agonist is shown in formula (I), 【Chemistry 19】 Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5 to 1:

150. Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10 to 1:

50. Preferably, the protein or polypeptide drug is used in combination with a delivery enhancer. Preferably, the combination includes using a protein or polypeptide drug and a delivery enhancer simultaneously in the form of a pharmaceutical composition, or using them sequentially in a specific order. Preferably, the combination involves using a protein or polypeptide-based drug and a 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, filler, disintegrant, flavoring agent, coloring agent, binder, excipient, buffer, diluent, solubilizer, tension modifier, surfactant, preservative, isotonic agent, stabilizer and / or 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 carboxymethylcellulose sodium. Preferably, the pharmaceutical composition further comprises one or more active drug components for use in combination with the protein or polypeptide drug, Preferably, the active drug component is selected from antidiabetic agents, anti-obesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and symptoms caused by or associated with diabetes, and agents for treating and / or preventing complications and symptoms caused by or associated with obesity. Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersants, or powders. Preferably, the dosage form of the pharmaceutical composition is a tablet. Preferably, the tablets are manufactured by a dry granulation process and / or a direct mixing process. Preferably, the hardness of the tablet is 30 to 90 N. The pharmaceutical composition according to claim 14.

16. The use of a pharmaceutical composition according to any one of claims 11, 12, 14, and 15 in the manufacture of a drug for preventing and / or treating metabolic disorders, neurological disorders, or brain disorders, Preferably, the metabolic-related diseases include glucose metabolism disorders and / or lipid metabolism disorders. Preferably, the glucose metabolism disorder includes blood glucose abnormality-related diseases. Preferably, the blood glucose-related diseases include diabetes mellitus, diabetic eye disease, diabetic heart disease, diabetic kidney disease, diabetic neuropathy and distal limb necrosis, atherosclerosis, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, osteoporosis, hyperlipidemia, hypertension, obesity, fatty liver and / or cirrhosis. Preferably, the diabetes includes hyperglycemia, type II diabetes, impaired glucose tolerance, type I diabetes, non-insulin-dependent diabetes, juvenile-onset diabetes (MODY), and / or gestational diabetes. Preferably, the lipid metabolism disorder includes weight abnormality-related disorders. Preferably, the weight abnormality-related diseases include anemia, gastroptosis, inflammatory bowel disease, indigestion, gastrointestinal ulcers, endocrine disorders, osteoporosis, obesity, hypertension, hyperlipidemia, coronary heart disease, diabetes mellitus, fatty liver, joint deformities, pain, cancer, respiratory failure, kidney disease, hyperlipidemia, atherosclerosis, cirrhosis, angina pectoris and / or myocardial infarction. Preferably, the neurological disease includes neurodegenerative diseases. Preferably, the neurodegenerative diseases include cerebral 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. use.

17. A reagent kit comprising the pharmaceutical composition according to any one of claims 11, 12, 14, and 15.

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