A polypeptide drug oral delivery composition

Abstract

The present invention relates to a pharmaceutical composition suitable for oral delivery of polypeptide drugs, comprising a first type of particles containing 280-300 mg of SNAC and 5-20% of a GLP-1 receptor agonist, and a second type of particles containing 5-20 mg of SNAC and 80-95% of a GLP-1 receptor agonist. The orally deliverable pharmaceutical composition of the present invention can more effectively deliver GLP-1 derivatives or GLP-1-related multi-target agonists, exhibits excellent oral bioavailability, and has broad application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of polypeptides and their oral delivery, and in particular to a polypeptide drug oral delivery composition, particularly a pharmaceutical composition suitable for oral delivery of GLP-1 receptor agonists and GLP-1 receptor-related multi-target co-agonists. Background Art

[0002] In modern society, diabetes and its complications have become a serious, chronic, non-communicable disease, following cardiovascular and cerebrovascular diseases and cancer. Diabetes is primarily categorized into type 1, type 2, and other specialized types. Type 2 diabetes, caused by the ineffective functioning of insulin secretion, accounts for the highest prevalence, exceeding 90%.

[0003] Currently, the main drugs used clinically to treat type 2 diabetes include biguanides, sulfonylureas, thiazolidinediones, DPP-4 receptor inhibitors, SGLT-2 receptor inhibitors, and long-acting glucagon-like peptide-1 derivatives (GLP-1 derivatives). Among them, GLP-1 derivatives are gradually becoming the main treatment for type 2 diabetes and a research hotspot because they have similar blood sugar-lowering effects to insulin, with almost no risk of hypoglycemia, and both weight loss and cardiovascular protection.

[0004] Semaglutide is a long-acting GLP-1 derivative developed by Novo Nordisk. This drug only requires a once-weekly subcutaneous injection and has been approved for marketing in multiple countries. Structurally, semaglutide is formed by attaching the 26th Lys residue on the GLP-1 (7-37) chain to the side chains of AEEA, glutamic acid, and octadecanoic acid. The 8th amino acid is replaced with the unnatural amino acid aminoisobutyric acid (Aib), while the 34th Lys residue is replaced with Arg. Compared to liraglutide, semaglutide has a longer fatty chain and increased hydrophobicity. However, the short-chain AEEA modification of semaglutide significantly enhances its hydrophilicity. The AEEA modification not only allows it to bind tightly to albumin, masking the DPP-4 enzymatic hydrolysis site, but also reduces renal excretion, prolonging its biological half-life and achieving a long-circulation effect. Multiple clinical trials have shown that semaglutide, when combined with different oral hypoglycemic drugs, can effectively control blood sugar, and enable patients to lose weight, reduce systolic blood pressure, and improve pancreatic beta cell function.

[0005] At present, there are two dosage forms of semaglutide, namely injection and oral preparation. The injection is injected subcutaneously once a week, which is a pain for diabetic patients who need long-term or even lifelong treatment. Not only is the compliance poor, but it is also easy to cause infection, which brings physical and psychological burdens to patients. Compared with injections, oral dosage forms have great advantages in efficacy, safety, applicable population, and drug interactions, which will greatly increase patient compliance. However, from a structural point of view, semaglutide is a GLP-1 (7-37) chain in which Ala at position 8 is replaced by Aib, Lys at position 34 is replaced by Arg, and Lys at position 26 is connected to an octadecanoic acid fatty chain. That is, there is a long fatty chain in the structure of semaglutide, which increases the hydrophobicity and makes it difficult to ensure the dissolution behavior of oral administration.

[0006] CN201611150925.X discloses an oral sustained-release formulation containing semaglutide and its preparation method. The active pharmaceutical ingredient is the GLP-1 analog semaglutide, and also includes a sulfonylurea, biguanide, or thiazolidinedione hypoglycemic drug that has a synergistic effect with semaglutide. This active pharmaceutical ingredient is encapsulated in a sustained-release carrier material to prepare sustained-release microspheres, which are then mixed with pharmaceutically acceptable excipients and pressed into tablets of a certain shape for oral use, thereby achieving a long-lasting sustained-release effect. Its disadvantage is that semaglutide is easily decomposed prematurely during subsequent administration, its stability is difficult to ensure, and it is very easy to cause waste of semaglutide.

[0007] Semaglutide has low oral bioavailability. After oral administration, only a very small amount or even no amount can be detected in the blood. Therefore, an optimized pharmaceutical composition for oral administration is needed to enable semaglutide to have better oral bioavailability. Summary of the Invention

[0008] In order to solve the above technical problems, the present invention provides a polypeptide drug oral delivery composition. The oral delivery composition provided by the present invention has excellent oral bioavailability and broad application prospects.

[0009] For purposes of the present invention, the term "GLP-1 receptor agonist" can be defined as a compound that binds to the receptor and elicits a response typical of the natural ligand. A full agonist can be defined as one that elicits a response of the same magnitude as the natural ligand (see, for example, "Principles of Biochemistry," AL Lehninger, DL Nelson, MM Cox, 2nd ed., Worth Publishers, 1993, p. 763). Thus, for example, a "GLP-1 receptor agonist" can be defined as a compound that binds to and activates the GLP-1 receptor.

[0010] In the present invention, the term SNAC refers to sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, which is a low-toxic oral permeation enhancer.

[0011] In the present invention, the term "semaglutide" refers to N-ε 26 -[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib 8 Arg 34 ]GLP-1(7-37).

[0012] In the present invention, the term "derivative" with respect to a peptide (e.g., GLP-1 or insulin) refers to a peptide or analog thereof that has been chemically modified (e.g., covalently modified). Typical modifications are amides, sugars, alkyl groups, acyl groups, esters, etc. An example of a GLP-1(7-37) derivative is N-ε 26 -((4S)-4-(Hexadecanoylamino)-carboxy-butyryl)[Arg 34 Lys 26 ]GLP-1-(7-37).

[0013] As used herein, the term "excipient" broadly refers to any component other than the active therapeutic ingredient (also referred to in the art as a drug substance or active pharmaceutical ingredient). An excipient can be an inert substance, in the sense that it does not substantially have any therapeutic and / or prophylactic effect on its own. An excipient can serve a variety of different purposes, for example, as an enhancer, absorption enhancer, vehicle, filler (also referred to as a diluent), binder, lubricant, glidant, disintegrant, crystallization retardant, acidifier, alkalizer, preservative, antioxidant, buffer, chelating agent, complexing agent, surfactant, emulsifier and / or solubilizer, sweetener, wetting agent, stabilizer, colorant, flavoring agent, and / or to improve the administration and / or absorption of the active substance.

[0014] In the present invention, the term "lubricant" refers to stearic acid, magnesium stearate, calcium stearate or other metal stearates, talc, wax, glyceride, light mineral oil, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycol, alkyl sulfate or sodium benzoate.

[0015] In the present invention, the term "filler" includes lactose (e.g., spray-dried lactose, α-lactose, β-lactose, various grades), microcrystalline cellulose (various grades), other cellulose derivatives, sucrose, sorbitol, mannitol, dextrin, dextran, maltodextrin, dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starch or modified starch (including potato starch, corn starch and rice starch), calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, hydrated dicalcium phosphate), calcium sulfate, calcium carbonate or sodium alginate.

[0016] In the present invention, the term "binder" includes lactose (e.g., spray-dried lactose, α-lactose, β-lactose, various grades), microcrystalline cellulose (various grades), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low-substituted), hypromellose (HPMC, such as Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as 4,000 cps grade Methocel E and Metolose 60SH, 4,000 cps grade Methocel F and Metolose 65SH, 4,000, 15,000 and 100,000 cps grade Methocel K; and 4,000, 15,000, 39,000 and 100,000 grades Metolose 90SH), methylcellulose polymers (e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, other cellulose derivatives, sucrose, dextrin, maltodextrin, starch or modified starch (including potato starch, corn starch and rice starch), calcium lactate, calcium carbonate, gum arabic, sodium alginate, agar, carrageenan, gelatin, guar gum, pectin, PEG or povidone.

[0017] As used herein, the term "bioavailability" refers to the proportion of an administered dose of a drug substance (e.g., a GLP-1 peptide or derivative thereof) that reaches the systemic circulation unchanged. By definition, when a drug substance is administered intravenously, its bioavailability is 100%. However, when a drug substance is administered by other routes (e.g., orally), its bioavailability decreases (due to degradation and / or incomplete absorption and first-pass metabolism). Knowledge of bioavailability is very important when calculating doses for non-intravenous routes of administration of a drug substance. Following oral and intravenous administration, a graph is drawn of plasma concentration versus time. Absolute bioavailability is (AUC - oral divided by dose) divided by (AUC - intravenous divided by dose).

[0018] In a first aspect, the present invention provides a solid composition for oral administration of a GLP-1 receptor agonist, wherein the solid composition comprises a first type of particles and a second type of particles. Furthermore, the composition further comprises a pharmaceutically acceptable excipient added to the above particles, wherein the excipient is preferably magnesium stearate, wherein the particles may be:

[0019] (1) The first type of particles contains 280-300 mg of SNAC and 5-20% of GLP-1 receptor agonist, and the second type of particles contains 80-95% of GLP-1 receptor agonist and 5-20 mg of SNAC; the total amount of the GLP-1 receptor agonist is 2-25 mg, preferably 2-20 mg, 3-20 mg, 3-15 mg, 2 mg, 3 mg, 5 mg, 7 mg, 9 mg, 12 mg, 14 mg, 15 mg, and 20 mg.

[0020] Preferably, the GLP-1 receptor agonist accounts for 5-20%, 5-15% or 10-15% of the total amount of polypeptide in the first type of particles; and the GLP-1 receptor agonist accounts for 80-95%, 85-95% or 85-90% of the total amount of polypeptide in the second type of particles. Alternatively, the GLP-1 receptor agonist accounts for 5-15% of the total amount of polypeptide in the first type of particles and the GLP-1 receptor agonist accounts for 85-95% of the total amount of polypeptide in the second type of particles; or the GLP-1 receptor agonist accounts for 10-15% of the total amount of polypeptide in the first type of particles and the GLP-1 receptor agonist accounts for 85-90% of the total amount of polypeptide in the second type of particles.

[0021] Furthermore, the SNAC content in the first type of granules is 290 mg or 300 mg, and the SNAC content in the second type of granules is 10 mg or 20 mg. Preferably, the SNAC content in the first type of granules is 290 mg, and the SNAC content in the second type of granules is 10 mg. Alternatively, the SNAC content in the first type of granules is 300 mg, and the SNAC content in the second type of granules is 20 mg.

[0022] Furthermore, the content of SNAC in the first type of particles is 290 mg, and the content of GLP-1 agonist is 0.5 mg; the content of SNAC in the second type of particles is 10 mg, and the content of GLP-1 agonist is 2.5 mg. Preferably, the content of SNAC in the first type of particles is 290 mg, and the content of GLP-1 agonist is 1 mg; the content of SNAC in the second type of particles is 10 mg, and the content of GLP-1 agonist is 6 mg. Alternatively, the content of SNAC in the first type of particles is 290 mg, and the content of GLP-1 agonist is 2 mg; the content of SNAC in the second type of particles is 10 mg, and the content of GLP-1 agonist is 12 mg.

[0023] Preferably, the first type of particles further comprises a lubricant, such as magnesium stearate; and / or a filler, such as microcrystalline cellulose. The second type of particles further comprises a filler, such as microcrystalline cellulose; and / or a binder, such as povidone. Furthermore, in addition to the first type of particles and the second type of particles described above, the composition further comprises extragranularly added magnesium stearate. Preferably, in the composition described in this section, the first type of particles further comprises magnesium stearate and microcrystalline cellulose; and the second type of particles further comprises microcrystalline cellulose and povidone. Preferably, the microcrystalline cellulose is microcrystalline cellulose PH101 and the povidone is povidone K90.

[0024] Preferably, the content of microcrystalline cellulose PH101 in the first type of granules is 20-60 mg, and the content of magnesium stearate is 5-10 mg; the content of microcrystalline cellulose PH101 in the second type of granules is 5-30 mg, and the content of povidone K90 is 5-10 mg; and the amount of extragranular magnesium stearate is 1-5 mg. Preferably, the content of microcrystalline cellulose PH101 in the first type of granules is 57 mg, and the content of magnesium stearate is 7.7 mg; the content of microcrystalline cellulose PH101 in the second type of granules is 23 mg, and the content of povidone K90 is 8 mg; and the amount of extragranular magnesium stearate is 2 mg. Alternatively, preferably, the content of microcrystalline cellulose PH101 in the first type of granules is 37 mg, and the content of magnesium stearate is 7.7 mg; the content of microcrystalline cellulose PH101 in the second type of granules is 13 mg, and the content of povidone K90 is 8 mg; and the amount of extragranular magnesium stearate is 2 mg.

[0025] In a second aspect, the present invention provides a method for preparing the solid composition for oral administration according to the first aspect, the preparation method comprising:

[0026] (1) mixing a formulated amount of a GLP-1 receptor agonist and SNAC with an optional lubricant and a filler and granulating to obtain a first type of granules;

[0027] (2) mixing a formulated amount of a GLP-1 receptor agonist and SNAC with an optional filler and a binder and granulating to obtain a second type of granules;

[0028] (3) Mixing the granules obtained in steps (1) and (2) and an optional lubricant to obtain the oral solid composition.

[0029] Preferably, the step (1) comprises: mixing magnesium stearate and SNAC by an equal-increment method to obtain a first mixture; semaglutide is mixed with microcrystalline cellulose and then sieved, and mixed with an equal volume of the first mixture of microcrystalline cellulose and then with the remaining amount of the first mixture, and granulated to obtain the first type of particles.

[0030] Preferably, the step (2) comprises: semaglutide and povidone are sieved separately, and then semaglutide, povidone, SNAC and microcrystalline cellulose are mixed, tableted, crushed and sieved to obtain the second type of particles.

[0031] Preferably, the step (3) comprises: mixing the granules obtained in steps (1) and (2) and then mixing with magnesium stearate, and tableting to obtain the oral solid composition.

[0032] The technical solution provided by the embodiment of the present invention has the following advantages compared with the existing technology:

[0033] The oral delivery pharmaceutical composition of the present invention can more effectively orally deliver GLP-1 derivatives or GLP-1 related multi-target agonists, has excellent oral bioavailability, and has broad application prospects. DETAILED DESCRIPTION

[0034] In order to more clearly understand the above-mentioned objectives, features and advantages of the present invention, the scheme of the present invention will be further described below. It should be noted that, in the absence of conflict, the embodiments of the present invention and the features therein can be combined with each other.

[0035] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein; it is obvious that the embodiments in the specification are only part of the embodiments of the present invention, rather than all the embodiments.

[0036] Example 1

[0037] This embodiment provides a method for preparing a polypeptide oral tablet

[0038] (1) The composition of the prescription is shown in Table 1:

[0039] Table 1

[0040]

[0041]

[0042] (2) Preparation of oral tablets

[0043] 2.1 Preparation of Prescription 1:

[0044] Preparation of Granule 1: The materials were weighed according to the recipe. Magnesium stearate was mixed with an equal volume of SNAC in a weighing boat for 60 seconds. An equal volume of SNAC was then taken and mixed in a weighing boat for 60 seconds. The mixture was then mixed with the remaining SNAC for 6 minutes. An equal volume of the mixture with microcrystalline cellulose was taken and mixed with the microcrystalline cellulose in a weighing boat for 60 seconds. The above mixture was then mixed with the remaining mixture of SNAC and magnesium stearate for 3 minutes. Then, a dry granulator was controlled to perform granulation. The parameters of the dry granulator are shown in Table 2:

[0045] Table 2

[0046] parameter Numerical Spiral horizontal speed 15rpm Spiral vertical speed 30rpm Roller speed 4rpm Roller gap 1.9mm Granulating speed 100rpm Roller pressure 15bar Adjust the sieve aperture 0.8mm Roller surface texture Straight lines

[0047] Preparation of Granule 2: Semaglutide was passed through an 80-mesh sieve and weighed; povidone was passed through a 50-mesh sieve and weighed; semaglutide, microcrystalline cellulose, and povidone were mixed in a weighing boat for 3 minutes, passed through a 50-mesh sieve twice, and mixed for 4 minutes. Tablets of Granule 2 were compressed using a tablet press, crushed in a mortar, and passed through a 24-mesh sieve.

[0048] Total mixing and tableting: Granules 1, granules 2 and magnesium stearate were weighed according to the prescription; Granules 1 and granules 2 were mixed for 5 minutes, and then the mixture was mixed with magnesium stearate for 2 minutes; and tablets were prepared from the mixture.

[0049] 2.2 Preparation of Prescription 2:

[0050] Preparation of Granule 1: Semaglutide was weighed through an 80-mesh sieve; magnesium stearate and an equal volume of SNAC were mixed in a weighing boat for 60 seconds, and then an equal volume of SNAC was taken and mixed in a weighing boat for 60 seconds. The mixture was mixed with the remaining SNAC for 6 minutes. Semaglutide and microcrystalline cellulose were mixed in a weighing boat and passed through a 50-mesh sieve. The SNAC and magnesium stearate mixture with the microcrystalline cellulose was taken out and mixed with the microcrystalline cellulose and semaglutide mixture in a weighing boat for 60 seconds. The remaining SNAC and magnesium stearate mixture was added and mixed for 3 minutes. The above mixture was granulated in a granulator. The parameters for controlling the dry granulator are shown in Table 3:

[0051] Table 3

[0052] parameter Numerical Spiral horizontal speed 15rpm Spiral vertical speed 30rpm Roller speed 4rpm Roller gap 1.9mm Granulating speed 100rpm Roller pressure 15bar Adjust the sieve aperture 0.8mm Roller surface texture Straight lines

[0053] Preparation of Granule 2: Semaglutide was passed through an 80-mesh sieve and weighed; povidone was passed through a 50-mesh sieve and weighed; semaglutide, microcrystalline cellulose, povidone, and SNAC were mixed in a weighing boat for 3 minutes, passed through a 50-mesh sieve twice, and mixed for 4 minutes; tablets of Granule 2 were compressed using a tablet press, crushed in a mortar, and passed through a 24-mesh sieve.

[0054] Total mixing and tableting: Weigh Granule 1, Granule 2 and magnesium stearate according to the prescription; mix Granule 1 and Granule 2 for 5 minutes; mix the mixture with magnesium stearate for 2 minutes; and prepare tablets from the mixture.

[0055] Example 2: Disintegration and dissolution test experiments

[0056] (1) Three tablets prepared in Example 1 were randomly selected for disintegration test. The results are shown in Table 4:

[0057] Table 4

[0058] Disintegration time Prescription 1 Prescription 2 Film 1 11min11s 12min24s Film 2 12min02s 12 minutes and 57 seconds Film 3 12 minutes and 23 seconds 13 minutes and 29 seconds

[0059] (2) Perform dissolution test according to the method in Table 5:

[0060] Table 5

[0061]

[0062] The dissolution results of semaglutide are shown in Table 6, and the dissolution results of SNAC are shown in Table 7:

[0063] Table 6

[0064]

[0065]

[0066] Table 7

[0067] Time / min Prescription 1 (100%) Prescription 2 (100%) 0 0 0 5 31.1 30.1 10 55.8 54.3 15 76.2 73.3 20 90.9 86.9 30 102.9 95.7 45 103.7 97.5 60 104.3 98.3

[0068] As shown in Tables 5-7, the polypeptide oral tablets of Prescription 2 provided by the present invention have disintegration and dissolution results that are basically consistent with those of Prescription 1.

[0069] Example 3: Bioavailability assay

[0070] (1) Experimental materials:

[0071] a. Animal Experimentation:

[0072] Healthy male beagle dogs aged 7-9 months, weighing 9-10 kg were selected;

[0073] b. Dosage regimen

[0074] The drug was administered according to the specific dosing regimen shown in Table 8:

[0075] Table 8

[0076]

[0077]

[0078] (2) Experimental results

[0079] The blood drug concentration 2 hours after each administration is shown in Table 9:

[0080] Table 9

[0081]

[0082] Bioavailability 2 hours after each dose (using Cmax 口服 :Cmax 静脉 Calculation) see Table 10:

[0083] Table 10

[0084]

[0085] As shown in Tables 9-10, in animal experiments, the bioavailability of the polypeptide oral tablets of Prescription 2 provided by the present invention gradually increased within 7 days and was significantly higher than the bioavailability of Prescription 1. On the 7th day, its bioavailability was more than twice that of Prescription 1.

[0086] Example 4

[0087] This embodiment provides a method for preparing a polypeptide oral tablet.

[0088] In this example, the GLP-1 receptor agonist used was HS-G3, a GLP-1 analogue constructed in the early stage of this laboratory, with the structure: N-ε 34 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanamido)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Ile 8 Glu 22 Arg 26 Lys 34 Arg 35 Gly 36 ]GLP-1(7-37), see CN202210113945.9 for details.

[0089] (1) The composition of the prescription is shown in Table 11:

[0090] Table 11

[0091]

[0092] (2) Prepare the formulation 3 in this example by the same method as in Example 1.

[0093] Example 5: Bioavailability assay

[0094] (1) Referring to the same method as in Example 3, a bioavailability experiment was conducted on the formulation of Prescription 3 prepared in Example 4, and Prescription 1 was also used as a control.

[0095] (2) Experimental results

[0096] Bioavailability 2 hours after each dose (using Cmax 口服 :Cmax 静脉 Calculation) see Table 12:

[0097] Table 12

[0098]

[0099] As shown in Table 12, in animal experiments, the bioavailability of the polypeptide oral tablets of Prescription 3 provided by the present invention was significantly higher than that of Prescription 1 over 7 days, and even reached nearly 3 times that of Prescription 1 at one point.

[0100] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprises," "comprising," or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article, or device comprising a series of elements includes not only those elements, but also other elements not explicitly listed, or elements inherent to such process, method, article, or device. In the absence of further limitations, an element defined by the phrase "comprising a ..." does not exclude the presence of other identical elements in the process, method, article, or device comprising the element.

[0101] The foregoing description is intended only to provide specific embodiments of the present invention, which will enable those skilled in the art to understand and implement the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not intended to be limited to the embodiments described herein, but is to be construed in the widest manner consistent with the principles and novel features disclosed herein.

Claims

1. A solid composition for oral administration, characterized in that: The solid composition comprises a first type of particles and a second type of particles; The first type of particles contains 280-300 mg of SNAC and 5-20% of a GLP-1 receptor agonist, and the second type of particles contains 5-20 mg of SNAC and 80-95% of a GLP-1 receptor agonist; In the solid composition, the amount of the GLP-1 receptor agonist is 2-25 mg; The GLP-1 receptor agonist is HS-G3, and its structure is: N-ε 34 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanamido)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Ile 8 Glu 22 Arg 26 Lys 34 Arg 35 Gly 36 ]GLP-1(7-37).

2. The solid composition for oral administration according to claim 1, wherein The content of SNAC in the first type of particles is 290 mg, and the content of SNAC in the second type of particles is 10 mg.

3. The solid composition for oral administration according to claim 1, wherein The amount of the GLP-1 receptor agonist is 3-15 mg.

4. The solid composition for oral administration according to claim 3, characterized in that The amount of the GLP-1 receptor agonist is 3 mg, 7 mg or 15 mg.

5. The solid composition for oral administration according to claim 1, wherein The first type of particles further comprise a lubricant and a filler, and the second type of particles further comprise a filler and a binder.

6. The solid composition for oral administration according to claim 5, characterized in that The lubricant in the first type of granules is magnesium stearate, and the filler is microcrystalline cellulose; the filler in the second type of granules is microcrystalline cellulose, and the binder is povidone.

7. The solid composition for oral administration according to claim 6, characterized in that The components of the solid composition further include a lubricant added in addition to the first type of particles and the second type of particles, and the lubricant is selected from magnesium stearate.

8. The method for preparing the solid composition for oral administration according to any one of claims 1 to 7, characterized in that: The preparation method comprises: (1) mixing a formulated amount of a GLP-1 receptor agonist and SNAC with an optional lubricant and a filler and granulating to obtain a first type of granules; (2) mixing a formulated amount of a GLP-1 receptor agonist and SNAC with an optional filler and a binder and granulating to obtain a second type of granules; (3) Mixing the granules obtained in steps (1) and (2) and an optional lubricant to obtain the oral solid composition.

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