An oral polypeptide formulation and a method of preparing the same

Abstract

The present application relates to a kind of oral polypeptide preparation and its preparation method, specifically including oral polypeptide preparation and oral polypeptide enteric capsule and its preparation method, wherein, oral polypeptide preparation includes polypeptide drug, ionic liquid or eutectic solvent, silicon dioxide and enteric material, oral polypeptide enteric capsule includes polypeptide drug, ionic liquid or eutectic solvent, adsorption material and hollow enteric capsule, polypeptide drug, ionic liquid or eutectic solvent and adsorption material form the drug-loaded particle surface without coating layer and directly into hollow enteric capsule.The preparation of the present application can realize polypeptide drug stable, promote polypeptide drug absorption, polypeptide drug is hardly released in stomach, release faster in intestinal tract.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to an oral polypeptide preparation and its preparation method. Background Technology

[0002] In recent years, with the rapid development of biomedical technology, peptide drugs have shown broad prospects in the treatment of diabetes, tumors, and immune diseases due to their advantages such as high efficiency, high specificity, and low toxicity. However, peptide drugs generally suffer from bottlenecks such as large molecular weight, high sensitivity to intestinal enzymatic hydrolysis, and low transmembrane permeation efficiency, resulting in oral bioavailability generally below 1%. For example, even with the extensive use of sodium 8-(2-hydroxybenzamido)octanoate (SNAC) as a potent absorption enhancer, the bioavailability of semaglutide tablets is still only 0.4%-1%. Currently, clinical administration is still mainly by injection, which seriously affects patients' long-term medication adherence and may cause adverse events such as injection site reactions.

[0003] To improve the efficiency of oral delivery of peptides, researchers have explored various strategies, including nanocarriers, enzyme inhibitors, and permeation enhancers. However, these technologies still face challenges such as low drug loading, insufficient membrane permeability, and intestinal irritation. In recent years, ionic liquids (ILs) and eutectic solvents (DES) have attracted widespread attention due to their unique physicochemical properties: they possess near-zero volatility, high thermal stability, and strong designability, significantly improving drug solubility. Simultaneously, their ionization properties can disrupt the mucus layer structure and temporarily open tight junctions in epithelial cells, synergistically enhancing transmembrane drug transport. However, free ionic liquid formulations generally suffer from insufficient physical stability and rapid dissociation in gastric juice, necessitating the development of efficient solidification strategies to meet the demands of industrial production.

[0004] In the field of solidification of pharmaceutical preparations, adsorption methods have become an ideal choice due to their mild process and simple operation. Mesoporous silica, as a novel porous carrier material, possesses adjustable pore size distribution and a large specific surface area (>1000 m²). 2 With properties such as high per-g and flexible surface functionalization, its drug loading capacity can reach over 50% (w / w), far exceeding traditional carriers (such as microcrystalline cellulose and starch). By immobilizing drug-loaded ionic liquids in a mesoporous silica framework through adsorption technology, the inherent permeation-enhancing advantages of ionic liquids can be retained while avoiding their storage stability defects. At the same time, combined with enteric coating technology, precise delivery can be achieved, providing a new technological paradigm for constructing high-performance oral peptide delivery systems.

[0005] Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, exhibits significant long-acting hypoglycemic and weight-loss effects in the treatment of type 2 diabetes and obesity. However, its polypeptide structure (molecular weight ≈ 4113 Da) presents several challenges for oral administration. Digestive enzymes such as pepsin, trypsin, and chymotrypsin in the gastrointestinal tract readily hydrolyze it, causing inactivation before it enters the circulatory system. Therefore, coating is necessary to protect semaglutide from rapid exposure to the enzymatic environment of gastrointestinal fluids. However, traditional particle coating processes (such as...) The process of pre-drying (using a series of methods) at high temperatures to remove solvents exacerbates the molecular denaturation or aggregation of semaglutide due to its sensitivity to moisture and heat, leading to a loss of biological activity. Furthermore, the release rate of coated particles in the small intestine is limited by the polymer dissolution rate, preventing efficient drug contact with absorption sites, and the uniformity of the particle coating is difficult to control, resulting in uneven drug release rates. Therefore, there is an urgent need to design a delivery system that avoids enzymatic hydrolysis and high-temperature processing to improve the efficiency and stability of oral administration of semaglutide. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides an oral polypeptide preparation and its preparation method.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] In a first aspect, an oral enteric-coated polypeptide capsule comprises a polypeptide drug, an ionic liquid or a eutectic solvent, an adsorbent material, and a hollow enteric-coated capsule, wherein the drug-loaded particles formed by the polypeptide drug, the ionic liquid or the eutectic solvent, and the adsorbent material are directly loaded into the hollow enteric-coated capsule without a coating layer on their surface.

[0009] In some embodiments, the polypeptide drug includes one or more of smegglutide, liraglutide, telposide, exenatide, canagliflozin, insulin, eptifibatide, octreotide acetate, calcitonin, leuprorelin, busereline, and glucagon.

[0010] In some embodiments, the ionic liquid includes: (a) a hydrogen bond acceptor; and (b) a hydrogen bond donor, wherein the hydrogen bond acceptor is selected from at least one of choline chloride, choline bicarbonate, choline hydroxide, acetylcholine chloride, phosphocholine, and tartrate choline, and the hydrogen bond donor is selected from an acid.

[0011] In some embodiments, the hydrogen bond acceptor in the ionic liquid is selected from choline bicarbonate, and the hydrogen bond donor is selected from at least one of citric acid, geranilic acid, malic acid, sorbic acid, caprylic acid, hexanoic acid, decanoic acid, oleic acid, and linoleic acid.

[0012] In some embodiments, the ionic liquid is selected from choline-based ionic liquids, including but not limited to geraniol-choline ionic liquid, malate-choline ionic liquid, citrate-choline ionic liquid, sorbate-choline ionic liquid, caprylic acid-choline ionic liquid, and hexanoic acid-choline ionic liquid.

[0013] In some embodiments, the ionic liquid is prepared by reacting a hydrogen bond acceptor and a hydrogen bond donor using a solvent method or a melt method to obtain the ionic liquid.

[0014] In some embodiments, the solvent method is specifically operated as follows: the hydrogen bond acceptor and the hydrogen bond donor are dissolved in a solvent, the reaction is completed, and then rotary evaporated and dried under vacuum to obtain the ionic liquid.

[0015] In some embodiments, the melting method specifically involves uniformly mixing hydrogen bond acceptors and hydrogen bond donors in solid form, then heating and melting them to obtain the ionic liquid.

[0016] In some embodiments, the melting temperature of the melting method is 50-80°C.

[0017] In some embodiments, in the solvent method or melt method, the molar fraction of hydrogen bond acceptor is 50-75%, and the molar fraction of hydrogen bond donor is 25-50%.

[0018] In some embodiments, the eutectic solvent comprises: (a) a hydrogen bond acceptor; and (b) a hydrogen bond donor, wherein the hydrogen bond acceptor is selected from sugars and the hydrogen bond donor is selected from acids.

[0019] In some embodiments, the sugar is selected from at least one of sucrose, glucose, fructose, maltose, sorbitol, mannose, rhamnose, trehalose, and lactose, and the acid is selected from at least one of citric acid, geranilic acid, malic acid, sorbic acid, caprylic acid, hexanoic acid, decanoic acid, oleic acid, and linoleic acid.

[0020] In some embodiments, the eutectic solvent includes, but is not limited to, eutectic solvents formed by fructose with octanoic acid, citric acid, and malic acid, respectively.

[0021] In some embodiments, the eutectic solvent is prepared by mixing a hydrogen bond acceptor and a hydrogen bond donor to form a transparent homogeneous solution.

[0022] In some embodiments, the eutectic solvent preparation method involves forming a transparent homogeneous solution at 25-40°C, with a eutectic melting point of 14.2-50°C.

[0023] In some embodiments, the molar ratio of hydrogen bond donor to hydrogen bond acceptor in the ionic liquid or eutectic solvent is (0.25-5):1; preferably, the molar ratio is (1-4):1, for example 1:1, 1.5:1, 2:1, 3:1, 4:1.

[0024] In some embodiments, the adsorbent material includes at least one or more combinations of silica, carbon, chitosan, polylactic acid-glycolic acid copolymer, polylactic acid, polycaprolactone, gelatin, sodium alginate, β-cyclodextrin, hydroxyapatite, zeolite, activated carbon, polyacrylic acid, polystyrene microspheres, calcium phosphate, dicalcium phosphate, titanium dioxide, diatomaceous earth, alumina, metal-organic framework materials, zirconium oxide, polyglycolic acid, polyhydroxyalkanoates, cellulose microspheres, zinc oxide, iron oxide, nanoclay, magnesium oxide, cerium oxide, tin oxide, hafnium oxide, polyurethane, and polyethylene glycol.

[0025] In some embodiments, the adsorbent material is an adsorbent material with a particle size in the micrometer range, for example, with a particle size of 1-50 μm, such as 1 μm, 2 μm, 5 μm, 7 μm, 10 μm, 12 μm, 15 μm, 17 μm, 20 μm, 22 μm, 25 μm, 27 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm;

[0026] In some embodiments, the adsorbent material is micron-sized silica, such as silica with a particle size of 5-25 μm;

[0027] In some embodiments, the adsorbent material is a mesoporous adsorbent material, including mesoporous silica, such as micron-sized mesoporous silica.

[0028] In some embodiments, the mass ratio of the ionic liquid or eutectic solvent to the polypeptide drug is (0.1-100):1; preferably, the mass ratio is (1-20):1, for example 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1.

[0029] In some embodiments, the mass ratio of the adsorbent material to the ionic liquid or eutectic solvent is (0.1-100):1; preferably, the mass ratio is (0.5-10):1, for example 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1.

[0030] In some implementations, the empty enteric-coated capsule is made of gelatin as the main material, and the capsule surface is coated with an enteric coating material.

[0031] In some embodiments, the empty enteric-coated capsule is made of gelatin as the main material, and the capsule surface is coated with hydroxypropyl methylcellulose phthalate.

[0032] In some embodiments, the oral enteric-coated polypeptide capsules further include an enzyme inhibitor loaded in an adsorbent material.

[0033] In some embodiments, the enzyme inhibitor is selected from protease inhibitors.

[0034] In some embodiments, the protease inhibitor is selected from leucopeptidase, pepsin inhibitor, serine protease inhibitor, trypsin inhibitor, and chymotrypsin inhibitor.

[0035] In some embodiments, the oral enteric-coated polypeptide capsules completely disintegrate within 30 minutes in an environment with pH ≥ 5.5.

[0036] Secondly, a method for preparing the above-mentioned oral enteric-coated polypeptide capsule includes the steps of: mixing an adsorbent material, an ionic liquid, and a polypeptide drug, or mixing an adsorbent material, a eutectic solvent, and a polypeptide drug; adsorbing the ionic liquid or eutectic solvent and the polypeptide drug into the adsorbent material by impregnation to obtain drug-loaded particles formed by the polypeptide drug, the ionic liquid or eutectic solvent, and the adsorbent material; and loading the drug-loaded particles into an enteric-coated capsule.

[0037] In some embodiments, the method for preparing the oral enteric-coated polypeptide capsules further includes adsorbing an enzyme inhibitor into an adsorbent material.

[0038] Thirdly, an oral polypeptide formulation includes a polypeptide drug, an ionic liquid or a eutectic solvent, silica, and an enteric coating material, wherein the polypeptide drug and the eutectic solvent have the same meaning as the components described in the aforementioned oral enteric polypeptide capsules, and the ionic liquid includes: (a) a hydrogen bond acceptor; (b) a hydrogen bond donor, wherein the hydrogen bond acceptor is selected from choline bicarbonate, and the hydrogen bond donor is selected from at least one of citric acid, malic acid, caprylic acid, and hexanoic acid, and the silica has a particle size in the micrometer range, preferably 5-25 μm.

[0039] In some embodiments, the mass ratio of the ionic liquid or eutectic solvent to the polypeptide drug is (0.1-100):1; preferably, the mass ratio is (1-20):1, for example 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1.

[0040] In some embodiments, the mass ratio of the silica to the ionic liquid or eutectic solvent is (0.1-100):1; preferably, the mass ratio is (0.5-10):1, for example 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1.

[0041] In some embodiments, the enteric coating material is one or more of Eutectic L100-55, Eutectic L100, Eutectic S100, hydroxypropyl methylcellulose phthalate, and cellulose acetate phthalate.

[0042] In some embodiments, the oral peptide formulation further includes an enzyme inhibitor loaded in silica.

[0043] In some embodiments, the enzyme inhibitor is selected from protease inhibitors.

[0044] In some embodiments, the protease inhibitor is selected from leucopeptidase, pepsin inhibitor, serine protease inhibitor, trypsin inhibitor, and chymotrypsin inhibitor.

[0045] In some embodiments, the oral polypeptide formulation is a tablet, capsule, granule, or liquid formulation.

[0046] In some embodiments, the oral polypeptide formulation has a dissolution rate of <5% in the gastric fluid environment.

[0047] Fourthly, a method for preparing the above-mentioned oral polypeptide formulation includes the steps of: mixing silica, an ionic liquid and a polypeptide drug, or mixing silica, a eutectic solvent and a polypeptide drug; adsorbing the ionic liquid or eutectic solvent and the polypeptide drug into silica by impregnation to obtain drug-loaded particles formed by the polypeptide drug, the ionic liquid or eutectic solvent and silica; and coating the drug-loaded particles with an enteric coating material.

[0048] In some embodiments, the coating step includes fluidized bed coating of peptide drugs, ionic liquids or eutectic solvents and silica-formed drug-loaded particles with an enteric coating material, resulting in a coating weight gain of 50-150% and a coating thickness of 50-100 μm.

[0049] Fifthly, the above-mentioned oral enteric-coated polypeptide capsules and oral polypeptide preparations are provided for the application of at least one of the following in the treatment of type II diabetes, obesity, cardiovascular disease, non-alcoholic steatohepatitis, polycystic ovary syndrome, Alzheimer's disease, chronic kidney disease, drug addiction, non-diabetic heart failure, non-diabetic obesity-related diseases, and inflammatory diseases.

[0050] In some implementations, the above-mentioned oral enteric-coated polypeptide capsules and oral polypeptide preparations are used in the preparation of medicaments for treating at least one of type II diabetes, obesity, cardiovascular disease, non-alcoholic steatohepatitis, polycystic ovary syndrome, Alzheimer's disease, chronic kidney disease, drug addiction, non-diabetic heart failure, non-diabetic obesity-related diseases, and inflammatory diseases.

[0051] Beneficial effects

[0052] In this invention, oral enteric-coated polypeptide capsules and oral polypeptide formulations are prepared by combining ionic liquids or eutectic solvents with adsorbent materials. Ionic liquids and eutectic solvents that achieve stability and promote absorption of polypeptide drugs are screened. Furthermore, the drug-loaded particles formed by the polypeptide drug, ionic liquid or eutectic solvent, and adsorbent material can be directly encapsulated in enteric-coated capsules, avoiding problems such as loss of bioactivity due to coating processes, inefficient drug contact with absorption sites, and uneven drug release rates caused by difficulty in controlling particle coating uniformity. Oral enteric-coated polypeptide capsules exhibit almost no release in the stomach but faster release in the intestines, resulting in better drug absorption. Attached Figure Description

[0053] Figure 1 Infrared spectra of the six ionic liquids prepared in this invention and their raw materials, six organic acids and bicarbonate choline.

[0054] Figure 2 Pharmacokinetic curves of smegglutide enteric-coated capsules in different ionic liquids.

[0055] Figure 3 Pharmacokinetic curves of enteric-coated capsules in Example 6 and enteric-coated microparticle capsules in Comparative Example 1.

[0056] Figure 4 Dissolution curves of the enteric-coated capsules in Example 6 and the enteric-coated microparticle capsules in Comparative Example 1 in pH 1.2 medium.

[0057] Figure 5 Dissolution curves of the enteric-coated capsules in Example 6 and the enteric-coated microparticle capsules in Comparative Example 1 in a medium of pH 6.8.

[0058] Figure 6 Pharmacodynamic curves of smegglutide-coated granules in different ionic liquids after oral administration.

[0059] Figure 7 Stability curves of different ionic liquids.

[0060] Figure 8 Pharmacokinetic profiles of smegglutide enteric-coated capsules in different eutectic solvents.

[0061] Figure 9Infrared spectra of the eutectic solvent and its raw materials prepared in this invention. Detailed Implementation

[0062] [Ionic liquids]

[0063] The ionic liquid (IL) described in this invention refers to a liquid composed entirely of ions, which includes at least the following components: (a) hydrogen bond acceptor; (b) hydrogen bond donor.

[0064] In some embodiments, the hydrogen bond acceptor is selected from at least one of quaternary ammonium salts, amines, acids (such as organic acids), alcohols, sugars, water, and urea; the hydrogen bond donor is selected from at least one of acids (such as organic acids), alcohols, sugars, amines, and water.

[0065] In some embodiments, the choline chloride, choline bicarbonate, choline hydroxide, phospholipids or glycerophosphate choline, acetylcholine chloride, phosphate choline, and tartrate choline are selected from at least one of betaine, ethanolamine, ethylene glycolamine, acetamide, methylamine, ethylamine, dimethylamine, trimethylamine, and aniline; the sugar is selected from at least one of sucrose, glucose, fructose, maltose, sorbitol, mannose, rhamnose, trehalose, lactose, glyceraldehyde, starch, cellulose, xylose, chitosan, fucose, lipopolysaccharide, dextran, and cyclodextrin.

[0066] In some embodiments, the alcohol is selected from at least one of sorbitol, xylitol, mannitol, lactitol, maltitol, erythritol, glucol, methanol, ethanol, propylene glycol, glycerol, ethylene glycol, butanol, pentanol, hexanol, arabinitol, tert-butanol, isopropanol, polyethylene glycol, benzyl alcohol, phenethyl alcohol, phenylpropanol, and menthol; the acid is selected from at least one of citral, benzenesulfonic acid, geranilic acid, sorbic acid, citric acid, malic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, ascorbic acid, benzoic acid, salicylic acid, oleic acid, palmitic acid, butyric acid, acetic acid, glycolic acid, malonic acid, caprylic acid (e.g., n-caprylic acid), hexanoic acid (e.g., n-hexanoic acid), decanoic acid (e.g., n-decanoic acid), linoleic acid, linolenic acid, stearic acid, adipic acid, lauric acid, myristic acid, amino acids, levulinic acid, gluconic acid, and pyruvic acid.

[0067] [Euclidean solvent]

[0068] The eutectic solvent (DES) described in this invention refers to a two- or three-component eutectic mixture composed of hydrogen bond acceptors and hydrogen bond donors in a certain stoichiometric ratio, whose freezing point is significantly lower than the melting point of each component pure substance. The eutectic solvent includes at least the following components: (a) hydrogen bond acceptors; (b) hydrogen bond donors.

[0069] In some embodiments, the hydrogen bond acceptor and hydrogen bond donor have the same definition as the components in the ionic liquid.

[0070] [Enteric Coating Material]

[0071] The enteric coating material described in this invention may be selected from at least one of the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyacrylic acid resin, shellac, cellulose acetate phthalate, methacrylic acid copolymer, polyvinyl alcohol phthalate, polyvinyl acetate phthalate, methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose, polyvinylpyrrolidone phthalate, hydroxypropyl methylcellulose acetate succinate, polyammonium methacrylate, hydroxypropyl cellulose phthalate, polyethylene glycol phthalate, cellulose acetate tribenzoate, polyethyl acrylate-methacrylic acid copolymer, polymethyl methacrylate-ethyl acrylate copolymer, and hydroxypropyl methylcellulose phthalate; preferably, polymethyl methacrylate.

[0072] [Enteric-coated empty capsules]

[0073] The empty enteric-coated capsules described in this invention are empty capsules made of capsule gelatin and enteric material.

[0074] In some embodiments, the empty enteric-coated capsule is made of gelatin and coated with hydroxypropyl methylcellulose phthalate.

[0075] [Drug-loaded particles and their preparation methods]

[0076] The drug-loaded particles described in this invention are obtained by mixing an adsorbent material, an ionic liquid, and a peptide drug, or by mixing an adsorbent material, a eutectic solvent, and a peptide drug, and then using an impregnation method to adsorb the ionic liquid or eutectic solvent and the peptide drug into the adsorbent material, thereby obtaining drug-loaded particles formed from peptide drug, ionic liquid or eutectic solvent, and adsorbent material.

[0077] The preparation method of the drug-loaded particles described in this invention is specifically a stirring method or a rotary evaporation method, wherein the stirring method includes the following steps:

[0078] S1: The peptide drug is added to an ionic liquid or eutectic solvent and dissolved by ultrasonication in a water bath; and optionally an enzyme inhibitor is added after dissolution and stirred until homogeneous.

[0079] S2: Add adsorbent material and stir to allow the ionic liquid or eutectic solvent containing the polypeptide drug to be adsorbed into the pores of the adsorbent material, thus obtaining drug-loaded particles;

[0080] S3: Freeze-dry the obtained drug-loaded particles to remove residual moisture;

[0081] The preparation steps of the rotary evaporation method include:

[0082] S1': Add the adsorbent material to water and use ultrasound to disperse it evenly;

[0083] S2': Add peptide drugs, ionic liquids, or eutectic solvents to water containing dispersed adsorbent materials, and then sonicate and stir in a water bath to allow the peptide drugs to enter the pores of the adsorbent materials; enzyme inhibitors may also be added to S2' for further sonication and stirring in a water bath.

[0084] S3': Rotary evaporation removes free water, and the resulting drug-loaded particles are freeze-dried to remove remaining moisture.

[0085] Silicon dioxide

[0086] The silica described in this invention has good adsorption properties and a porous structure, making it an excellent loading material with wide applications in various fields.

[0087] In some embodiments, the silica particles are in the micrometer range, preferably 2 to 50 μm.

[0088] In some embodiments, the silica has a large specific surface area, reaching 600-1000 m² / g, or even >1000 m² / g. 2 / g.

[0089] In some embodiments, the silica is mesoporous silica, whose pore structure can be controlled by changing the synthesis conditions, and the pore size is between 2-200 nm, for example, pore sizes of 2 nm, 4 nm, 6 nm, 8 nm, 10 nm, 15 nm, 20 nm, 25 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 120 nm, 140 nm, 160 nm, 180 nm, and 200 nm.

[0090] In some embodiments, the silica is mesoporous silica with a micron-sized particle size.

[0091] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0092] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0093] Laboratory animals:

[0094] Male SD rats, weighing 200-250g, were purchased from Slac Animal (Shanghai) Co., Ltd.

[0095] Type II diabetic C57 mice, weighing 20-30g, were purchased from Slac Animal (Shanghai) Co., Ltd.

[0096] All animals were housed in SPF-grade environments. Animal care and use were approved by the Laboratory Animal Center. All experimental procedures were conducted in accordance with the guidelines of the Laboratory Animal Welfare and Ethics Committee of the Institute of Animal Sciences.

[0097] Silica: Parteck SLC 500, a pharmaceutical excipient from Merck, with a particle size of 5-25 μm.

[0098] Enteric-coated capsules: The main material is gelatin, and the capsule surface is coated with hydroxypropyl methylcellulose phthalate.

[0099] The meanings of the abbreviations in this invention are as follows:

[0100]

[0101]

[0102] Example 1: Preparation of octanoic acid ionic liquid

[0103] 1. Prescription

[0104] Table 1 Composition and proportions of octanoic acid ionic liquid

[0105] Sour 144.21 50 41.1 Choline bicarbonate (80%) 165.19 50 58.9

[0106] 2. Preparation of ionic liquids

[0107] (1) Weigh out octanoic acid and bicarbonate choline according to the raw materials and raw material ratios in Table 1.

[0108] (2) Dissolve the weighed octanoic acid in an appropriate amount of ethanol by ultrasonication in a water bath.

[0109] (3) Place bicarbonate choline in a round-bottom flask, slowly add octanoic acid ethanol solution to the round-bottom flask, and stir magnetically at 40°C for 24 hours at 300 rpm until fully reacted.

[0110] (4) The liquid obtained in the previous step was rotary evaporated at 40°C for 4 hours, and then placed in a vacuum drying oven at room temperature for 12 hours to allow the ethanol to fully evaporate, thus obtaining octanoic acid choline ionic liquid ([Oc][Ch]).

[0111] Example 2: Preparation of citric acid ionic liquid

[0112] 1. Prescription

[0113] Table 2 Composition and proportions of citrate ionic liquids

[0114] Citric acid 192.12 25 23.7 Choline bicarbonate (80%) 165.19 75 76.3

[0115] 2. Preparation of ionic liquids

[0116] (1) Weigh out citric acid and bicarbonate choline according to the raw materials and raw material ratios in Table 2.

[0117] (2) Dissolve the weighed citric acid in an appropriate amount of ethanol by ultrasonic water bath.

[0118] (3) Place bicarbonate choline in a round-bottom flask, slowly add citric acid ethanol solution to the round-bottom flask, and stir magnetically at 40°C for 24 hours at 300 rpm until fully reacted.

[0119] (4) The liquid obtained in the previous step was rotary evaporated at 40°C for 4 hours, and then placed in a vacuum drying oven to dry at room temperature for 12 hours to allow the ethanol to fully evaporate, thus obtaining citrate choline ionic liquid ([Ci][Ch]).

[0120] Example 3: Preparation of malic acid ionic liquid

[0121] 1. Prescription

[0122] Table 3 Composition and proportions of malic acid ionic liquids

[0123] malic acid 134.09 33.3 24.5 Choline bicarbonate (80%) 165.19 66.7 75.5

[0124] 2. Preparation of ionic liquids

[0125] (1) Weigh malic acid and bicarbonate choline according to the raw materials and raw material ratios in Table 3.

[0126] (2) Dissolve the weighed malic acid in an appropriate amount of ethanol by ultrasonic water bath.

[0127] (3) Place bicarbonate choline in a round-bottom flask, slowly add the ethanol solution of malic acid to the round-bottom flask, and stir magnetically at 40°C for 24 hours at 300 rpm until the reaction is complete.

[0128] (4) The liquid obtained in the previous step was rotary evaporated at 40°C for 4 hours, and then placed in a vacuum drying oven at room temperature for 12 hours to allow the ethanol to fully evaporate, thus obtaining malic acid choline ionic liquid ([Ma][Ch]).

[0129] Example 4: Preparation of sorbic acid ionic liquid

[0130] 1. Prescription

[0131] Table 4 Composition and proportions of sorbic acid ionic liquids

[0132] Sorbic acid 112.13 50 35.2 Choline bicarbonate (80%) 165.19 50 64.8

[0133] 2. Preparation of ionic liquids

[0134] (1) Weigh out sorbic acid and bicarbonate choline according to the raw materials and raw material ratios in Table 4.

[0135] (2) Dissolve the weighed sorbic acid in an appropriate amount of ethanol by ultrasonic water bath.

[0136] (3) Place bicarbonate choline in a round-bottom flask, slowly add sorbic acid ethanol solution to the round-bottom flask, and stir magnetically at 40°C for 24 hours at 300 rpm until fully reacted.

[0137] (4) The liquid obtained in the previous step was rotary evaporated at 40°C for 4 hours, and then placed in a vacuum drying oven at room temperature for 12 hours to allow the ethanol to fully evaporate, thus obtaining sorbic choline ionic liquid ([So][Ch]).

[0138] Example 5: Preparation of Geranilic Acid Ionic Liquid

[0139] 1. Prescription

[0140] Table 5 Composition and proportions of geranium acid ionic liquid

[0141]

[0142]

[0143] 2. Preparation of ionic liquids

[0144] (1) Weigh geranic acid and choline bicarbonate according to the raw materials and raw material ratios in Table 5.

[0145] (2) Dissolve the weighed geranium acid in an appropriate amount of ethanol by ultrasonic water bath.

[0146] (3) Place bicarbonate choline in a round-bottom flask, slowly add geranium acid ethanol solution to the round-bottom flask, and stir magnetically at 40°C for 24 hours at 300 rpm until fully reacted.

[0147] (4) The liquid obtained in the previous step was rotary evaporated at 40°C for 4 hours, and then placed in a vacuum drying oven to dry at room temperature for 12 hours to allow the ethanol to fully evaporate, thus obtaining geraniol choline ionic liquid ([Ge][Ch]).

[0148] Example 5-1: Preparation of hexanoic acid ionic liquid

[0149] Referring to Example 1, hexanoic acid choline ionic liquid ([Hex][Ch]) was prepared using the same method as in Example 1, except that hexanoic acid and bicarbonate choline were weighed in a molar ratio of 1:1, and the weighed hexanoic acid was fully dissolved in an appropriate amount of ethanol by ultrasonication in a water bath.

[0150] Example 6: Preparation of enteric-coated capsules and coated granules based on octanoic acid ionic liquid from Example 1

[0151] 1. Prescription for drug-loaded particles in capsules

[0152] Table 6. Composition and ratio of drug-loaded particles based on octanoic acid ionic liquid.

[0153] [Oc][Ch](Example 1: Octanoic acid ionic liquid) 33 Smegglutide 6.7 Protease inhibitor (Beyotime) 0.3 Parteck SLC 500 60

[0154] 2. Preparation of drug-loaded particles within capsules

[0155] 2.1 Preparation by stirring method

[0156] (1) Add smegglutinin to the ionic liquid according to the proportion in Table 6, sonicate it in a water bath to dissolve it completely, and then add enzyme inhibitor according to the proportion in Table 6 and stir evenly.

[0157] (2) Add silica carrier powder in three batches according to the proportions in Table 6, with 20% added in each batch. Stir to allow the ionic liquid containing smegglutinin to be fully absorbed into the carrier pores to obtain drug-loaded particles.

[0158] (3) If significant heat is released during the preparation process, the container can be placed in an ice bath to cool it down in order to avoid drug degradation or dust explosion caused by excessive temperature.

[0159] (4) Freeze-dry the obtained drug-loaded particles for 4 hours to remove the remaining moisture.

[0160] 2.2 Preparation by rotary evaporation

[0161] (1) Add silica to water in advance and use a 100W probe to sonicate it for 10 minutes to disperse it completely.

[0162] (2) Add smegglutinin, enzyme inhibitor and [Oc][Ch] to water containing silica according to the proportions in Table 6. After sonicating in a water bath for 30 min, stir magnetically at room temperature for 12 h at 300 rpm to allow the drug to fully enter the silica pores.

[0163] (3) The main free water was removed by rotary evaporation at 40℃ for 6 hours, and the drug-loaded particles were freeze-dried for 4 hours to remove the remaining water.

[0164] 3. Capsule filling

[0165] Enteric-coated capsules are filled with drug-loaded particles according to the required specifications to form enteric-coated capsule formulations.

[0166] 4. Preparation of coated granules

[0167] Prepare a 10% (w / v) L100 methanol solution; use the 10% (w / v) L100 solution for enteric coating. Take a certain amount of the drug-loaded particles obtained in step 2 and add a 10% (w / v) L100 solution (i.e., the weight ratio of L100 solids in the coating solution to the weight of the drug-loaded particles) containing 100% enteric material relative to 100% of the weight of the drug-loaded particles for coating. After coating, dry under reduced pressure at room temperature to remove residual solvent. After drying, the finished product is appropriately ground and passed through an 80-mesh sieve to control the particle size, thus obtaining Sema enteric-coated particles.

[0168] Example 7: Preparation of enteric-coated capsules and coated granules based on citrate ionic liquid

[0169] The preparation method is the same as that in Example 6, except that the ionic liquid used is [Ci][Ch].

[0170] Example 8: Preparation of enteric-coated capsules and coated granules based on malic acid ionic liquid

[0171] The preparation method is the same as that in Example 6, except that the ionic liquid used is [Ma][Ch].

[0172] Example 9: Preparation of enteric-coated capsules and coated granules based on sorbic acid ionic liquid

[0173] The preparation method is the same as that in Example 6, except that the ionic liquid used is [So][Ch].

[0174] Example 10: Preparation of enteric-coated capsules and coated granules based on geranate ionic liquid

[0175] The preparation method is the same as that in Example 6, except that the ionic liquid used is [Ge][Ch].

[0176] Example 10-1: Preparation of enteric-coated capsules and coated granules based on hexanoic acid ionic liquid

[0177] The preparation method is the same as that in Example 6, except that the ionic liquid used is [Hex][Ch].

[0178] Example 11: Preparation of fructose-octanoic acid, fructose-citric acid, and fructose-malic acid eutectic solvents

[0179] Fructose, octanoic acid, citric acid, and malic acid were precisely weighed in a 1:1 molar ratio, with water added as a viscosity adjuster, and then the mixture was heated in a water bath to 50°C with stirring at 500 rpm for approximately 6 hours, until no solid particles remained and the product was clear, transparent, and had good flowability. After cooling to room temperature, and if the product showed no change in appearance within 48 hours, it was considered a eutectic solvent synthesized and stored at 4°C.

[0180] Example 12: Preparation of enteric-coated capsules and coated granules based on the fructose-octanoic acid eutectic solvent of Example 11

[0181] 1. Prescription for drug-loaded particles in capsules

[0182] Table 7 Composition ratio of drug-loaded particles based on fructose-octanoic acid eutectic solvent

[0183] Fructose-octanoic acid eutectic solvent 33 Smegglutide 6.7 Protease inhibitor (Beyotime) 0.3 Parteck SLC 500 60

[0184] 2. Preparation of drug-loaded particles within capsules

[0185] 2.1 Preparation by stirring method

[0186] (1) Add smegglutinin to the eutectic solvent according to the proportions in Table 7, and sonicate it in a water bath to dissolve it completely. Then add the enzyme inhibitor according to the proportions in Table 7 and stir evenly.

[0187] (2) Add silica carrier powder in three batches according to the proportions in Table 7, with 20% added in each batch. Stir to allow the eutectic solvent containing smegglutinin to be fully absorbed into the carrier pores to obtain drug-loaded particles.

[0188] (3) If significant heat is released during the preparation process, the container can be placed in an ice bath to cool it down in order to avoid drug degradation or dust explosion caused by excessive temperature.

[0189] (4) Freeze-dry the obtained drug-loaded particles for 4 hours to remove the remaining moisture.

[0190] 2.2 Preparation by rotary evaporation

[0191] (1) Add silica to water in advance and use a 100W probe to sonicate it for 10 minutes to disperse it completely.

[0192] (2) Add smegglutinin, enzyme inhibitor and eutectic solvent to water containing silica according to the proportions in Table 7. After sonicating in a water bath for 30 min, stir magnetically at room temperature for 12 h at 300 rpm to allow the drug to fully enter the silica pores.

[0193] (3) The main free water was removed by rotary evaporation at 40℃ for 6 hours, and the drug-loaded particles were freeze-dried for 4 hours to remove the remaining water.

[0194] 3. Capsule filling

[0195] Drug-loaded particles are filled into ordinary capsules or enteric-coated capsules according to the required specifications to form capsule formulations.

[0196] 4. Preparation of coated granules

[0197] Prepare a 10% (w / v) L100 methanol solution; use the 10% (w / v) L100 solution for enteric coating. Take a certain amount of the drug-loaded particles obtained in step 2 and add a 10% (w / v) L100 solution (i.e., the weight ratio of L100 solids in the coating solution to the weight of the drug-loaded particles) containing 100% enteric material relative to 100% of the weight of the drug-loaded particles for coating. After coating, dry under reduced pressure at room temperature to remove residual solvent. After drying, the finished product is appropriately ground and passed through an 80-mesh sieve to control the particle size, thus obtaining Sema enteric-coated particles.

[0198] Example 13: Preparation of enteric-coated capsules and coated granules based on fructose-citric acid eutectic solvent

[0199] The preparation method is the same as that in Example 12, except that the eutectic solvent used is a fructose-citric acid eutectic solvent.

[0200] Example 14: Preparation of enteric-coated capsules and coated granules based on fructose-malic acid eutectic solvent

[0201] The preparation method is the same as that in Example 12, except that the eutectic solvent used is a fructose-malic acid eutectic solvent.

[0202] Comparative Example 1: Preparation of Enteric-Coated Microcapsules Based on Sorbitol-Cholesterol Ionic Liquid

[0203] The sorbate-choline ionic liquid-based coated particles described in Example 9 are filled into ordinary capsules according to the required specifications to form a capsule formulation.

[0204] Example 1: Infrared Characterization of Ionic Liquids and Eutectic Solvents

[0205] Appropriate amounts of octanoic acid, citric acid, malic acid, sorbic acid, geranilic acid, hexanoic acid, bicarbonate choline, and the aforementioned prepared ILs ([Oc][Ch], [Ci][Ch], [Ma][Ch], [So][Ch], [Ge][Ch], and [Hex][Ch]) were taken respectively. The ATR accessory module was correctly placed into the detection optical path system of the Fourier Transform Infrared Spectrometer (FTIR), and an air background baseline scan was performed first. Subsequently, the sample to be tested was precisely attached to the optical contact interface of the ATR prism, and appropriate pressure was applied to ensure that the sample and the crystal surface formed effective optical contact. Finally, the characteristic infrared absorption spectrum data of the surface molecules of the sample were acquired. The infrared characterization results are shown in […]. Figure 1 .

[0206] contrast Figure 1 Infrared spectra of various organic acids and bicarbonate choline revealed that after the formation of ionic bonds, the characteristic peaks of each functional group on the choline fragment did not change significantly; however, the C=O stretching vibration signal of the carboxyl group in the acid underwent a red shift to varying degrees due to the formation of carboxylate ions, indicating that the ionic liquid was successfully synthesized.

[0207] The characteristic infrared absorption spectra of fructose, caprylic acid, citric acid, malic acid, and the fructose-caprylic acid eutectic solvent, fructose-citric acid eutectic solvent, and fructose-malic acid eutectic solvent prepared above were obtained using the same method described above. The results are shown in [Figure number missing]. Figure 9 Eutectic solvent at 3600-3650 cm⁻¹ -1 The -OH stretching vibration peak in the region shifted significantly to lower wavenumbers (redshift phenomenon), and the absorption peak broadened significantly and redshifted. The stretching vibration absorption peak of the carbonyl group (C=O) also redshifted, indicating that the eutectic solvent was successfully synthesized.

[0208] Example 2: Pharmacokinetic Study of Smegglutide Enteric-coated Capsules in Different Ionic Liquids

[0209] Type II diabetic C57 mice were randomly divided into four groups of seven mice each. Each group was administered the experimental formulation and a control formulation: Cap-OCP group (Enteric-coated capsules, Example 6), Cap-SCP group (Enteric-coated capsules, Example 9), Cap-GCP group (Enteric-coated capsules, Example 10), and the original drug tablet group (Rybelsus, original smegglutide tablets) for comparison. Both the experimental and control formulations were administered orally at a dose of 2 mg / kg. Mice were fasted for 12 hours before the experiment. Blood was collected from the tail tip of the mice after administration, and blood drug concentrations were detected by HPLC-MS / MS. The experimental results are as follows: Figure 2 As shown.

[0210] The results showed that various ionic liquids had a certain absorption-promoting effect on smegglutide. The Cap-OCP group and the Cap-SCP group could significantly promote the oral absorption of smegglutide, and the bioavailability of the Cap-OCP group was higher than that of the Cap-SCP group. The Cap-GCP group also showed an improvement compared with the original tablet group.

[0211] Example 3: Pharmacokinetic Comparison of Smegglutide Enteric-coated Capsules and Enteric-coated Capsules Based on Ionic Liquids

[0212] SD rats weighing approximately 250g were acclimatized for one week and then randomly divided into two groups of seven rats each. Each group was administered either an enteric-coated capsule formulation or an enteric-coated microparticle formulation: the enteric-coated capsule group (Cap-OCP group, Example 6, enteric-coated capsules) and the enteric-coated microparticle group (Comparative Example 1, enteric-coated microparticle capsules) for comparison. All cases were administered orally at a dose of 2 mg / kg using a rat capsule applicator. Rats were fasted for 12 hours before the experiment. Blood was collected from the tail tip of the rats after administration, and blood concentrations were detected by HPLC-MS / MS. The experimental results are as follows: Figure 3 As shown.

[0213] The results showed that the absorption of enteric-coated capsules was significantly higher than that of enteric-coated microparticle capsules.

[0214] Experimental Example 4: Comparison of in vitro dissolution of ionic liquid-based smegglutide enteric-coated capsules and enteric-coated microparticle capsules

[0215] 500 mL of dissolution medium was placed in each dissolution vessel, and the temperature was set to 37°C. After reaching the temperature, the enteric-coated capsules of Example 6 (Cap-OCP group) and the enteric-coated microparticle capsules of Comparative Example 1 (EC group) were placed into the dissolution apparatus containers to investigate the dissolution effect in hydrochloric acid (pH 1.2, containing 0.1% SDS) and phosphate buffer (pH 6.8, containing 0.1% SDS). The rotation speed was set to 75 rpm. Sampling points were set at 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, and 100 min, with a sampling volume of 1 mL. After sampling, the samples were filtered through a 0.22 μm membrane filter (PES) and directly injected. The concentration was determined by HPLC. Dissolution curves were plotted under different pH media.

[0216] like Figure 4 As shown, the enteric-coated capsules in Example 6 can protect the drug from almost any release in a medium environment of pH 1.2, providing better protection for semaglutide. In contrast, the enteric-coated microparticle capsules in Comparative Example 1 release the drug rapidly, with approximately 13% of the drug released into the medium within 10 minutes and more than 15% released within 100 minutes. Figure 5As shown, in an environment of pH 6.8, the enteric-coated capsules of Example 6 released more quickly in the intestines and the smegglutinin was better absorbed than the enteric-coated microparticle capsules of Comparative Example 1.

[0217] Experimental Example 5: Pharmacodynamic Results of Smegglutide-Coated Granules with Different Ionic Liquids After Oral Administration

[0218] Type II diabetic C57 mice were randomly divided into four groups of seven mice each, including oral formulations, blank carriers, and injectable formulations. The oral formulations were caprylic acid choline group (EOCP, coated granules from Example 7), sorbate choline group (ESCP, coated granules from Example 10), sorbate choline ionic liquid blank carrier group (Blank ESCP, oral), and subcutaneous injection group (semaglutide injection, sc). The dosage of the oral formulations was 2 mg / kg, and the dosage of the injectable groups was 0.2 mg / kg. Mice were fasted for 12 hours before the experiment. Blood was collected from the tail tip of mice before administration and at 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. The first drop was discarded, and the second drop was used to measure blood glucose levels using a glucometer. A curve was plotted with time on the x-axis and the ratio of real-time blood glucose to initial blood glucose on the y-axis.

[0219] according to Figure 6 The absorption-promoting effects of different solvents vary significantly, with EOCP showing a more pronounced effect than ESCP.

[0220] Experimental Example 6: Comparison of the stability of different ionic liquids

[0221] Smegglutide was dissolved in citrate choline ([Ci][Ch]), sorbate choline ([So][Ch]), malate choline ([Ma][Ch]), caprylate choline ([Oc][Ch]), and hexanoate choline ([Hex][Ch]), and its stability was determined at 4°C and room temperature. The mass ratio of citrate choline, sorbate choline, malate choline, caprylate choline, and hexanoate choline to smegglutide was 20:1. Furthermore, after dissolving smegglutide in the above ionic liquids, it was adsorbed onto silica (Parteck SLC 500) and left for 21 days (60% silica content). Its stability was then determined at 4°C and room temperature. The results are as follows. Figure 7 As shown in the figure. According to stability test results, smegglutinin is extremely unstable in sorbate choline, but very stable in caprylic acid and hexanoic acid choline, making it more suitable for use as a peptide absorption enhancer.

[0222] Example 7: Pharmacokinetic Study of Smegglutide Enteric-coated Capsules Based on Eutectic Solvent

[0223] SD rats weighing approximately 250g were acclimatized for one week and then randomly divided into two groups of seven rats each. The groups were administered the experimental formulation and the control formulation, respectively: the OCT-Fru group (enteric-coated capsules as described in Example 12) and the original drug tablet group (Rybelsus, original drug smegglutide tablets). Both formulations were administered orally at a dose of 2 mg / kg using a rat capsule applicator.

[0224] Mice were fasted for 12 hours before the experiment. Blood was collected from the tail tip of mice after drug administration, and the blood drug concentration was detected by HPLC-MS / MS. The experimental results are as follows: Figure 8 As shown.

[0225] Pharmacokinetic results show that eutectic solvents have excellent absorption-enhancing effects.

[0226] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. An oral enteric-coated polypeptide capsule, characterized in that, The formulation includes a polypeptide drug, an ionic liquid or a eutectic solvent, an adsorbent material, and an empty enteric-coated capsule. The drug-loaded particles formed by the polypeptide drug, the ionic liquid or eutectic solvent, and the adsorbent material are directly loaded into the empty enteric-coated capsule without a coating layer. The ionic liquid comprises: (a) a hydrogen bond acceptor; and (b) a hydrogen bond donor, wherein the hydrogen bond acceptor in the ionic liquid is choline bicarbonate, and the hydrogen bond donor is octanoic acid. The eutectic solvent comprises: (a) a hydrogen bond acceptor; and (b) a hydrogen bond donor, wherein the hydrogen bond acceptor in the eutectic solvent is fructose, and the hydrogen bond donor is octanoic acid. The molar ratio of the hydrogen bond donor to the hydrogen bond acceptor in the ionic liquid or eutectic solvent is 1:

1. The polypeptide drug is smegglutide. The adsorbent material is silica.

2. The oral enteric-coated polypeptide capsule according to claim 1, characterized in that, The adsorbent material is silicon dioxide with a particle size of micrometers.

3. The oral enteric-coated polypeptide capsule according to claim 2, characterized in that, The particle size of the adsorbent material is 1-50 μm.

4. The oral enteric-coated polypeptide capsule according to claim 3, characterized in that, The particle size of the adsorbent material is 5-25 μm.

5. The oral enteric-coated polypeptide capsule according to claim 2, characterized in that, The adsorbent material is a mesoporous adsorbent material.

6. The oral enteric-coated polypeptide capsule according to claim 1, characterized in that, The mass ratio of the ionic liquid or eutectic solvent to the polypeptide drug is (1-20):1, and the mass ratio of the adsorbent material to the ionic liquid or eutectic solvent is (0.5-10):

1.

7. The oral enteric-coated polypeptide capsule according to claim 1, characterized in that, The hollow enteric-coated capsule is made of gelatin as its main material, and the capsule surface is coated with an enteric coating material.

8. The oral enteric-coated polypeptide capsule according to claim 1, characterized in that, The main material of the hollow enteric-coated capsule is gelatin, and the capsule surface is coated with hydroxypropyl methylcellulose phthalate.

9. The oral enteric-coated polypeptide capsule according to claim 1, characterized in that, The oral enteric-coated polypeptide capsules also include a protease inhibitor, which is loaded in an adsorbent material.

10. The oral enteric-coated polypeptide capsule according to claim 9, characterized in that, The protease inhibitor is selected from leucopeptidase, pepsin inhibitor, serine protease inhibitor, trypsin inhibitor, and chymotrypsin inhibitor.

11. The oral enteric-coated polypeptide capsule according to claim 1, characterized in that, The ionic liquid is prepared by solvent extraction of hydrogen bond acceptor and hydrogen bond donor; the eutectic solvent is prepared by mixing hydrogen bond acceptor and hydrogen bond donor to form a transparent homogeneous solution.

12. The oral enteric-coated polypeptide capsule according to claim 11, characterized in that, The solvent method includes: dissolving the hydrogen bond acceptor and hydrogen bond donor in a solvent, rotating the solvent after the reaction is complete, and drying under vacuum to obtain the ionic liquid.

13. The method for preparing oral enteric-coated polypeptide capsules according to any one of claims 1-12, characterized in that, The preparation method includes: mixing an adsorbent material, an ionic liquid, and a polypeptide drug, or mixing an adsorbent material, a eutectic solvent, and a polypeptide drug; adsorbing the ionic liquid or eutectic solvent and the polypeptide drug into the adsorbent material by impregnation to obtain drug-loaded particles formed by the polypeptide drug, the ionic liquid or eutectic solvent, and the adsorbent material; and loading the drug-loaded particles into enteric-coated capsules.

14. An oral polypeptide formulation, characterized in that, The mixture includes a peptide drug, an ionic liquid or a eutectic solvent, silica, and an enteric coating material. The peptide drug is semaglutide. The eutectic solvent comprises: (a) a hydrogen bond acceptor; and (b) a hydrogen bond donor, wherein the hydrogen bond acceptor in the eutectic solvent is fructose and the hydrogen bond donor is octanoic acid. The ionic liquid comprises: (a) a hydrogen bond acceptor; and (b) a hydrogen bond donor, wherein the hydrogen bond acceptor in the ionic liquid is choline bicarbonate and the hydrogen bond donor is octanoic acid. The molar ratio of hydrogen bond donor to hydrogen bond acceptor in the ionic liquid or eutectic solvent is 1:

1. The silica has a particle size in the micrometer range. The enteric coating material is one or more of the following: Eutectic L100-55, Eutectic L100, Eutectic S100, hydroxypropyl methylcellulose phthalate, and cellulose acetate phthalate.

15. The oral polypeptide formulation according to claim 14, characterized in that, The silica particles have a diameter of 5-25 μm.

16. The oral polypeptide formulation according to claim 14, characterized in that, The mass ratio of the ionic liquid or eutectic solvent to the polypeptide drug is (1-20):

1.

17. The oral polypeptide formulation according to claim 14, characterized in that, The mass ratio of silicon dioxide to ionic liquid or eutectic solvent is (0.5-10):

1.

18. The oral polypeptide formulation according to claim 14, characterized in that, The oral polypeptide formulation also includes a protease inhibitor, which is loaded in silica.

19. The oral polypeptide formulation according to claim 18, characterized in that, The protease inhibitor is selected from leucopeptidase, pepsin inhibitor, serine protease inhibitor, trypsin inhibitor, and chymotrypsin inhibitor.

20. The oral polypeptide formulation according to claim 14, characterized in that, The oral polypeptide preparation is in the form of tablets, capsules, or granules.

21. A method for preparing an oral polypeptide formulation according to any one of claims 14-20, characterized in that, The process includes the following steps: mixing silica, ionic liquid and peptide drug, or mixing silica, eutectic solvent and peptide drug, and adsorbing the ionic liquid or eutectic solvent and peptide drug into silica by impregnation to obtain drug-loaded particles formed by peptide drug, ionic liquid or eutectic solvent and silica, and coating the drug-loaded particles with an enteric material.

22. The method for preparing the oral polypeptide formulation according to claim 21, characterized in that, The coating process includes fluidized bed coating of peptide drugs, ionic liquids or eutectic solvents and silica with enteric materials, resulting in a coating weight gain of 50-150% and a coating thickness of 50-100 μm.

23. The use of the oral enteric-coated polypeptide capsules according to any one of claims 1-12 and the oral polypeptide preparations according to any one of claims 14-20 in the preparation of medicaments for treating type II diabetes and obesity.

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