Use of bismuth agents to enhance bioavailability of orally administered drugs

Abstract

The application discloses application of a bismuth agent in promoting bioavailability of oral drugs, a method for promoting bioavailability of protein and polypeptide drugs, and a high-bioavailability drug composition with protein and polypeptide drugs as active ingredients. The bismuth agent of the application can effectively increase oral bioavailability of GLP-1 receptor agonists, and can also reduce the dosage of delivery agents to a certain extent. The composition has excellent oral absorption capacity, and can effectively promote the body to take in polypeptide active drugs.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to the application of bismuth preparations in promoting the bioavailability of oral drugs. Background Technology

[0002] Protein and peptide drugs cannot be effectively administered orally due to the gastrointestinal barrier. These drugs are typically administered intravenously or intramuscularly, requiring hospitalization or specialized medical care, which demands a high level of expertise, poses potential trauma to patients, and may even increase costs. Furthermore, the vast majority of protein and peptide drugs currently suffer from low oral bioavailability. Therefore, improving the bioavailability of orally administered protein and peptide drugs is of great significance. Summary of the Invention

[0003] To overcome the shortcomings of the prior art, the present invention provides the application of bismuth preparations in promoting the bioavailability of oral drugs.

[0004] To achieve the above objectives, the present invention adopts the following technical solution:

[0005] A first aspect of the present invention provides the use of bismuth preparations in improving the oral bioavailability of protein and peptide drugs.

[0006] Furthermore, the bismuth agent includes bismuth aluminate, potassium bismuth citrate, colloidal pectin bismuth, basic bismuth carbonate, and / or bismuth subsalicylate.

[0007] Furthermore, the bismuth agent includes bismuth aluminate, potassium bismuth citrate, colloidal pectin bismuth, and / or basic bismuth carbonate.

[0008] Furthermore, the protein and polypeptide drugs include hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters, and / or antibodies.

[0009] Furthermore, the protein and peptide drugs also include receptor agonists or antagonists.

[0010] Furthermore, the receptor agonist or antagonist includes GLP-1 receptor agonists, GLP-1 receptor antagonists, GIP receptor agonists, GIP receptor antagonists, and insulin receptor agonists.

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

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

[0013] Furthermore, the structure of the GLP-1 receptor agonist is shown in Formula (I):

[0014]

[0015] Furthermore, the bismuth agent can be administered before protein and peptide drugs, or formulated into a pharmaceutical composition for substantially simultaneous administration.

[0016] Furthermore, bismuth preparations are formulated with protein and peptide drugs to form pharmaceutical compositions that are administered substantially simultaneously.

[0017] Furthermore, the dosage form of the pharmaceutical composition includes tablets, capsules, powders, suspensions, solutions, emulsions, or syrups.

[0018] Furthermore, the dosage form of the pharmaceutical composition is a tablet.

[0019] Furthermore, the tablets are prepared by a dry granulation process and / or a direct mixing process.

[0020] Furthermore, the pharmaceutical composition also includes a delivery agent.

[0021] Furthermore, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

[0022] Furthermore, the salts of N-(8-(2-hydroxybenzoyl)amino)octanoic acid include sodium salts, potassium salts, and / or ammonium salts.

[0023] Furthermore, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salts, and its structure is shown in formula (II):

[0024]

[0025] Furthermore, the mass ratio of the delivery agent to the bismuth agent is 1:0.1-1:3.

[0026] Furthermore, the mass ratio of the delivery agent to the bismuth agent is 1:0.3-1:2.

[0027] Furthermore, the pharmaceutical composition also includes pharmaceutically acceptable excipients.

[0028] Furthermore, the pharmaceutically acceptable excipients include binders, fillers, lubricants, and / or disintegrants.

[0029] Furthermore, the lubricant includes magnesium stearate, stearic acid, sodium oleate, silica and / or talc.

[0030] Furthermore, the lubricant is selected from magnesium stearate.

[0031] A second aspect of the invention provides a method for improving the oral bioavailability of protein and peptide drugs, the method comprising co-administering a bismuth agent with the protein and peptide drug.

[0032] Furthermore, the bismuth agent includes bismuth aluminate, potassium bismuth citrate, colloidal pectin bismuth, basic bismuth carbonate, and / or bismuth subsalicylate.

[0033] Furthermore, the bismuth agent includes bismuth aluminate, potassium bismuth citrate, colloidal pectin bismuth, and / or basic bismuth carbonate.

[0034] Furthermore, the protein and polypeptide drugs include hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters, and / or antibodies.

[0035] Furthermore, the protein and peptide drugs include receptor agonists or antagonists.

[0036] Furthermore, the receptor agonist or antagonist includes GLP-1 receptor agonists, GLP-1 receptor antagonists, GIP receptor agonists, GIP receptor antagonists, and insulin receptor agonists.

[0037] Furthermore, the receptor agonist or antagonist includes a GLP-1 receptor agonist.

[0038] Furthermore, the method also includes use in conjunction with a delivery agent.

[0039] Furthermore, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

[0040] Furthermore, the combined use of bismuth preparations with protein and peptide drugs includes simultaneous administration of bismuth preparations and protein and peptide drugs, or administration of bismuth preparations followed by administration of protein and peptide drugs.

[0041] Furthermore, bismuth preparations are administered concurrently with protein and peptide drugs.

[0042] Furthermore, bismuth preparations are administered simultaneously with protein and peptide drugs in the form of a pharmaceutical composition.

[0043] A third aspect of the present invention provides a highly bioavailable pharmaceutical composition comprising a protein and a polypeptide drug as active ingredients, the pharmaceutical composition including a bismuth agent.

[0044] Furthermore, the bismuth agent includes bismuth aluminate, potassium bismuth citrate, colloidal pectin bismuth, basic bismuth carbonate, and / or bismuth subsalicylate.

[0045] Furthermore, the bismuth agent includes bismuth aluminate, potassium bismuth citrate, colloidal pectin bismuth, and / or basic bismuth carbonate.

[0046] Furthermore, the bismuth content in the pharmaceutical composition is 2%-50%.

[0047] Furthermore, the bismuth content in the pharmaceutical composition is 3%-40%.

[0048] Furthermore, the bismuth content in the pharmaceutical composition is 3.7%-38.6%.

[0049] Furthermore, the protein and polypeptide drugs include hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters, and / or antibodies.

[0050] Furthermore, the protein and peptide drugs include receptor agonists or antagonists.

[0051] Furthermore, the receptor agonist or antagonist includes GLP-1 receptor agonists, GLP-1 receptor antagonists, GIP receptor agonists, GIP receptor antagonists, and insulin receptor agonists.

[0052] Furthermore, the receptor agonist or antagonist includes a GLP-1 receptor agonist.

[0053] Furthermore, the pharmaceutical composition also includes a delivery agent.

[0054] Furthermore, the delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

[0055] Furthermore, the pharmaceutical composition also includes pharmaceutically acceptable excipients.

[0056] Furthermore, the pharmaceutically acceptable excipients include binders, fillers, lubricants, and / or disintegrants.

[0057] Furthermore, the lubricant includes magnesium stearate, stearic acid, sodium oleate, silica and / or talc.

[0058] Furthermore, the lubricant is selected from magnesium stearate.

[0059] Advantages and beneficial effects of the present invention:

[0060] The addition of bismuth to this invention effectively increases the oral bioavailability of GLP-1 receptor agonists and can also reduce the dosage of the delivery agent to some extent. The resulting composition exhibits excellent oral absorption and effectively promotes the uptake of the peptide-active drug by the body. Attached Figure Description

[0061] Figure 1 This is an oral absorption curve of the GLP-1 receptor agonist after colloidal bismuth pectin is added to the composition. Detailed Implementation

[0062] The following provides definitions for some of the terms used in this specification. Unless otherwise stated, 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 invention pertains.

[0063] This invention provides the application of bismuth agents in improving the bioavailability of protein and peptide drugs.

[0064] In this invention, bioavailability, or oral bioavailability, refers to the fraction of the administered dose of a drug that reaches systemic circulation after oral administration. By definition, when a drug is administered intravenously, its bioavailability is 100%, while when a drug is administered orally, its bioavailability generally decreases.

[0065] Standard tests for determining drug bioavailability are known to those skilled in the art, and in particular include measuring the relative area under the curve (AUC) of the concentrations of the drug administered orally and intravenously (iv) in the same species.

[0066] In this invention, protein and polypeptide drugs refer to protein or polypeptide compounds contained in oral medications that function directly as active pharmaceutical ingredients or indirectly assist active pharmaceutical ingredients in preventing or / and treating diseases in vivo.

[0067] In some embodiments of the present invention, the protein and polypeptide drugs may be natural proteins or polypeptide compounds (e.g., hormones, growth factors, cytokines, analgesic peptides, enzymes, coagulation factors, peptide neurotransmitters, and antibodies) or artificially synthesized polypeptides or proteins, as well as analogs, derivatives, conjugates, or fusion proteins of the above polypeptides or proteins, or pharmaceutically acceptable salts thereof.

[0068] In some embodiments of the present invention, the protein and polypeptide drugs may be compounds having receptor agonist or antagonist activity. The receptor agonists or antagonists mentioned 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 (tyrosine peptide) receptor agonists, oxygen-regulating hormone 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.

[0069] In some embodiments of the present invention, the protein or polypeptide drug simultaneously includes the active functions of one or more receptor agonists or antagonists.

[0070] In this invention, an agonist refers to a compound, molecule, or reagent that can stimulate biological activity.

[0071] In this invention, an analogue refers to a substance that has a similar structure and / or function to the protein or polypeptide of this invention.

[0072] In some embodiments of the present invention, the protein and peptide drugs include GLP-1 receptor agonists.

[0073] In this invention, GLP-1 receptor agonist or GLP-1 agonist refers to a substance (ligand) that activates a GLP-1 receptor (e.g., human GLP-1 receptor), including but not limited to exendin, GLP-1(7-36) amide, acid secretion regulating peptide, glucagon, gastric inhibitory polypeptide (GIP), GLP-1(7-37) or its analogues, fragments, derivatives, fusion proteins, conjugates or pharmaceutically acceptable salts thereof.

[0074] Among them, exendin includes naturally occurring exendin or synthetic forms of naturally occurring exendin, which can be found in the salivary secretions of venomous lizards. Exendin includes exendin-3 and exendin-4.

[0075] The bismuth preparation can be administered before oral protein and peptide drugs, or in the form of a pharmaceutical composition for substantially simultaneous administration.

[0076] In this invention, bismuth preparations can be administered before oral administration of protein and peptide drugs. Bismuth preparations can be administered via intravenous injection or orally.

[0077] In embodiments of the present invention, bismuth preparations are administered substantially simultaneously with protein and polypeptide drugs in the form of a pharmaceutical composition.

[0078] The pharmaceutical composition also includes a delivery agent.

[0079] In this invention, the delivery agent or absorption enhancer is an excipient capable of increasing oral exposure to a therapeutically active ingredient such as a GLP-1 receptor agonist.

[0080] The delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

[0081] In some embodiments of the present invention, the salts of the N-(8-(2-hydroxybenzoyl)amino)octanoic acid include, but are not limited to, sodium salts, potassium salts and / or ammonium salts.

[0082] In a specific embodiment of the present invention, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salts, that is, the delivery agent is potassium N-(8-(2-hydroxybenzoyl)amino)octanoate.

[0083] The mass ratio of the delivery agent to the bismuth agent can be any value between 1:0.1 and 1:3, preferably any value between 1:0.3 and 1:2.

[0084] In some embodiments of the present invention, the mass ratio of the delivery agent to bismuth aluminate, bismuth potassium citrate, and basic bismuth carbonate is 1:1, and the mass ratio of the delivery agent to colloidal bismuth pectin is 1:0.3-1:2. Preferably, the mass ratio of the delivery agent to colloidal bismuth pectin is 1:1, 1:2, 1:0.6, or 3:1.

[0085] The bismuth content in the pharmaceutical composition is 2%-50%.

[0086] In some embodiments of the present invention, the bismuth content in the pharmaceutical composition refers to the mass ratio of bismuth in the composition. A preferred content is any value between 3% and 40%, and a more preferred content is any value between 3.7% and 38.6%, for example, it can be 3.7%, 5.3%, 7.1%, 9.7%, 17.6%, 21.0%, or 38.6%.

[0087] The pharmaceutical composition also includes pharmaceutically acceptable excipients.

[0088] In this invention, pharmaceutically acceptable means an ingredient suitable for contact with human or other mammalian tissues within the bounds of reasonable medical judgment, which does not produce undue toxicity, irritation, allergic response, etc., and which has a commensurate and reasonable benefit / risk ratio. Excipients refer to any component other than an active therapeutic ingredient or active pharmaceutical ingredient. Excipients can be pharmaceutically inert substances, inactive substances, and / or therapeutically or medically inactive substances.

[0089] Pharmaceutically acceptable excipients can be used for a variety of purposes, such as as carriers, mediators, fillers, binders, lubricants, flow aids, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, antioxidants, emulsifiers, or combinations thereof, and / or to improve the administration and / or absorption of therapeutically active substances or active pharmaceutical ingredients. The amount of each excipient used can vary within the usual ranges in the art. Techniques and excipients that can be used to formulate oral dosage forms are described in the following literature: Handbook of Pharmaceutical Excipients, 8th Edition, edited by Sheskey et al., American Pharmaceuticals Association and the Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain Publishing House (2017); and Remington: the Science and Practice of Pharmacy, 22nd Edition, edited by Remington and Allen, Pharmaceutical Press (2013).

[0090] Pharmaceutical compositions may be provided in bulk or in dose units. For ease of administration and dosage uniformity, formulation in dose units is particularly advantageous. The dose unit form used in this invention refers to physically discrete units suitable as a total dose for a subject to be treated; each unit contains a predetermined amount of active compound calculated to bind with a desired drug carrier to produce the desired therapeutic effect. The specifications of the dose unit form of this invention are determined and directly depended upon by the unique characteristics of the active compound and the specific therapeutic effect to be achieved. The dose unit form may be an ampoule, vial, suppository, sugar-coated pill, tablet, capsule, IV bag, or a single pump on an aerosol inhaler.

[0091] In therapeutic applications, among other factors influencing the selected dosage, the dosage varies depending on the drug, the patient's age, weight, and clinical symptoms, as well as the experience and judgment of the clinician or practitioner administering the therapy. Generally, the dosage should be a therapeutically effective amount. The dosage can be provided in milligrams per kilogram per day (this dosage can be adjusted for the patient's weight (in kilograms), body surface area (in square meters), and age (in years). An effective amount of the pharmaceutical composition is the amount that provides an objectively identifiable improvement noticeable to a clinician or other qualified observer.

[0092] Effective dose, drug effective dose, and therapeutic effective dose refer to a non-toxic amount of reagent sufficient to provide the desired biological outcome. This outcome may be a reduction and / or alleviation of the signs, symptoms, or cause of disease, or any other desired alteration of a biological system. In any individual case, a person skilled in the art can determine the appropriate therapeutic dose using routine laboratory methods.

[0093] Subjects refer to any animal, including both human and non-human animals. Non-human animals include all vertebrates, such as mammals, including non-human primates (especially higher primates), sheep, dogs, rodents (such as mice or rats), guinea pigs, goats, pigs, cats, rabbits, cattle, and any livestock or pets; as well as non-mammals, such as chickens, amphibians, reptiles, etc.

[0094] In some embodiments of the invention, the pharmaceutical composition is administered in an orally acceptable dosage form, including but not limited to capsules, tablets, powders, sublingual forms, troche, lozenges, and oral liquids in the form of emulsions, suspensions, syrups, or solutions. Capsules may contain a mixture of the compounds of the invention with inert fillers and / or diluents such as pharmaceutically acceptable starches (e.g., corn, potato, or cassava starch), sugars, artificial sweeteners, powdered cellulose such as crystalline cellulose and microcrystalline cellulose, flour, gelatin, gums, etc. In the case of tablets for oral administration, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate may also be added. For oral administration in capsule form, usable diluents include lactose and dried corn starch. When administered orally as an aqueous suspension and / or emulsion, the pharmaceutical composition of the invention may be suspended or dissolved in an oil phase combined with an emulsifier and / or suspending agent. If desired, certain sweeteners and / or flavoring agents and / or coloring agents may be added.

[0095] In a specific embodiment of the present invention, the dosage form of the pharmaceutical composition is a tablet. The tablet composition may contain binders and granulators, disintegrants, lubricants, preservatives, antioxidants, and buffers.

[0096] The adhesives and granulators include, but are not limited to, polyvinylpyrrolidone.

[0097] Disintegrants include, but are not limited to, sodium starch glycolate, potassium polacolin, crospovidone, croscarmellose, sodium carboxymethyl cellulose, or dried corn starch, or water-soluble growth promoters such as nicotinamide or resorcinol.

[0098] Lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, zinc stearate, glyceryl betaine, glyceryl di-betaine, betaine yl polyoxyethylene-8 glyceryl ester, polyethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearoyl fumarate, stearic acid, and hydrogenated vegetable oil.

[0099] Preservatives include, but are not limited to, parabens.

[0100] Antioxidants include, but are not limited to, BHT, lecithin, propyl gallate, citric acid, EDTA, sorbitol, tartaric acid, and phosphoric acid.

[0101] Buffers include, but are not limited to, phosphate or citrate buffers.

[0102] The tablet composition may also contain one or more elastomeric solvents such as rosin and resins. Non-limiting examples of these solvents may be used alone or in combination with the tablet composition of the present invention. Furthermore, the tablet composition may also contain waxes such as beeswax and microcrystalline wax, fats or oils such as soybean oil and cottonseed oil, and combinations thereof. Additionally, the tablet composition may further contain plasticizers such as softeners or emulsifiers. These plasticizers, for example, can help reduce the viscosity of the gastric juice dissolving the tablet to a desired consistency and improve its overall texture and mouthfeel, and help promote the release of the therapeutic agent. Non-limiting examples of these plasticizers may be used alone or in combination with the tablet composition of the present invention.

[0103] The tablet composition may further comprise one or more additives. These additives may comprise or consist of one or more surfactants. An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of surfactants is the hydrophilic-lipophilic balance (HLB value). Surfactants with lower HLB values ​​are more hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Therefore, hydrophilic surfactants are generally considered to be those compounds with HLB values ​​greater than about 10, and hydrophobic surfactants are generally those with HLB values ​​less than about 10. However, these HLB values ​​are merely guidelines, as for many surfactants, depending on the empirical method chosen to determine the HLB value, the value can vary by up to about 8 HLB units.

[0104] Surfactants used in the tablet compositions of the present invention include polyethylene glycol (PEG)-fatty acids and PEG-fatty acid monoesters and diesters, PEG glycerides, alcohol-oil transesterification products, polyglycerol fatty acids, propylene glycol fatty acid esters, sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugars and their derivatives, polyethylene glycol alkylphenols, polyoxyethylene-polyoxypropylene (POE-POP) block copolymers, ionic surfactants, fat-soluble vitamins and their salts, water-soluble vitamins and their amphiphilic derivatives, amino acids and their salts, and organic acids and their esters and anhydrides.

[0105] The tablet composition can be a coated tablet. The coating can be a protective film coating (e.g., wax or varnish) or a coating designed to control the release of the active agent, such as sustained release (releasing the active ingredient after a predetermined lag time following ingestion) or release at a specific location in the digestive tract. The latter can be achieved, for example, using an enteric coating.

[0106] Tablet compositions can be prepared by conventional compression, wet granulation, dry granulation, or direct mixing processes, and the components in the tablet composition are homogeneous or uniformly mixed throughout the solid dosage form. Regardless of whether the active agent is randomly or non-randomly distributed, the tablet may contain one or more types of active agents and / or one or more types of coating materials. The non-random distribution of the active agent can be quantitatively represented by different amounts in different layers or qualitatively represented by different forms of the active agent in different layers; for example, as the outer particles may contain more coating material than the inner layers of the tablet, or vice versa.

[0107] For example, the specific steps of the dry granulation process can be as follows: ① Material pretreatment: Protein and polypeptide drugs are sieved through a 100-mesh sieve; if necessary, they can be pulverized before sieving. The delivery agent is sieved through a 50-mesh sieve; any that does not pass through the sieve is ground and sieved again. Bismuth agents are treated the same as delivery agents. Lubricants are used directly. ② First mixing: A certain amount of protein and polypeptide drugs, delivery agents, bismuth agents, and lubricants are manually mixed evenly to obtain mixed powder I. ③ Dry granulation: The above mixed powder I is rolled into strips of suitable hardness, and then pulverized into particles of appropriate size. ④ Second mixing: The above particles are collected, and an appropriate amount of lubricant is added again, and the mixture is manually mixed evenly. ⑤ Tableting: Tableting is performed as required, with the tablet hardness controlled within the range of 30-90N.

[0108] The specific steps of the direct mixing process can be as follows: ① Material pretreatment: Protein and polypeptide drugs are passed through a 100-mesh sieve; if necessary, they can be pulverized before sieving. Delivery agents are passed through a 50-mesh sieve; those that do not pass through the sieve are ground and then sieved again. Bismuth agents are passed through a 20-mesh sieve. Lubricants are used directly. ② Mixing: A certain amount of protein and polypeptide drugs, delivery agents, bismuth agents, and lubricants are manually mixed evenly to obtain mixed powder I. ③ Tableting: Tablets are compressed as required, with tablet hardness controlled within the range of 30-90N.

[0109] In a specific embodiment of the present invention, the tablets are prepared using a direct mixing process.

[0110] The pharmaceutical compositions of the present invention can be packaged in any packaging that promotes the stability of the pharmaceutical formulation. For example, they can be packaged in sealed high-density polyethylene (HDPE) bottles containing silica gel desiccant or in aluminum blister packs or aluminum-aluminum blister packs lined with PVC (thermoformed PVC blister packs). The application of such packaging helps prevent unwanted oxidation of the product and the ingress of moisture.

[0111] The pharmaceutical compositions of the present invention can be used to prevent and / or treat diseases, preferably metabolic-related diseases or neurological / brain-related diseases, including but not limited to disorders of glucose metabolism and / or lipid metabolism and / or neurodegenerative diseases. Preferably, the glucose metabolism disorder is abnormal blood glucose, and the lipid metabolism disorder is abnormal weight. The abnormal blood glucose disease is selected from one or more of the following: diabetes mellitus, diabetic retinopathy, diabetic cardiomyopathy, diabetic nephropathy, 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, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes mellitus, MODY (adolescent onset diabetes), gestational diabetes, and / or for reducing HbA1C; delaying or preventing the progression of diabetes, such as the progression of type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to insulin-dependent type 2 diabetes, and / or delaying the progression of insulin-free type 2 diabetes to insulin-dependent type 2 diabetes; improving β-cell function, such as reducing β-cell apoptosis, improving β-cell function and / or β-cell quality, and / or restoring β-cell glucose sensitivity.

[0112] The abnormal weight condition is 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 deformities, pain, cancer, respiratory failure, kidney disease, hyperlipidemia, hypertension, arteriosclerosis, cirrhosis, angina pectoris, and myocardial infarction.

[0113] The neurodegenerative diseases mentioned therein are 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, Creutzfeldt-Jakob disease.

[0114] The invention is further illustrated below with reference to specific embodiments. It should be understood that the specific embodiments described herein are by way of example and are not intended to limit the invention. The main features of the invention can be used in various embodiments without departing from the scope of the invention.

[0115] Example

[0116] 1 Experimental Methods

[0117] 1.1 Detection of Bismuth (Bi) Content in Different Formulations

[0118] The method for detecting bismuth content is based on the 2020 edition of the Chinese Pharmacopoeia. The detection methods vary slightly for different bismuth-containing substances, as described below.

[0119] Bismuth aluminate: Accurately weigh approximately 0.2 g of this product and place it in a 500 ml Erlenmeyer flask. Add 15 ml of nitric acid solution (3→10). Place a small funnel at the mouth of the flask and heat gently until completely dissolved. Let cool. Add 200 ml of water and add ammonia solution to adjust the pH to approximately 1. Add 5 drops of xylenol orange indicator and titrate with 0.05 mol / L disodium ethylenediaminetetraacetate solution until a yellow solution is obtained. Each 1 ml of 0.05 mol / L disodium ethylenediaminetetraacetate solution is equivalent to 10.45 mg of Bi.

[0120] Bismuth potassium citrate: Accurately weigh approximately 0.5 g of this product, dissolve it in 50 ml of water, then add 3 ml of nitric acid solution (l→3) and 2 drops of xylenol orange indicator. Titrate with disodium ethylenediaminetetraacetate titrant (0.05 mol / L) until the solution turns yellow. Each 1 ml of disodium ethylenediaminetetraacetate titrant (0.05 mol / L) is equivalent to 10.45 mg of Bi.

[0121] Colloidal bismuth pectin: Accurately weigh 0.5g of this product, add 5ml of nitric acid solution (1→2), heat to dissolve, then add 150ml of water and 2 drops of xylenol orange indicator solution, and titrate with disodium ethylenediaminetetraacetate titrant (0.05mol / L) until the solution turns yellow. Each 1ml of disodium ethylenediaminetetraacetate titrant (0.05mol / L) is equivalent to 10.45mg of Bi.

[0122] Basic bismuth carbonate: Accurately weigh approximately 0.2 g of this product, dissolve it in 5 ml of nitric acid solution (3→10), then add 100 ml of water and 3 drops of xylenol orange indicator solution. Titrate with disodium ethylenediaminetetraacetate titrant (0.05 mol / L) until pale yellow. Each 1 ml of disodium ethylenediaminetetraacetate titrant (0.05 mol / L) is equivalent to 10.45 mg of Bi.

[0123] 1.2 Analysis of GLP-1 receptor agonist content

[0124] For the content analysis of the active substance GLP-1 receptor agonist, HPLC method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512) was used. The specific experimental procedure is as follows: Take 5 tablets of this product, weigh the total weight, grind and mix them finely. Weigh an appropriate amount and dissolve it in diluent (0.01% Tween 20 + 0.05M Na2HPO4). After complete dissolution, dilute to the appropriate volume, shake well, and let stand for 30 minutes for thorough extraction. After shaking well, centrifuge the sample (4℃).

[0125] Centrifuge at 12000 rpm for 10 min, transfer the supernatant to an appropriate volume of HPLC vial, and inject for analysis using a Waters HPLC system. The reversed-phase column is a YMC UltraHT Pro C18 column. Other equipment used includes an electronic balance (1 / 100,000), an ultrasonic instrument, volumetric flasks, reagent bottles, and sealing film. 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 at a ratio of 830:170:2 (v / v). Mobile phase B is acetonitrile:isopropanol:TFA at a ratio of 850:150:2 (v / v). Calculate the content of the GLP-1 receptor agonist in the tablet composition based on the peak area relative to the GLP-1 receptor agonist reference standard.

[0126] 1.3 Pharmacokinetic Study (PK) in Beagles

[0127] The beagle dogs used were male, approximately 0.5 to 6 years old, and weighed approximately 9-12 kg. Some of these beagle dogs will undergo repeated pharmacokinetic studies. After the previous round of administration, the beagle dogs will be given an appropriate washout period during which their condition will be assessed, such as their mental state, food intake / amount, and weight. Only those dogs that pass the assessment will be allowed to enter the next round of administration.

[0128] The administration requirements are as follows: fast overnight (but water is allowed) before each dose. Dissolve the tablet in 10 ml of water (a fixed amount) and swallow, ensuring the tablet remains intact and is not chewed. Resume eating 4 hours after administration. Collect blood samples before and after administration at predetermined time points, continuing until 24 hours after administration, to fully cover the complete plasma concentration-time absorbance profile of the GLP-1 receptor agonist.

[0129] Blood samples were collected at each blood collection time point. The preparation process was roughly as follows: approximately 1.5 mL of whole blood was anticoagulated and centrifuged at 5000 × g for 10 min at 4°C. The resulting plasma was extracted and collected in EDTA-anticoagulated EP tubes, at a rate of 600 μL or more per tube. The tubes were stored at -80°C until analysis.

[0130] The active ingredients in the blood samples were detected using liquid chromatography-mass spectrometry (LC-MS). The mass spectrometer was a Thermo QEXACTIVE model, and the high-performance liquid chromatograph was a Thermo Ultimate 3000 model.

[0131] Plasma concentrations of GLP-1 receptor agonist molecules were analyzed using LCMS to obtain plasma concentration-time curves, determining GLP-1 receptor agonist exposure over 0-3 hours, and obtaining AUC (0-3 hours) and C. max (Within 0-3 hours), and normalized by (dose / kg body weight)*100 to obtain dose-corrected exposure.

[0132] 1.4 Tablet Preparation Method

[0133] ① Material Pretreatment: Protein and peptide drugs are sieved through a 100-mesh sieve; if necessary, they can be pulverized before sieving. Delivery agents are sieved through a 50-mesh sieve; those that do not pass through the sieve are ground and sieved again. Bismuth agents are treated the same as delivery agents. Lubricants are used directly. ② First Mixing: A certain amount of protein and peptide drugs, delivery agents, bismuth agents, and lubricants are manually mixed evenly to obtain mixed powder I. ③ Dry Granulation: The above mixed powder I is rolled into strips of suitable hardness, and then pulverized into granules of appropriate particle size. ④ Second Mixing: The granules are collected, and an appropriate amount of lubricant is added again, and the mixture is manually mixed evenly. ⑤ Tableting: Tableting is performed as required, with the tablet hardness controlled within the range of 30-90N.

[0134] 2 Experimental Results

[0135] The structure of the GLP-1 receptor agonist is shown in formula (Ⅰ), named N-ε30-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutyrylamino]ethoxy)ethoxy]acetamido)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide is a glucagon-like peptide-1 receptor (GLP-1R) polypeptide agonist. PNAC is an amorphous sample of potassium N-(8-(2-hydroxybenzoyl)amino)octanoate, with the structure shown in formula (II).

[0136]

[0137] The bismuth content in different compositions is shown in Table 1, and the content of each composition in the different compositions prepared is shown in Table 2.

[0138] Table 1. Bismuth content in different compositions

[0139]

[0140] Table 2 shows the prepared solid compositions.

[0141]

[0142]

[0143] The compositions in Table 2, after the addition of bismuth, underwent pharmacokinetic studies evaluating GLP-1 receptor agonist exposure, demonstrating an increased dose-corrected exposure after oral administration of the bismuth-containing compositions. The results lead to the following conclusions:

[0144] Conclusion 1: At the same delivery agent (PNAC) dosage, bismuth-containing compositions resulted in increased peptide exposure in beagle dogs after oral administration. These results indicate that, with the same delivery agent, bismuth-containing compositions can effectively increase the oral bioavailability of peptides.

[0145] Conclusion 2: At different delivery agent (PNAC) dosages, without bismuth, post-oral exposure decreased significantly with decreasing delivery agent dosage; with bismuth, decreasing delivery agent dosage did not significantly reduce post-oral exposure. The results indicate that the addition of bismuth can effectively improve the oral bioavailability of the peptides in the composition (Table 3). Figure 1 ).

[0146] Table 3. Pharmacokinetic studies evaluating exposure to GLP-1 receptor agonists.

[0147]

[0148]

[0149] The above description of the embodiments is only for understanding the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications will also fall within the protection scope of the claims of the present invention.

Claims

1. The use of bismuth preparations in the preparation of pharmaceutical compositions for improving the oral bioavailability of protein and peptide drugs; said pharmaceutical composition for the treatment of type 2 diabetes or obesity; The bismuth agent is selected from colloidal pectin bismuth; The structures of the protein and polypeptide drugs are shown in Formula (I): 。 2. The application according to claim 1, characterized in that, Bismuth preparations are administered simultaneously with the protein and polypeptide drugs to form a pharmaceutical composition.

3. The application according to claim 1, characterized in that, The dosage forms of the pharmaceutical composition include tablets, capsules, powders, suspensions, solutions, emulsions, or syrups.

4. The application according to claim 3, characterized in that, The dosage form of the pharmaceutical composition is a tablet.

5. The application according to claim 4, characterized in that, The tablets are prepared by dry granulation and / or direct mixing processes.

6. The application according to claim 1, characterized in that, The pharmaceutical composition also includes a delivery agent.

7. The application according to claim 6, characterized in that, The delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

8. The application according to claim 7, characterized in that, The salts of N-(8-(2-hydroxybenzoyl)amino)octanoic acid include sodium, potassium and / or ammonium salts.

9. The application according to claim 8, characterized in that, The salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from potassium salts, and its structure is shown in formula (II): 。 10. The application according to claim 6, characterized in that, The mass ratio of the delivery agent to the bismuth agent is 1:0.1-1:

3.

11. The application according to claim 10, characterized in that, The mass ratio of the delivery agent to the bismuth agent is 1:0.3-1:

2.

12. The application according to claim 1, characterized in that, The pharmaceutical composition also includes pharmaceutically acceptable excipients.

13. The application according to claim 12, characterized in that, Pharmaceutically acceptable excipients include binders, fillers, lubricants, and / or disintegrants.

14. The application according to claim 13, characterized in that, The lubricant includes magnesium stearate, stearic acid, sodium oleate, silica and / or talc.

15. The application according to claim 14, characterized in that, The lubricant is selected from magnesium stearate.

16. A highly bioavailable pharmaceutical composition comprising protein and polypeptide drugs as active ingredients, characterized in that, The pharmaceutical composition includes a bismuth preparation; The bismuth agent is selected from colloidal pectin bismuth; The structures of the protein and polypeptide drugs are shown in Formula (I): 。 17. The pharmaceutical composition according to claim 16, characterized in that, The bismuth content in the pharmaceutical composition is 2%-50%.

18. The pharmaceutical composition according to claim 17, characterized in that, The bismuth content in the pharmaceutical composition is 3%-40%.

19. The pharmaceutical composition according to claim 18, characterized in that, The bismuth content in the pharmaceutical composition is 3.7%-38.6%.

20. The pharmaceutical composition according to claim 16, characterized in that, The pharmaceutical composition also includes a delivery agent.

21. The pharmaceutical composition according to claim 20, characterized in that, The delivery agent comprises a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

22. The pharmaceutical composition according to claim 16, characterized in that, The pharmaceutical composition also includes pharmaceutically acceptable excipients.

23. The pharmaceutical composition according to claim 22, characterized in that, Pharmaceutically acceptable excipients include binders, fillers, lubricants, and / or disintegrants.

24. The pharmaceutical composition according to claim 23, characterized in that, The lubricant includes magnesium stearate, stearic acid, sodium oleate, silica and / or talc.

25. The pharmaceutical composition according to claim 24, characterized in that, The lubricant is selected from magnesium stearate.

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