Compositions and methods for improving oral bioavailability of drugs

Abstract

The invention discloses a composition capable of improving oral bioavailability of drugs and a method thereof, and further discloses application of a delivery synergist in improving oral bioavailability of protein or polypeptide drugs. After the delivery synergist is added into the pharmaceutical composition provided by the invention, the delivery effect of a delivery agent can be exerted to the greatest extent under a certain proportion of the delivery synergist and the delivery agent, so that not only can the use amount of the delivery agent be reduced, but also the oral bioavailability of the medicine can be increased.

Description

Technical Field

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

[0002] Oral administration has always been the preferred method of administration for mainstream therapeutic drugs due to its simple operation, safety, effectiveness, and the variety of formulations that can be developed. It is also popular with patients and has good patient compliance. However, many high-demand drugs are still administered by other methods such as injection due to various restrictions. For example, currently, most peptide drugs such as insulin and GLP-1 agonists are administered by injection, which has the disadvantage of low patient adaptability, making it more difficult for patients to use the drug and causing long-term pain.

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

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

[0005] To achieve the above objectives, this application adopts the following technical solutions:

[0006] The first aspect of the present application provides: the use of a delivery enhancer in improving the oral bioavailability of a protein or polypeptide drug, wherein the protein or polypeptide drug is used in combination with a delivery enhancer, and the delivery enhancer includes aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; the protein or polypeptide drug is delivered by a delivery agent.

[0007] In some preferred technical solutions, the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

[0008] In the application provided in the first aspect of the present application, the protein or polypeptide drug can be any type commonly used in the art, including but not limited to hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters and / or antibodies.

[0009] In the application provided in the first aspect of the present application, the protein or polypeptide drug may also include a receptor agonist or antagonist commonly used in the art.

[0010] In some preferred technical solutions, the receptor agonist or antagonist includes a GLP-1 receptor agonist, a GLP-1 receptor antagonist, a GIP receptor agonist, a GIP receptor antagonist and / or an insulin receptor agonist.

[0011] Furthermore, the receptor agonist or antagonist includes a GLP-1 receptor agonist.

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

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

[0014]

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

[0016]

[0017] In formula (II), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + .

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

[0019] Furthermore, L represents a C7-C9 straight chain alkylene group, and M represents K + .

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

[0021] Furthermore, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid includes sodium salt, potassium salt and / or 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 salt, and its structure is shown in formula (III):

[0023]

[0024] In the application provided in the first aspect of the present application, the structure of the delivery agent may also be as shown in formula (IV):

[0025] CH3-(CH2) n -COOM,

[0026] (IV)

[0027] In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + .

[0028] Furthermore, n represents an integer of 6 to 8, and M represents Na + .

[0029] In some preferred embodiments, the delivery agent comprises a salt of caprylic acid, capric acid and / or lauric acid.

[0030] Further, the delivery agent includes sodium, potassium and / or ammonium salts of caprylic acid, capric acid and / or lauric acid.

[0031] In some most preferred embodiments, the delivery agent comprises sodium salts of caprylic acid, capric acid and / or lauric acid.

[0032] In the application provided in the first aspect of the present application, the delivery agent may further include a salt of chenodeoxycholic acid.

[0033] Furthermore, the delivery agent comprises sodium salt, potassium salt and / or ammonium salt of chenodeoxycholic acid.

[0034] In some preferred technical embodiments, the delivery agent includes sodium chenodeoxycholate.

[0035] In the application provided in the first aspect of the present application, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:3.

[0036] In some preferred technical solutions, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:2.

[0037] In the application provided in the first aspect of the present application, the combined use includes using the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; or using them separately in a specific order, for example, using the delivery enhancer first and then the protein or polypeptide drug.

[0038] Furthermore, the combined use is to use the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition.

[0039] In the application provided in the first aspect of the present application, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5-1:150.

[0040] In some preferred technical solutions, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10-1:50, for example, 1:10-1:30.

[0041] In the application provided in the first aspect of the present application, the pharmaceutical composition also includes a pharmaceutically acceptable carrier, which can be any type commonly used in the art, including but not limited to one or more of lubricants, fillers, disintegrants, flavoring agents, colorants, binders, excipients, buffers, diluents, solubilizers, tonicity regulators, surfactants, preservatives, isotonic agents, stabilizers, and chelating agents.

[0042] In some preferred technical solutions, the pharmaceutically acceptable carrier includes a lubricant, a filler and a disintegrant.

[0043] Furthermore, the lubricant includes magnesium stearate, glyceryl tribehenate and / or stearic acid.

[0044] In some most preferred technical solutions, the lubricant is selected from magnesium stearate; and / or the filler is selected from mannitol and / or microcrystalline cellulose; and / or the disintegrant is selected from cross-linked sodium carboxymethyl cellulose.

[0045] In the application provided in the first aspect of the present application, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug.

[0046] In some preferred technical schemes, the active pharmaceutical ingredients include anti-diabetic agents, anti-obesity agents, appetite regulators, anti-hypertensive agents, agents for treating and / or preventing complications and conditions caused by or related to diabetes, and agents for treating and / or preventing complications and conditions caused by or related to obesity.

[0047] In the application provided in the first aspect of the present application, the dosage form of the pharmaceutical composition can be any dosage form commonly used in the art.

[0048] In some preferred technical solutions, the dosage form of the pharmaceutical composition can be an oral dosage form, including but not limited to one or more of tablets, capsules, emulsions, aqueous suspensions, dispersions, and powders.

[0049] In some most preferred technical solutions, the dosage form of the pharmaceutical composition is a tablet.

[0050] In some most preferred technical solutions, the tablets can be prepared by dry granulation process and / or direct mixing process commonly used in the art.

[0051] In some preferred technical solutions, the tablet hardness is 30-90N.

[0052] The second aspect of the present application provides: a method for improving the oral bioavailability of a protein or polypeptide drug, the method comprising: using the protein or polypeptide drug in combination with a delivery enhancer, the delivery enhancer comprising aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; the protein or polypeptide drug is delivered via a delivery agent.

[0053] In some preferred technical solutions, the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

[0054] In the method provided in the second aspect of the present application, the protein or polypeptide drug is as defined in the first aspect of the present application.

[0055] In the method provided in the second aspect of the present application, the delivery agent is as defined in the first aspect of the present application.

[0056] In the method provided in the second aspect of the present application, the manner of combined use is as defined in the first aspect of the present application.

[0057] In the method provided in the second aspect of the present application, the mass ratio of the delivery agent to the delivery enhancer, and the mass ratio of the protein or polypeptide drug to the delivery agent are as defined in the first aspect of the present application.

[0058] In the method provided in the second aspect of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, which is as defined in the first aspect of the present application.

[0059] In the method provided in the second aspect of the present application, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug, which are as defined in the first aspect of the present application.

[0060] In the method provided in the second aspect of the present application, the dosage form of the pharmaceutical composition and the preparation method thereof can be any dosage form and process commonly used in the art, for example, as defined in the first aspect of the present application.

[0061] The third aspect of the present application provides: a pharmaceutical composition with improved oral bioavailability and containing a protein or polypeptide drug as an active ingredient, the pharmaceutical composition comprising a delivery enhancer, the delivery enhancer comprising aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; the pharmaceutical composition also comprises a delivery agent.

[0062] In some preferred technical solutions, the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

[0063] In the pharmaceutical composition provided in the third aspect of the present application, the protein or polypeptide drug is as defined in the first aspect of the present application.

[0064] In the pharmaceutical composition provided in the third aspect of the present application, the delivery agent is as defined in the first aspect of the present application.

[0065] In the pharmaceutical composition provided in the third aspect of the present application, the mass ratio of the delivery agent to the delivery enhancer, and the mass ratio of the protein or polypeptide drug to the delivery agent are as defined in the first aspect of the present application.

[0066] In the pharmaceutical composition provided in the third aspect of the present application, the protein or polypeptide drug is used in combination with a delivery enhancer, and the manner of the combined use is as defined in the first aspect of the present application.

[0067] In the pharmaceutical composition provided in the third aspect of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, which is as defined in the first aspect of the present application.

[0068] In the pharmaceutical composition provided in the third aspect of the present application, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug, which are as defined in the first aspect of the present application.

[0069] In the pharmaceutical composition provided in the third aspect of the present application, the dosage form and preparation method of the pharmaceutical composition can be any dosage form and process commonly used in the art, for example, as defined in the first aspect of the present application.

[0070] The fourth aspect of the present application provides: the use of the following substances as enhancers for drug delivery agents: aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; wherein the delivery agent is as defined in the first aspect of the present application.

[0071] The fifth aspect of the present application provides: a pharmaceutical composition comprising a delivery agent and a delivery enhancer, wherein the delivery agent is as defined in the first aspect of the present application, and the delivery enhancer comprises aluminum carbonate, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide.

[0072] In some preferred technical solutions, the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate.

[0073] In the pharmaceutical composition provided in the fifth aspect of the present application, the pharmaceutical composition also includes a protein or polypeptide drug, which is as defined in the first aspect of the present application.

[0074] In the pharmaceutical composition provided in the fifth aspect of the present application, the delivery agent is as defined in the first aspect of the present application.

[0075] In the pharmaceutical composition provided in the fifth aspect of the present application, the mass ratio of the delivery agent to the delivery enhancer, and the mass ratio of the protein or polypeptide drug to the delivery agent are as defined in the first aspect of the present application.

[0076] In the pharmaceutical composition provided in the fifth aspect of the present application, the protein or polypeptide drug is used in combination with a delivery enhancer, and the manner of the combined use is as defined in the first aspect of the present application.

[0077] In the pharmaceutical composition provided in the fifth aspect of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, which is as defined in the first aspect of the present application.

[0078] In the pharmaceutical composition provided in the fifth aspect of the present application, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug, which are as defined in the first aspect of the present application.

[0079] In the pharmaceutical composition provided in the fifth aspect of the present application, the dosage form and preparation method of the pharmaceutical composition can be any dosage form and process commonly used in the art, for example, as defined in the first aspect of the present application.

[0080] The sixth aspect of the present application provides: the use of the pharmaceutical composition described in the third aspect and the fifth aspect of the present application as a medicine (i.e., for use in treatment).

[0081] The seventh aspect of the present application provides: the use of the pharmaceutical composition described in the third aspect of the present application and the fifth aspect of the present application in the preparation of drugs for preventing and / or treating metabolic-related diseases, neurological-related diseases or brain-related diseases.

[0082] The eighth aspect of the present application provides: a method for preventing and / or treating metabolic-related diseases, neurological-related diseases or brain-related diseases, comprising administering a therapeutically effective dose of the pharmaceutical composition described in the third aspect of the present application and the fifth aspect of the present application to a patient in need.

[0083] In the seventh and eighth aspects of the present application, the metabolism-related diseases include glucose metabolism disorders and / or fat metabolism disorders.

[0084] In some preferred technical solutions, the glucose metabolism disorder disease includes a disease related to abnormal blood sugar.

[0085] Furthermore, the diseases related to abnormal blood sugar include diabetes, diabetic eye disease, diabetic heart disease, diabetic nephropathy, diabetic neuropathy and distal limb necrosis of the lower limbs, atherosclerosis, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, osteoporosis, hyperlipidemia, hypertension, obesity, fatty liver and / or cirrhosis.

[0086] Furthermore, the diabetes mellitus includes hyperglycemia, type II diabetes, impaired glucose tolerance, type I diabetes, non-insulin-dependent diabetes mellitus, maturity-onset diabetes of the young (MODY) and / or gestational diabetes.

[0087] In some preferred technical solutions, the fat metabolism disorder disease includes a disease related to abnormal body weight.

[0088] Furthermore, the abnormal weight-related diseases include anemia, gastroptosis, inflammatory bowel disease, indigestion, gastrointestinal ulcers, endocrine disorders, osteoporosis, obesity, hypertension, hyperlipidemia, coronary heart disease, diabetes, fatty liver, joint deformity, pain, cancer, respiratory insufficiency, kidney disease, hyperlipidemia, hypertension, atherosclerosis, cirrhosis, angina pectoris and / or myocardial infarction.

[0089] In the seventh and eighth aspects of the present application, the nerve-related diseases include neurodegenerative diseases.

[0090] Furthermore, the neurodegenerative diseases include brain atrophy, cerebral ischemia, brain injury, epilepsy, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, spinocerebellar ataxia, Pick's disease, bovine spongiform encephalopathy and / or Creutzfeldt-Jakob disease.

[0091] The ninth aspect of the present application provides: a kit comprising the pharmaceutical composition described in the third aspect of the present application and the fifth aspect of the present application.

[0092] Advantages and beneficial effects of this application:

[0093] After adding the delivery enhancer described in the present application, the pharmaceutical composition provided in the present application can maximize the delivery effect of the delivery agent in a certain ratio with the delivery agent, which can not only reduce the amount of delivery agent used, but also increase the oral bioavailability of the drug (for example, protein or polypeptide drugs). BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figure 1 This is a graph showing the oral absorption of the GLP-1 receptor agonist after calcium carbonate and aluminum hydroxide are respectively added to the composition in Example 1.

[0095] Figure 2 5 is a plasma concentration-time curve of the pharmacokinetic study of each composition on Day 7 in Example 3 in cynomolgus monkeys. DETAILED DESCRIPTION

[0096] The following provides definitions of some terms used in this specification. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0097] In the present application, "protein or polypeptide drugs" refer to protein or polypeptide compounds contained in oral drugs that directly act as active pharmaceutical ingredients in the body or indirectly help active pharmaceutical ingredients to prevent and / or treat diseases.

[0098] In some embodiments of the present application, the protein or polypeptide drug can be a natural protein or polypeptide compound (such as hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters and antibodies) or an artificially synthesized polypeptide or protein, as well as analogs, derivatives, conjugates or fusion proteins of the above polypeptides or proteins or their pharmaceutically acceptable salts.

[0099] In some embodiments of the present application, the protein or polypeptide drug may be a compound having receptor agonist or antagonist activity. The receptor agonists or antagonists include, but are not limited to, GLP-1 receptor agonists, GLP-1 receptor antagonists, GIP receptor agonists, GIP receptor antagonists, Amylin receptor agonists, heparin receptor agonists, growth hormone receptor agonists, interferon receptor agonists, interleukin receptor agonists, follicle-stimulating hormone receptor agonists, gonadotropin receptor agonists, erythropoietin receptor agonists, PYY (peptide tyrosine) receptor agonists, oxygenomodulin receptor agonists, GLP-2 (glucagon-like peptide-2) receptor agonists, calcitonin receptor agonists, PTH (parathyroid hormone) receptor agonists, ghrelin receptor agonists, endocannabinoid receptor agonists, leptin receptor agonists, serotonin receptor agonists, fibroblast growth factor 21 (FGF21) receptor agonists, cholecystokinin (CCK) receptor agonists, and glucagon receptor agonists.

[0100] In some embodiments of the present application, the protein or polypeptide drug simultaneously includes the active functions of one or more receptor agonists or antagonists.

[0101] In some embodiments of the present application, the protein or polypeptide drug is preferably a GLP-1 receptor agonist; the GLP-1 receptor agonist includes compounds having GLP-1 receptor agonist activity, especially polypeptides / proteins, as well as analogs, derivatives, conjugates or fusion proteins of the above polypeptides / proteins or pharmaceutically acceptable salts thereof.

[0102] In some embodiments of the present application, the GLP-1 receptor agonist includes exendin, exendin analogs, exendin agonists, GLP-1 (7-37), GLP-1 (7-37) analogs or derivatives, conjugates or fusion proteins or pharmaceutically acceptable salts thereof. The GLP-1 receptor agonist compound may be optionally amidated. The terms GLP-1 receptor agonist and GLP-1 receptor agonist compound have the same meaning.

[0103] Among them, exendins include naturally occurring exendins (or synthetic versions of naturally occurring ones) found in the saliva secretions of Gila monsters. Exendins of particular interest include exendin-3 and exendin-4. Exendins, exendin analogs and exendin agonists used in the present application may be optionally amidated and may also exist in the acid form of the molecule, in a pharmaceutically acceptable salt form or in any other physiologically active form.

[0104] GLP-1 (7-37) analogs refer to peptides that can elicit biological activity similar to that of GLP-1 (7-37) when assessed by a measurement method known in the art (such as a receptor binding assay or an in vivo blood glucose assay, e.g., as described in Hargrove et al., Regulatory Peptides, 141: 113-119 (2007), the disclosure of which is incorporated herein by reference). In one embodiment, the term GLP-1 (7-37) analog refers to a peptide having an amino acid sequence that has 1, 2, 3, 4, 5, 6, 7 or 8 amino acid substitutions, insertions, deletions, or a combination of two or more thereof when compared to the amino acid sequence of GLP-1 (7-37). GLP-1 (7-37) analogs include amidated forms, acid forms, and any other physiologically active forms of the molecule.

[0105] As used herein, "agonist" refers to a compound, molecule or agent that stimulates a biological activity.

[0106] In the present application, "analog" refers to a substance having a similar structure and / or function to the protein or polypeptide of the present application.

[0107] In this application, "pharmaceutically acceptable salt" refers to any adduct between two or more chemical species that are capable of undergoing proton transfer. Thus, pharmaceutically acceptable salts include adducts in which complete proton transfer has occurred; adducts in which partial proton transfer has occurred (e.g., in which an equilibrium mixture of charged and uncharged species is formed); and / or adducts in which proton transfer has not yet occurred, but the chemical species are bound, for example, by hydrogen bonding. It should be understood that pharmaceutically acceptable salts also encompass adducts in which tight ion pairs exist. It should also be understood that pharmaceutically acceptable salts encompass a continuum of adducts between the following adducts: those adducts in which complete proton transfer has occurred to form discrete ions and / or adducts in which two species are bound but no or only partial proton transfer has occurred. See, for example, Childs et al. Mol. Pharmaceutics, 2007, 4(3), pp 323-338. A given pharmaceutically acceptable salt may contain one or more adducts on the continuum.

[0108] Pharmaceutically acceptable salts include salts with acidic or basic groups. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, methanesulfonate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sucrose acid salt, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)). Suitable alkali salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.

[0109] In the present application, the mass ratio of the delivery agent to the delivery enhancer can be any mass ratio that can improve the delivery effect, for example, it can be 1:0.3-1:3, including about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2, about 1:2.1, about 1:2.2, about 1:2.3, about 1:2.4, about 1:2.5, about 1:2.6, about 1:2.7, about 1:2.8, about 1:2.9, about 1:3 mass ratios and any mass ratio interval.

[0110] In the present application, the mass ratio of the protein or polypeptide drug to the delivery agent can be any mass ratio that can achieve the delivery of the protein or polypeptide drug, for example, it can be 1:5-1:150, including mass ratios of about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, about 1:100, about 1:105, about 1:110, about 1:115, about 1:120, about 1:125, about 1:130, about 1:135, about 1:140, about 1:145, about 1:150 and any mass ratio interval.

[0111] In the present application, "bioavailability" refers to the degree and rate at which a substance such as a drug, peptide or hormone is available at a physiologically active site. In the field of pharmacology, the term bioavailability is understood to be the fraction of the dose of an unchanged drug, compound or drug that reaches systemic circulation, and is one of the main pharmacokinetic properties of a drug. According to definition, when a drug is administered intravenously, its bioavailability is 100%. However, when a drug is administered by other routes (such as oral or intramuscular), its bioavailability is usually reduced due to factors such as incomplete absorption and first-pass metabolism. Due to differences in, for example, individual metabolism, these factors may vary from patient to patient.

[0112] Standard assays for determining the bioavailability of a drug are known to those skilled in the art and involve, inter alia, measuring the relative area under the curve (AUC) of the concentration of the drug administered orally and intravenously (iv) in the same species.

[0113] In the present application, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be crystalline and / or amorphous, including but not limited to sodium salt, potassium salt and / or ammonium salt. In the present application, "pharmaceutically acceptable carrier" refers to a non-toxic material that does not interfere with the effect of the pharmaceutically active ingredient or pharmaceutical composition of the present application or the biological activity of the pharmaceutically active ingredient or pharmaceutical composition of the present application. The formulation of pharmaceutically active ingredients with pharmaceutically acceptable carriers is known in the art, such as Remington: The Science and Practice of Pharmacy (e.g., 21st edition (2005), and any subsequent editions). Non-limiting examples of pharmaceutically acceptable carriers include but are not limited to salts (e.g., acid salts / anionic salts, basic salts / cationic salts), excipients, buffers, diluents, solubilizers, tonicity regulators, surfactants, preservatives, isotonic agents, flavoring agents, colorants, stabilizers, binders, disintegrants, fillers, lubricants and chelating agents. One or more pharmaceutically acceptable carriers can be used to formulate the pharmaceutical composition of the present application.

[0114] In some embodiments of the present application, the pharmaceutically acceptable carrier includes an acid salt / anion salt. Non-limiting examples of acid salts / anionic salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, etopoate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolylaminophenylarsonic acid salt, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, and triethiodide.

[0115] In some embodiments of the present application, pharmaceutically acceptable carriers include alkali salts / cationic salts. Non-limiting examples of alkali salts / cationic salts include, but are not limited to, aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethamine or TRIS), ammonia, benzathine penicillin, tert-butylamine, chloroprocaine, choline, cyclohexylamine, diethanolamine, ethylenediamine, lithium, L-lysine, magnesium, meglumine, N-methyl-D-glucamine, piperidine, potassium, procaine, quinine, sodium, triethanolamine or zinc.

[0116] 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, bishydroxyethylglycine, citrate, disodium hydrogen phosphate, fumaric acid, glycine, glycine, 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.

[0117] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a preservative. Non-limiting examples of preservatives include, but are not limited to, benzethonium chloride, benzoic acid, benzyl alcohol, bromononitropropylene glycol, butyl 4-hydroxybenzoate, chlorobutanol, chlorocresol, chlorhexidine, chlorphenesin ether, o-cresol, m-cresol, p-cresol, ethyl 4-hydroxybenzoate, imidurea, methyl 4-hydroxybenzoate, phenol, 2-phenoxyethanol, 2-phenylethanol, propyl 4-hydroxybenzoate, sodium dehydroacetate, thimerosal, and combinations thereof.

[0118] In some embodiments of the present application, a pharmaceutically acceptable carrier includes an isotonic agent. Non-limiting examples of isotonic agents include, but are not limited to, amino acids (such as glycine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan and threonine), sugar alcohols (such as glycerol, 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 includes sugar. Non-limiting examples of sugars can be monosaccharides, disaccharides or polysaccharides, or water-soluble glucans, including, for example, fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, trehalose, glucan, amylopectin, dextrin, cyclodextrin, α and β-HPCD, soluble starch, hydroxyethyl starch and sodium carboxymethyl cellulose. Another example of an isotonic agent is sugar alcohol, wherein the term "sugar alcohol" is defined as a C (4-8) hydrocarbon with at least one -OH group. Non-limiting examples of sugar alcohols include, but are not limited to, mannitol, sorbitol, inositol, galactitol, hexasol, xylitol, and arabitol.Medicaments comprising each of the isotonic agents listed in this paragraph constitute alternative embodiments of the present application.

[0119] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a chelating agent. Non-limiting examples of chelating agents include, but are not limited to, salts of citric acid, aspartic acid, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0120] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a stabilizer. Non-limiting examples of stabilizers include carboxy- / hydroxycellulose and its derivatives (such as HPC, HPC-SL, HPC-L and HPMC), cyclodextrin, 2-methylthioethanol, polyethylene glycol (such as PEG 3350), polyvinyl alcohol (PVA), polyvinyl pyrrolidone, salts (such as sodium chloride), sulfur-containing substances (such as thioglycerol or thioglycolic acid) and combinations thereof.

[0121] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a lubricant (also referred to as a "glidant"). Lubricants can be used to prevent the dosage form from adhering to the roller, die and punch surfaces, and to reduce friction between the particles. Lubricants can also facilitate the ejection of the dosage form from the die groove and improve the granulation flow rate during processing. Non-limiting examples of lubricants include, but are not limited to, magnesium stearate, glyceryl behenate, calcium stearate, zinc stearate, stearic acid, silicon dioxide, talc, polyethylene glycol, mineral oil, carnauba wax, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, palmitoyl stearin, myristic acid and hydrogenated vegetable oils and fats, white vaseline, white beeswax, sodium benzoate, sodium hyaluronate, poloxamer, glyceryl monostearate, dimethicone, mixed fatty acid glycerides (stearin), polyvinyl alcohol, leucine, light liquid paraffin, hydrogenated soybean oil, trioleic acid Sorbitan (Span 85), behenic acid glyceryl, cetostearyl alcohol, octyldodecanol, liquid paraffin, stearic acid, magnesium lauryl sulfate, almond oil, rapeseed oil, cetyl alcohol wax, stearyl palmitate glyceryl, isopropyl palmitate, light liquid paraffin, sodium stearyl fumarate, behenic acid glyceryl, potassium benzoate, sterilized corn starch, myristic acid, tricaprylin, lauric acid, magnesium oxide, calcium phosphate, powdered cellulose, magnesium silicate, magnesium trisilicate, calcium phosphate, hydrophobic silica gel and other known lubricants, and / or a mixture of two or more thereof. In one embodiment, if present, the lubricant for raw material granulation is magnesium stearate.

[0122] In some embodiments of the present application, the pharmaceutically acceptable carrier includes one or more surfactants, preferably one surfactant, at least one surfactant or two different surfactants. Surfactant refers to any molecule or ion composed of a water-soluble part (hydrophilic) and a fat-soluble part (lipophilic). For example, the surfactant is selected from: anionic surfactants, cationic surfactants, nonionic surfactants and / or zwitterionic surfactants.

[0123] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a flavoring agent. The flavoring agent can be used to improve the palatability of the pharmaceutical composition. Non-limiting examples of flavoring agents include, but are not limited to, natural and / or synthetic (i.e., artificial) compounds and combinations thereof, etc., with corresponding flavors (such as 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).

[0124] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a colorant. The colorant can be used to color code the pharmaceutical composition, for example, to indicate the type and dosage of the therapeutic agent therein. Non-limiting examples of colorants include, but are not limited to, natural and / or artificial compounds such as FD&C colorants, natural fruit juice concentrates; dyes such as titanium dioxide, silicon dioxide, and zinc oxide; and combinations thereof, etc.

[0125] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a disintegrant. Non-limiting examples of disintegrants include, but are not limited to, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl methylcellulose, starch, guar gum, magnesium aluminum silicate, alginic acid, sodium alginate, methylcellulose, cross-linked polyvidone, polycrilin potassium, microcrystalline cellulose, anhydrous citric acid, pregelatinized starch, carboxymethyl cellulose calcium, powdered cellulose, sodium carboxymethyl starch, chitosan, calcium alginate, and combinations thereof.

[0126] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a filler. Non-limiting examples of fillers include, but are not limited to, lactose, microcrystalline cellulose, starch, pregelatinized starch, mannitol, kaolin, cellulose acetate, fructose, dextrin, talc, calcium sulfate, sodium chloride, xylitol, glucose, sorbitol, anhydrous lactose, magnesium oxide, zinc oxide, ethyl cellulose, sucrose, anhydrous lactose, dextran, and combinations thereof.

[0127] In some embodiments of the present application, the pharmaceutically acceptable carrier includes a binder. Non-limiting examples of binders include, but are not limited to, low-substituted hydroxypropyl methylcellulose, starch, hydrogenated soybean oil, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, alpha-lactose, dextran, hydroxypropyl starch, vitamin E polyethylene glycol succinate, gum arabic, alginic acid, methylcellulose, polyacrylic acid resin, povidone, maltodextrin, ethylhydroxycellulose, zein, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, carob gum, carbomer, povidone, glyceryl behenate, chitosan, liquid glucose, hydroxyethyl methylcellulose, sunflower oil, hydrogenated vegetable oil, inulin.

[0128] In the present application, the pharmaceutical composition for oral administration can be any oral acceptable dosage form, including but not limited to capsules, tablets, powders, emulsions and aqueous suspensions, dispersants and solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are usually added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When aqueous suspensions or emulsions are orally administered, the active ingredient can be suspended or dissolved in an oil phase in conjunction with an emulsifier or suspending agent. If desired, certain sweeteners, flavorings or coloring agents can be added. Nasal aerosols or inhalation compositions can be prepared according to techniques known in the field of pharmaceutical preparations, and can be made into saline solutions, using benzyl alcohol or other suitable preservatives, absorption promoters, fluorocarbons and / or other solubilizers or dispersants known in the art. The pharmaceutical composition of the present application can also be administered rectally in the form of suppositories.

[0129] If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared using any pharmaceutical method. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then shaping the product into the desired form if necessary.

[0130] In a specific embodiment of the present application, the dosage form of the pharmaceutical composition is a tablet.

[0131] In some embodiments of the present application, the tablet preparation method can be any conventional tablet preparation method familiar to those skilled in the art, for example, it can be prepared using a dry granulation process or a direct mixing process.

[0132] The specific steps of the dry granulation process are as follows: ① Material pretreatment: The protein or polypeptide drug is passed through a 50-200 mesh sieve, preferably a 100 mesh sieve, and can be crushed first and then sieved if necessary. The delivery agent is passed through a 20-100 mesh sieve, preferably a 50 mesh sieve, and the one that does not pass through the sieve is ground and sieved again. The delivery enhancer is treated with the same delivery agent. The lubricant is taken directly. If present, other pharmaceutically acceptable carriers are all passed through a 20-80 mesh sieve, preferably a 40 mesh sieve. ② First mixing: A certain amount of protein or polypeptide drugs, delivery agents, delivery enhancers, part of the lubricant and other optional pharmaceutically acceptable carriers are manually mixed to obtain a mixed powder I. ③ Dry granulation: The above mixed powder I is rolled into a strip-shaped thin sheet with suitable hardness, and then crushed into particles of suitable particle size. ④ Mix again: Collect the above particles, add the remaining lubricant again, and mix them manually. ⑤ Tablet pressing: Tablet pressing is performed according to the conventional tableting process in this field, and the tablet hardness is controlled within the range of 30-90N.

[0133] The specific steps of the direct mixing process are as follows: ① Material pretreatment: The protein or polypeptide drug is passed through a 100-mesh sieve, and can be crushed first and then sieved if necessary. The delivery agent is passed through a 50-mesh sieve, and those that do not pass through the sieve are ground and sieved again. The delivery enhancer is passed through a 20-80 mesh sieve, preferably a 40-mesh sieve. The lubricant is taken directly. If present, other pharmaceutically acceptable carriers are passed through a 20-80 mesh sieve, preferably a 40-mesh sieve. ② Mixing: A certain amount of protein or polypeptide drugs, delivery agents, delivery enhancers, lubricants and other optional pharmaceutically acceptable carriers are manually mixed uniformly to obtain a mixed powder I. ③ Tabletting: Tabletting is performed according to the conventional tableting process in the art, and the tablet hardness is controlled within the range of 30-90N.

[0134] In a specific embodiment of the present application, the tablets are prepared using a direct blending process.

[0135] In a specific embodiment of the present application, the tablet is prepared using a granulation process, preferably dry granulation.

[0136] In the present application, in addition to the pharmaceutical composition, the kit may comprise one or more containers selected from bottles, vials, ampoules, blister packs and syringes. The kit may further include one or more instructions for use, one or more syringes, one or more applicators, or a sterile solution suitable for reconstitution of the pharmaceutical composition of the present application for treating and / or preventing a disease, condition or disorder.

[0137] In the present application, the active pharmaceutical ingredient used in combination can be any ingredient that is different from the aforementioned protein or polypeptide drug type but has the same or similar active function, or that acts together with the aforementioned protein or polypeptide drug to produce active functions, for example, it can be selected from antidiabetic agents, anti-obesity agents, appetite regulators, antihypertensive agents, agents for treating and / or preventing complications and diseases caused by or related to diabetes, and agents for treating and / or preventing complications and diseases caused by or related to obesity.Non-limiting examples of such pharmacologically active drug ingredients include, but are not limited to, insulin, sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV (dipeptidyl peptidase-IV) inhibitors, sodium glucose transporter 2 (SGLT2) inhibitors; canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, ipragliflozin, togliflozin, lupagliflozin, bexagliflozin, repagliflozin ectoate and sotaglifkozin, in particular dapagliflozin and empagliflozin, inhibitors of liver enzymes involved in stimulating gluconeogenesis and / or glycogenolysis, glucose uptake regulators, compounds that alter lipid metabolism such as antihyperlipidemic agents such as HMG coenzyme A inhibitors (statins), gastric inhibitory polypeptide (GIP analogs), compounds that reduce food intake, RXR agonists and agents that act on the ATP-dependent potassium channels of β-cells; cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, Pravastatin, simvastatin, probucol, dextrothyroxine, nateglinide, repaglinide; beta-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, and metoprolol; ACE (angiotensin-converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, fasidotril, quinapril, and ramipril; calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, and verapamil; and alpha-blockers such as doxazosin, urapidil, prazosin, and terazosin; CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, PYY agonists, Y2 receptor agonists, Y4 receptor agonists, mixed Y2 / Y4 receptor agonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin-releasing factor) agonists, CRF BP (corticotropin-releasing factor binding protein) antagonists, urocortin agonists, β3 agonists, oxyntomodulin and analogs, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, 5-hydroxytryptamine reuptake inhibitors, 5-hydroxytryptamine and norepinephrine reuptake inhibitors, mixed 5-hydroxytryptamine and norepinephrine compounds, 5HT (5-hydroxytryptamine) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyrotropin-releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, RXR (retinoid X receptor) modulators, TRβ agonists; histamine H3 antagonists, gastric inhibitory polypeptide agonists or antagonists (GIP analogs), gastrin and gastrin analogs.

[0138] The pharmaceutical composition of the present application can be used to prevent and / or treat diseases, preferably metabolic-related diseases or nerve-related diseases or brain-related diseases, including but not limited to glucose metabolism disorders and / or fat metabolism disorders and / or neurodegenerative diseases.

[0139] In some embodiments of the present application, the glucose metabolism disorder is a disease related to abnormal blood sugar, and the fat metabolism disorder is a disease related to abnormal weight. Wherein, the disease related to abnormal blood sugar refers to a disease / symptom accompanied by abnormal blood sugar or a complication / symptom caused by a disease accompanied by abnormal blood sugar, selected from one or more of the following: diabetes, diabetic eye disease, diabetic heart disease, diabetic nephropathy, diabetic neuropathy and distal limb necrosis of the lower limbs, atherosclerosis, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, osteoporosis, hyperlipidemia, hypertension, obesity, fatty liver, cirrhosis. The diabetes, such as hyperglycemia, type II diabetes, impaired glucose tolerance, type I diabetes, non-insulin-dependent diabetes, MODY (maturity-onset diabetes of the young), gestational diabetes. The abnormal weight-related diseases refer to diseases / symptoms associated with abnormal weight or complications / symptoms caused by diseases associated with abnormal weight, selected from one or more of the following: anemia, gastroptosis, inflammatory bowel disease, indigestion, gastrointestinal ulcers, endocrine disorders, osteoporosis, obesity, hypertension, hyperlipidemia, coronary heart disease, diabetes, fatty liver, joint deformity, pain, cancer, respiratory insufficiency, kidney disease, hyperlipidemia, hypertension, atherosclerosis, cirrhosis, angina pectoris, and myocardial infarction.

[0140] In some embodiments of the present application, the neurodegenerative disease is selected from one or more of the following: brain atrophy, cerebral ischemia, brain injury, epilepsy, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, spinocerebellar ataxia, Pick's disease, bovine spongiform encephalopathy, and Creutzfeldt-Jakob disease.

[0141] The pharmaceutical composition of the present application can also be used as a therapeutic agent to reduce HbA1C; delay or prevent the progression of diabetes, such as the progression of type 2 diabetes, delay the progression of impaired glucose tolerance (IGT) to type 2 diabetes requiring insulin, and / or delay the progression of type 2 diabetes not requiring insulin to type 2 diabetes requiring insulin; improve β-cell function, such as reducing β-cell apoptosis, improving β-cell function and / or β-cell mass, and / or restoring β-cell glucose sensitivity.

[0142] In this application, "treat" and other similar synonyms include alleviating, reducing or improving symptoms of a disease or condition, preventing other symptoms, improving or preventing potential metabolic causes of symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, and in addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and / or a preventive effect.

[0143] In this application, "patient" refers to an individual suffering from a disease, disorder or condition, etc., including mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.

[0144] In the present application, "C5-C11" means that the group has 5 to 11 carbon atoms, that is, the group contains 5 carbon atoms (C5), 6 carbon atoms (C6), 7 carbon atoms (C7), 8 carbon atoms (C8), 9 carbon atoms (C9), 10 carbon atoms (C10) or 11 carbon atoms (C11).

[0145] In the present application, a numerical range, such as "4 to 10" or "6 to 8" refers to each integer in the given range, including 4, 5, 6, 7, 8, 9 or 10.

[0146] The present application is further described below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are presented by way of example and are not intended to limit the present application. The main features of the present application may be used in various embodiments without departing from the scope of the present application.

[0147] The structure of the GLP-1 receptor agonist used in the examples and comparative examples is shown in formula (I), and is named N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide, which is a glucagon-like peptide-1 receptor (GLP-1R) polypeptide agonist, was prepared with reference to WO2019201328A1.

[0148]

[0149] The PNAC used in the examples and comparative examples is an anhydrous crystalline sample of potassium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. The structure of PNAC is shown in formula (III), and it was prepared according to CN 112661663B, i.e., crystalline form I.

[0150]

[0151] Unless otherwise specified, the experimental animals, experimental instruments, experimental reagents, etc. used in the examples and comparative examples are all common commercially available products.

[0152] The analysis method of the GLP-1 receptor agonist content used in the examples and comparative examples is as follows:

[0153] For the content analysis of the active substance GLP-1 receptor agonist, the HPLC method (General Rules 0512 of Part IV of the "Chinese Pharmacopoeia 2020 Edition") is used. The specific test process is as follows: Take 5 tablets of the composition, weigh the total weight, grind and mix them, weigh an appropriate amount and dissolve them in the diluent (0.01% Tween 20 + 0.05M Na2HPO4), dilute and fix the volume after fully dissolving, shake well, and continue to stand for 30 minutes for full extraction. After shaking, centrifuge the sample (4°C 12000rpm centrifugation for 10 minutes), take the supernatant into a HPLC liquid phase vial of appropriate volume, inject and analyze, and use Waters high performance liquid chromatograph for detection. The reverse phase chromatographic column is a YMC UltraHT ProC18 column. In addition, electronic balances (one hundred thousandth), ultrasonic instruments, volumetric flasks, reagent bottles, sealing films and other instruments will also be used. The reagents used include distilled water, acetonitrile (HPLC grade), isopropanol (HPLC grade), trifluoroacetic acid (HPLC grade), anhydrous disodium hydrogen phosphate, Tween 20, etc. Mobile phase A is water: acetonitrile: TFA at a volume ratio of 830:170:2. Mobile phase B is acetonitrile: isopropanol: TFA at a volume ratio of 850:150:2. Relative to the peak area of ​​the GLP-1 receptor agonist reference substance, its content in the composition tablet is calculated.

[0154] Example 1 Pharmacokinetic Study in Beagle Dogs

[0155] 1. Preparation of Composition Tablets

[0156] Tablets with the same amount of GLP-1 receptor agonist were prepared, but the contents of excipients, such as delivery agent PNAC, delivery enhancer and other excipients were different. Tables 1 and 2 provide the contents of each component in the prepared tablets of different compositions.

[0157] The specific preparation steps of the tablets are as follows: ① Material pretreatment: The GLP-1 receptor agonist is passed through a 100-mesh sieve and can be crushed and then sieved if necessary. The delivery agent PNAC is passed through a 50-mesh sieve, and those that do not pass through the sieve are ground and sieved again. The delivery enhancer is treated the same as PNAC. The lubricant magnesium stearate is used directly. ② First mixing: A certain amount of GLP-1 receptor agonist, delivery agent, delivery enhancer and an appropriate amount of magnesium stearate are manually mixed to obtain a mixed powder I. ③ Dry granulation: The above mixed powder I is rolled into strip-shaped flakes with appropriate hardness, and then crushed into granules. ④ Mixing again: Collect the above granules, add the remaining magnesium stearate again, and mix manually to obtain a uniform mixture. ⑤ Tabletting: The tablet hardness is controlled within the range of 30-90N.

[0158] Table 1 Compositions of tablets of different compositions

[0159]

[0160] Table 2 Compositions of calcium carbonate-containing tablets

[0161]

[0162] 2. Test methods and results

[0163] 2.1 Disintegration test

[0164] According to the disintegration time limit inspection method of Part IV of the Chinese Pharmacopoeia 2020 Edition, the tablet disintegration test in this embodiment was carried out to record the disintegration time of tablets of different compositions in vitro. The specific method is: the hanging basket is suspended on the bracket by a stainless steel shaft, immersed in a 1000mL beaker, and the position of the hanging basket is adjusted so that when it drops to the lowest point, the bottom screen is about 25mm away from the bottom of the cup. The beaker is filled with purified water at a temperature of 37±1°C, and the water level is adjusted so that when the hanging basket rises to the highest point, the screen is 15mm below the water surface, and the top of the hanging basket is not immersed in the solution.

[0165] This example uses the ZB-1D intelligent disintegrator of Tianjin Tianhe Analytical Instrument Co., Ltd., and measures the disintegration time according to the method described. The results are the median values ​​of 3-6 tablets of the composition.

[0166] The results are shown in Table 3. The disintegration time of tablets of different compositions changes with the type or proportion of the delivery enhancer, and increases to varying degrees relative to the reference composition A.

[0167] Table 3 Disintegration time results

[0168]

[0169] 2.2 Pharmacokinetic studies in beagle dogs

[0170] The beagles used are male, aged about 0.5 to 6 years old, and weigh about 9-12kg. Some of the beagles will undergo repeated pharmacokinetic studies. After the previous round of dosing, the beagles will be given an appropriate washout period during which their status will be evaluated, such as mental state, eating status / amount, weight status, etc. Only those who pass the evaluation can enter the next round of dosing experimental group.

[0171] The dosing requirements are: fasting overnight (water is not allowed) before each administration. The drug is administered in this state. When administering, the tablet is washed down with 10 mL of water (quantitative) to ensure that the tablet is not chewed and remains intact. Eating is resumed 4 hours after administration. Blood samples are collected before administration (0h) and 0.5h, 1.5h, 3h, 8h, and 24h after administration, and continue until 24 hours after administration to fully cover the complete plasma concentration-time absorption spectrum of the GLP-1 receptor agonist.

[0172] At each blood collection time point, the sample blood was collected. The preparation process was as follows: about 1.5 mL of whole blood was anticoagulated, centrifuged at 5000×g for 10 min at 4°C, and the resulting plasma was extracted and separated. The plasma was collected in EDTA anticoagulated EP tubes, more than 600 μL / tube. It was stored in a -80°C refrigerator until detection and analysis.

[0173] The active ingredients in the blood samples were detected by liquid chromatography-mass spectrometry (LC-MS), the mass spectrometer was Thermo's QEXACTIVE model instrument, and the high performance liquid chromatography was Thermo's Ultimate 3000 model instrument.

[0174] The plasma concentration of GLP-1 receptor agonist was analyzed by LC-MS to obtain the plasma concentration-time curve, and the exposure of GLP-1 receptor agonist from 0 to 3 hours was determined to obtain AUC (0-3小时) and C max , and normalized by calculating the ratio of (administered dose mg / body weight Kg)*100 to obtain dose-corrected exposure.

[0175] As shown in Table 4 and Figure 1 As shown, when the same delivery agent (PNAC) dosage was used, the composition tablet containing the delivery enhancer observed an increase in exposure in beagle dogs after oral administration; when the delivery enhancer was not included, the delivery agent (PNAC) dosage was reduced compared to composition B, and the exposure after oral administration was significantly reduced (composition A); by adding the delivery enhancer, the exposure after oral administration was significantly improved, and the overall amount of excipients was reduced. The results show that the delivery enhancer can effectively reduce the amount of delivery agent used and improve the oral bioavailability of the polypeptide.

[0176] Table 4 Results of pharmacokinetic studies evaluating in vivo exposure of GLP-1 receptor agonists

[0177]

[0178] Example 2 Steady-state pharmacokinetic study in beagle dogs

[0179] 1. Preparation of Composition Tablets

[0180] Table 3 provides the content of each component in the different composition tablets (compositions M1-M9) used in this embodiment. The preparation process of the tablets is to compress the tablets directly after mixing, and the specific steps are as follows: ① Material pretreatment: The GLP-1R agonist is passed through a 100-mesh sieve, and if necessary, it can be crushed first and then sieved. The delivery agent PNAC is passed through a 50-mesh sieve, and those that do not pass through the sieve are ground and sieved again. Other excipients are all passed through a 40-mesh sieve. ② Mixing: A certain amount of GLP-1R agonist, delivery agent, delivery enhancer and other excipients are manually mixed and uniformly mixed to obtain a mixed powder I. ③ Tableting: Tablets are pressed as required, and the tablet hardness is controlled within the range of 30-90N.

[0181] Table 5 Composition tablet composition for steady-state pharmacokinetic study in beagle dogs

[0182]

[0183]

[0184] 2. Test methods and results

[0185] A steady-state (multiple-dose) pharmacokinetic study in beagle dogs was conducted to determine the in vivo exposure of the GLP-1R agonist following multiple consecutive oral administrations of composition tablets in varying ratios.

[0186] The experimental animals and methods are the same as those in Section 2.2 of Example 1, except that the drug is administered once a day, 1 tablet each time, for seven consecutive days, and blood samples are collected before (0h), and 0.5h, 1.5h, 3h, 8h, and 24h after administration on the seventh day (Day7).

[0187] The plasma concentration of GLP-1R agonists was analyzed by LC-MS to obtain the blood concentration-time curve, and the exposure of GLP-1R agonists in animals from 0 to 24 hours at steady state (Day 7), namely AUC (0-24小时) and C max The dose-corrected exposure was obtained by calculating the ratio of (administered dose mg / body weight Kg)*100. The test results are shown in Table 6.

[0188] Table 6 Steady-state pharmacokinetic study results in beagle dogs

[0189]

[0190] The results showed that compared with composition B (control group) without delivery enhancer, the compositions M1-M9 in which delivery enhancer was mixed with PNAC at different contents and ratios had a significantly higher oral absorption (AUC) at steady state after multiple oral administration. 0-24h ) were improved to varying degrees compared with composition B (control group). On the other hand, compared with composition B (control group) with a PNAC dosage of up to 300 mg, due to the addition of a delivery enhancer, even if the PNAC content of the M4 group was only 50 mg, its oral absorption (AUC 0-24h ) can still be increased to 2 times compared with composition B (control group).

[0191] Example 3 Pharmacokinetic Study in Cynomolgus Monkeys

[0192] 1. Preparation of Composition Tablets

[0193] Table 7 provides the contents of the various components in the tablets of different compositions (compositions N1-N3) used in this example. The preparation process of the tablets is the same as that of Example 1, Section 1, except that mannitol and cross-linked sodium carboxymethyl cellulose are passed through a 40-mesh sieve in the "pretreatment" stage and mixed with the granules obtained by dry granulation and the remaining magnesium stearate in the "re-mixing" stage.

[0194] Table 7 Compositions of the pharmacokinetic study composition in cynomolgus monkeys

[0195]

[0196] 2. Test methods and results

[0197] A pharmacokinetic study of tablets of different dosages of the composition was conducted using cynomolgus monkeys to determine the in vivo exposure of different dosages of the GLP-1R agonist after multiple consecutive oral administrations of tablets of different compositions.

[0198] A total of 12 animals were tested, divided into 4 groups, 3 animals in each group, all male, weighing about 3-6 kg. Oral administration: Composition N1 (2 mg), Composition N2 and Composition B (7 mg), Composition N3 (15 mg). All were administered multiple times, once a day, 1 tablet each time, for 7 consecutive days. Plasma samples were collected from each group before administration (0h), 2h, 4h, 8h, and 24h after administration on the seventh day (Day 7).

[0199] The blood samples were processed according to the experimental method of Example 2 and the pharmacokinetic study of multiple administrations in cynomolgus monkeys was carried out. The plasma concentration of the GLP-1R agonist was analyzed and the plasma concentration-time curve was obtained, thereby obtaining the exposure of the GLP-1R agonist in the animal body within 0 to 24 hours at steady state (Day 7), that is, AUC (0-24小时) and C max, and normalized by calculating the ratio of (administered dose mg / body weight Kg)*100 to obtain dose-corrected exposure. The results are shown in Table 8 and Figure 2 .

[0200] Table 8 Pharmacokinetic study results in cynomolgus monkeys

[0201]

[0202]

[0203] The results showed that after continuous oral administration of compositions N1, N2, and N3 to cynomolgus monkeys for 7 days, the systemic exposure of GLP-1R agonists in cynomolgus monkeys (C max and AUC (0-24h) ) increased with the increase of dose, and was dose-dependent. The groups administered with compositions N1-N3 showed similar correction C max and corrected AUC 0-24 Compared with the 7 mg / tablet dosage group, the oral absorption of composition B without the addition of a delivery enhancer was significantly lower than that of composition N2 with the addition of a delivery enhancer, and composition N2 showed a significantly higher corrected AUC 0-24h , which indicates that the composition containing the delivery enhancer has better oral absorption.

[0204] Example 4 Comparative study of different delivery agents

[0205] 1. Preparation of Composition Tablets

[0206] To further verify the oral synergistic effect of the delivery enhancer on the oral delivery agent, the oral effects of different oral delivery agents sodium caprylate (C8Na), sodium caprate (C10Na), sodium laurate (C12Na), sodium chenodeoxycholate and the delivery enhancer composition (compositions J1-J4) were investigated. The composition components of the composition are shown in Table 9. The preparation method of the tablets is the same as in Example 2, that is, tableting after direct mixing.

[0207] Table 9 Compositions of different delivery agents for comparative study

[0208]

[0209] 2. Test methods and results

[0210] The pharmacokinetic study in beagle dogs was conducted according to the experimental method of Example 2.

[0211] Table 10 Comparative study results of different delivery agents

[0212]

[0213] Oral absorption (AUC0-24h ) The results are shown in Table 10. Compared with the control group of composition B, although the exposure of compositions J2-J4 was reduced to varying degrees, the content of the oral delivery agent was reduced by up to two-thirds. Surprisingly, compared with composition B, when the content of the delivery agent was reduced, composition J1 showed an increase in oral exposure, similar to composition M1. This shows that the delivery enhancer calcium carbonate also has a good synergistic effect on other delivery agents (such as sodium caprylate, sodium caprate, sodium laurate, sodium chenodeoxycholate, etc.).

[0214] Comparative study of different carrier reagents

[0215] 1. Preparation of Composition Tablets

[0216] The oral efficacy of the composition tablets (compositions F1-F7) prepared by compounding several other agents with potential delivery enhancement effects with the delivery agent PNAC was investigated. The composition components are shown in Table 11. The preparation method of the tablets was the same as that of Example 1.

[0217] Table 11 Composition of the comparative example composition

[0218]

[0219]

[0220] 2. Test methods and results

[0221] The pharmacokinetic test in beagle dogs was carried out according to the test method of Example 1. The results are shown in Table 12.

[0222] Table 12 Comparative pharmacokinetic study evaluating in vivo exposure results of GLP-1 receptor agonists

[0223]

[0224] The results show that when the delivery enhancer is not included, the amount of delivery agent (PNAC) in composition A is reduced compared to composition B, and the oral exposure is significantly reduced; when the amount of delivery agent (PNAC) is the same, several candidate enhancers in this comparative example are selected to form a composition tablet with the delivery agent, and the exposure in beagle dogs after oral administration is reduced. The results show that although there are similarities with the delivery enhancer of the present application in some structural features, oral administration of the composition tablet containing several candidate enhancers in this comparative example does not increase the exposure of the drug, but rather reduces it, indicating that similar carrier agents commonly used in the pharmaceutical field are not able to reduce the amount of delivery agent used and improve the bioavailability of the polypeptide.

[0225] The description of the above embodiments is only used to understand the method and core idea of ​​the present application. It should be noted that, for ordinary technicians in this field, several improvements and modifications can be made to the present application without departing from the principles of the present application, and these improvements and modifications will also fall within the scope of protection of the claims of the present application.

Claims

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

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

3. The use according to claim 1, characterized in that: The protein or polypeptide drugs include receptor agonists or antagonists.

4. The use according to any one of claims 1 to 3, characterized in that: The structure of the delivery agent is shown in formula (II): In formula (II), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2) n -COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + ; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:3; Preferably, the combined use includes using the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; or using them separately in sequence; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5-1:150; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug; Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersions or powders.

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

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

7. The method according to claim 5, characterized in that The protein or polypeptide drugs include receptor agonists or antagonists.

8. The method according to any one of claims 5 to 7, characterized in that: The combined use includes using the protein or polypeptide drug and the delivery enhancer simultaneously in the form of a pharmaceutical composition; or using them separately in sequence; Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersions or powders.

9. The method according to any one of claims 5 to 8, characterized in that: The structure of the delivery agent is shown in formula (II): In formula (II), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2) n -COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + ; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:3; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:2; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:10-1:50; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug.

10. A pharmaceutical composition with improved oral bioavailability and containing a protein or polypeptide drug as an active ingredient, characterized in that: The pharmaceutical composition includes a delivery enhancer, and the delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; The pharmaceutical composition further comprises a delivery agent; Preferably, the delivery enhancer comprises hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide and / or sucralfate; Preferably, the protein or polypeptide drugs include hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters and / or antibodies; Alternatively, the protein or polypeptide drug includes a receptor agonist or antagonist; Preferably, the structure of the delivery agent is as shown in formula (II): In formula (II), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2) n -COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + ; Preferably, the mass ratio of the delivery agent to the delivery enhancer is 1:0.3-1:3; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5-1:150; Preferably, the protein or polypeptide drug is used in combination with a delivery enhancer; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug; Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersions or powders.

11. Use of the following substances as synergists for drug delivery agents: hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; in, The structure of the delivery agent is shown in formula (II): In formula (II), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2) n -COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + .

12. A pharmaceutical composition comprising a delivery agent and a delivery enhancer, wherein: The structure of the delivery agent is shown in formula (II): In formula (II), L represents a C5-C11 straight chain or branched chain alkylene group, and M represents Na + , K + or NH4 + ; Alternatively, the structure of the delivery agent is as shown in formula (IV): CH3-(CH2) n -COOM, (IV) In formula (IV), n represents an integer of 4 to 10, and M represents Na + , K + or NH4 + ; The delivery enhancer includes hydrotalcite, aluminum phosphate, calcium carbonate, aluminum hydroxide, sucralfate, calcium bicarbonate, aluminum bicarbonate, magnesium bicarbonate and / or magnesium hydroxide; Preferably, the pharmaceutical composition further comprises a protein or polypeptide drug; Preferably, the mass ratio of the protein or polypeptide drug to the delivery agent is 1:5-1:150; Preferably, the protein or polypeptide drug is used in combination with a delivery enhancer; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; Preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients for use in combination with the protein or polypeptide drug; Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, emulsions, aqueous suspensions, dispersions or powders.

13. Use of the pharmaceutical composition according to claim 10 or 12 in the preparation of a medicament for preventing and / or treating metabolic-related diseases, nerve-related diseases or brain-related diseases; Preferably, the metabolism-related diseases include glucose metabolism disorders and / or fat metabolism disorders; Preferably, the glucose metabolism disorder disease includes a disease related to abnormal blood sugar; Preferably, the abnormal blood sugar related diseases include diabetes, diabetic eye disease, diabetic heart disease, diabetic nephropathy, diabetic neuropathy and distal limb necrosis of lower limbs, atherosclerosis, coronary heart disease, myocardial infarction, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, osteoporosis, hyperlipidemia, hypertension, obesity, fatty liver and / or cirrhosis; Preferably, the diabetes mellitus includes hyperglycemia, type II diabetes, impaired glucose tolerance, type I diabetes, non-insulin-dependent diabetes mellitus, maturity-onset diabetes of the young (MODY) and / or gestational diabetes; Preferably, the dyslipidemia disease includes a disease related to abnormal body weight; Preferably, the abnormal weight-related diseases include anemia, gastroptosis, inflammatory bowel disease, indigestion, gastrointestinal ulcers, endocrine disorders, osteoporosis, obesity, hypertension, hyperlipidemia, coronary heart disease, diabetes, fatty liver, joint deformity, pain, cancer, respiratory insufficiency, kidney disease, hyperlipidemia, hypertension, atherosclerosis, cirrhosis, angina pectoris and / or myocardial infarction; Preferably, the nerve-related diseases include neurodegenerative diseases; Preferably, the neurodegenerative disease comprises brain atrophy, cerebral ischemia, brain injury, epilepsy, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, spinocerebellar ataxia, Pick's disease, bovine spongiform encephalopathy and / or Creutzfeldt-Jakob disease.

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