A semaglutide pharmaceutical composition

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a semaglutide pharmaceutical composition and a preparation method thereof. The semaglutide pharmaceutical composition of the present invention comprises semaglutide, vorapaxar fumarate, sodium N-(8-(2-hydroxybenzoyl)amino) octanoate (SNAC), and pharmaceutically acceptable excipients. The dosage of SNAC in the composition is small. Vorapaxar fumarate can rapidly adjust the pH, can stay on gastric parietal cells for a long time and be more stable in an alkaline environment for a longer time, improve the dissolution of semaglutide, and the preparation has good stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a semaglutide pharmaceutical composition. Background Art

[0002] Semaglutide, with the molecular formula C 187 H 291 N 45 O 59 , is a GLP-1 receptor agonist and has 94% homology with GLP-1 in the human body. GLP-1 is an incretin secreted by intestinal L cells of the small intestine, and it exists in multiple sites including the pancreas, gastrointestinal tract, heart, brain, lung and kidney, and has the effect of reducing blood sugar. The structural formula is as follows:

[0003]

[0004] The stomach contains more gastric acid and pepsin. Semaglutide has low resistance to enzymes and is easily degraded by gastrointestinal digestive enzymes and hydrolases in body fluids, thus losing its activity. The oral bioavailability of polypeptide drugs is extremely low, and clinical application is extremely difficult. In 2019, the oral preparation of semaglutide developed by Novo Nordisk was approved by the FDA for the treatment of type II diabetes. An excipient, sodium 8-(2-hydroxybenzamide) octanoate (SNAC), which can promote the absorption of semaglutide in the stomach, is added to this oral preparation. The molecular formula of SNAC is C 15 H 22 NNaO4, and the structural formula is as follows:

[0005]

[0006] SNAC can effectively increase the local pH value around the semaglutide molecule in the stomach, prevent the degradation of the polypeptide by pepsin, and enable semaglutide to penetrate the gastric mucosa and be absorbed into the blood by means of the concentration gradient on the cell membrane surface; SNAC promotes the monomerization of semaglutide, making it more permeable. For the semaglutide molecule, most semaglutide exists in the form of oligomers in the stomach, while SNAC triggers a change in the polarity of the solution containing the dissolving tablet, weakening the hydrophobic interactions necessary for oligomerization; due to the lipophilicity of SNAC, it effectively inserts into the cell membrane of gastric epithelium, changing the inherent integrity of cholesterol phospholipids and proteins, and thus affecting the fluidity of the cell membrane. However it still has defects such as low bioavailability, great influence by food, and large individual differences.

[0007] The semaglutide compositions disclosed in the original patents CN201180060463.1 and CN201610420028.X contain 5 to 20 mg of semaglutide and 300 mg of SNAC. CN201380015554.2 and CN201711156842.6 disclose semaglutide compositions comprising a first type of particle and a second type of particle, the first type of particle containing N-(8-(2-hydroxybenzoyl)amino)octanoate and no semaglutide, and the second type of particle containing semaglutide and no N-(8-(2-hydroxybenzoyl)amino)octanoate. Among them, in the optimal formulation F, the first type of particle consists of SNAC, magnesium stearate, and microcrystalline cellulose, and the second type of particle consists of semaglutide, microcrystalline cellulose, and povidone, claiming to have improved bioavailability. Semaglutide is a pH-dependent drug. A large amount of SNAC (the dosage of SNAC is at least 0.6 mmol, 180 mg) is used in the above preparations. SNAC is a small molecule fatty acid derivative with low solubility in acidic media. Moreover, due to the large differences in gastric acid in the stomach among different individuals, even the same amount of SNAC has quite different effects on different individuals, resulting in low and variable bioavailability of semaglutide.

[0008] The pharmaceutical composition disclosed in CN201980031030.X contains semaglutide, a salt of NAC, and a solubilizer nicotinamide or resorcinol. The provided composition exhibits accelerated absorption, enabling rapid and effective uptake of the active pharmaceutical ingredient; CN201980011485.5 provides a semaglutide pharmaceutical composition consisting of semaglutide, SNAC, and a lubricant, with accelerated absorption within 15 - 30 minutes after administration, thereby improving the exposure of the GLP-1 agonist through oral administration. However, the gastric emptying of the above compositions also varies greatly among individuals.

[0009] The solid pharmaceutical composition disclosed in CN202180031965.5 contains semaglutide, a salt of NAC, and histidine, which can reduce the formation of hydrophobic impurities, semaglutide formaldehyde adducts, and semaglutide acetaldehyde adducts, but its stability still needs to be improved; CN201380032636.8 claims to provide semaglutide tablets with improved bioavailability, but it is necessary to strictly control the physical parameters of the tablets such as density, porosity, and / or crushing strength, which is not easily subjectively controlled and not suitable for industrial scale-up production.

[0010] WO2023065231A1 discloses a composition of semaglutide, SNAC and sodium caprate, which improves the oral bioavailability of semaglutide compared to the composition of semaglutide and SNAC. However, this composition requires adding semaglutide, SNAC, sodium caprate and other optional excipients to water for dissolution and then freeze-drying, and then pressing into tablets. The preparation process is not simple, and different freeze-drying parameters will affect the product quality; WO2023084118A1 discloses a solid composition of semaglutide containing a penetration enhancer acylated amino acid AC-aa or its salt, which has comparable bioavailability compared to ; WO2019193204A1 prepared semaglutide tablets with slow disintegration characteristics in gastric juice using arginine and sucrose stearate, and semaglutide capsules containing arginine and sodium caprate achieved an absolute oral bioavailability of 3.1%.

[0011] Therefore, in the prior art, semaglutide oral preparations still have defects such as low bioavailability, large variability and poor stability. Those skilled in the art need to study the above problems and find materials that can more quickly adjust the pH and extend the relatively high pH environment to obtain a more stable and high-bioavailability semaglutide preparation, so as to meet the clinical needs. Summary of the Invention

[0012] In view of the deficiencies of the prior art, the inventors provide a semaglutide pharmaceutical composition and its preparation method. The semaglutide pharmaceutical preparation prepared by the present invention has good stability and high bioavailability, and is suitable for industrial production.

[0013] Regarding the degradation problem of semaglutide by pepsin, the inventors conducted a large number of experiments. First, they tried to add sodium bicarbonate that can quickly neutralize gastric acid and increase the gastric pH value, but found that it could not effectively improve the bioavailability of semaglutide. Then they tried to add omeprazole to the formulation, and the results showed that the stability and bioavailability of the preparation were not ideal, probably because omeprazole degraded when encountering acid in the stomach and could not achieve good results. After adding omeprazole and sodium bicarbonate at the same time, the bioavailability of semaglutide was improved to a certain extent, but the preparation stability was not high.

[0014] The present invention is specifically realized through the following solutions:

[0015] A semaglutide pharmaceutical composition, comprising semaglutide, vorapaxar fumarate, N-(8-(2-hydroxybenzoyl)amino) sodium caprate (SNAC) and pharmaceutically acceptable excipients.

[0016] Preferably, the pharmaceutical composition further comprises copovidone.

[0017] Preferably, the weight ratio of semaglutide, vorapaxar fumarate, sodium N-(8-(2-hydroxybenzoyl)amino)octanoate and copovidone is 3-14:5-20:20-50:3-20.

[0018] More preferably, the weight ratio of semaglutide, vorapaxar fumarate, sodium N-(8-(2-hydroxybenzoyl)amino)octanoate and copovidone is 3-14:10-20:30-40:10-20; particularly preferably 3-14:12.5:35:11.5.

[0019] Preferably, the pharmaceutically acceptable excipients are fillers, disintegrants, lubricants;

[0020] More preferably, the weight ratio of semaglutide to the filler, disintegrant, and lubricant is 3-14:50-200:2-10:2-8.

[0021] More preferably, the filler is selected from one or more of lactose, starch, microcrystalline cellulose, sorbitol, and mannitol; particularly preferably a combination of microcrystalline cellulose and mannitol.

[0022] More preferably, the disintegrant is selected from one or more of sodium carboxymethyl starch, crospovidone, cross-linked carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; particularly preferably low-substituted hydroxypropyl cellulose.

[0023] More preferably, the lubricant is selected from one or more of magnesium stearate, calcium stearate, talc, and sodium stearyl fumarate; particularly preferably talc.

[0024] Preferably, each unit dosage form of the semaglutide pharmaceutical composition contains the following components: 3 mg - 14 mg of semaglutide, 5 mg - 20 mg of vorapaxar fumarate, 20 - 50 mg of sodium N-(8-(2-hydroxybenzoyl)amino)octanoate, 3 mg - 20 mg of copovidone, 50 - 200 mg of filler, 2 mg - 10 mg of disintegrant, and 2 mg - 8 mg of lubricant.

[0025] Preferably, each unit dosage form of the semaglutide pharmaceutical composition contains the following components: 3 mg - 14 mg of semaglutide, 10 mg - 20 mg of vorapaxar fumarate, 30 - 40 mg of sodium N-(8-(2-hydroxybenzoyl)amino)octanoate, 10 mg - 20 mg of copovidone, 50 - 200 mg of filler, 2 mg - 10 mg of disintegrant, and 2 mg - 8 mg of lubricant.

[0026] Further preferably, the semaglutide pharmaceutical composition contains the following components in each unit dosage form: semaglutide 3 mg to 14 mg, vorapaxar fumarate 12.5 mg, sodium N-(8-(2-hydroxybenzoyl)amino)octanoate 35 mg, copovidone 11.5 mg, filler 50 to 200 mg, disintegrant 2 mg to 10 mg, and lubricant 2 mg to 8 mg.

[0027] Preferably, the composition is a tablet; preferably a bilayer tablet or a core-in-shell tablet.

[0028] Further preferably, in the core-in-shell tablet, semaglutide and SNAC are located in the tablet core layer, and vorapaxar fumarate is located in the outer layer.

[0029] In a preferred embodiment, the semaglutide pharmaceutical composition in each unit dosage form contains the following components:

[0030]

[0031] In a preferred embodiment, the semaglutide pharmaceutical composition in each unit dosage form contains the following components:

[0032]

[0033] In a preferred embodiment, the semaglutide pharmaceutical composition in each unit dosage form contains the following components:

[0034]

[0035] The present invention also provides a preparation method of the above semaglutide pharmaceutical composition, including the following steps:

[0036] a. Weigh the prescribed amounts of vorapaxar fumarate, disintegrant, part of the prescribed amount of filler, and part of the lubricant, and mix them evenly to obtain mixture 1; [[ID=3i]]

[0037] b. Mix the prescribed amounts of semaglutide, SNAC, copovidone, the remaining filler, and the remaining lubricant evenly to obtain mixture 2;

[0038] c. Feed mixture 2 into a tableting machine, pre-press, and press the tablet core;

[0039] d. Feed mixture 1 into the tableting machine to prepare the outer layer of the tablet, and obtain the semaglutide core-in-shell tablet.

[0040] Alternatively, the present invention also provides another preparation method of the above semaglutide pharmaceutical composition, including the following steps:

[0041] a. Weigh the prescribed amounts of vorapaxar fumarate, disintegrant, part of the prescribed amount of filler, and part of the lubricant, and mix them evenly to obtain mixture 1;

[0042] b. Mix the prescribed amount of semaglutide, SNAC, copovidone, the remaining fillers and the remaining lubricants thoroughly and evenly to obtain Mixture 2;

[0043] c. Feed Mixtures 1 and 2 into a tabletting machine to prepare a double-layer tablet, thus obtaining the semaglutide double-layer tablet.

[0044] Preferably, in the preparation method, both the filler and the lubricant in Mixture 1 account for 1 / 2 of the prescribed amount.

[0045] Advantages of the present invention:

[0046] Compared with the prior art, in the semaglutide pharmaceutical composition of the present invention, the dosage of SNAC is small, vonoprazan fumarate can rapidly adjust the pH, can stay on gastric parietal cells for a long time and remain stable in an alkaline environment for a longer time, improving the dissolution of semaglutide, with small individual differences; made into sandwich tablets or double-layer tablets, the preparation has good stability and high bioavailability. Specific embodiments

[0047] The present invention will be further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are only given for the purpose of illustrating the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention fall within the scope claimed by the present invention.

[0048] Example 1

[0049]

[0050] Preparation Method 1: a. Weigh the prescribed amount of vonoprazan fumarate, mannitol, low-substituted hydroxypropyl cellulose and 1 / 2 of the prescribed amount of talc powder, mix them thoroughly and evenly to obtain Mixture 1; b. Mix the prescribed amount of semaglutide, SNAC, copovidone, microcrystalline cellulose and the remaining talc powder thoroughly and evenly to obtain Mixture 2; c. Feed Mixture 2 into a tabletting machine, pre-press and press the tablet core; d. Feed Mixture 1 into a tabletting machine to prepare the outer layer of the tablet, thus obtaining the semaglutide sandwich tablet.

[0051] Preparation Method 2: a. Weigh the prescribed amount of vonoprazan fumarate, mannitol, low-substituted hydroxypropyl cellulose and 1 / 2 of the prescribed amount of talc powder, mix them thoroughly and evenly to obtain Mixture 1; b. Mix the prescribed amount of semaglutide, SNAC, copovidone, microcrystalline cellulose and the remaining talc powder thoroughly and evenly to obtain Mixture 2; c. Feed Mixtures 1 and 2 into a tabletting machine to prepare a double-layer tablet.

[0052] Example 2

[0053] The unit dose of semaglutide is 3 mg, and the others are the same as in Example 1.

[0054] Example 3

[0055]

[0056] Preparation method 1: a. Weigh the prescribed amounts of vonoprazan fumarate, sodium carboxymethyl starch, 1 / 2 of the prescribed amount of sorbitol, and 1 / 2 of the prescribed amount of magnesium stearate, and mix them thoroughly to obtain mixture 1; b. Thoroughly mix the prescribed amounts of semaglutide, SNAC, copovidone, the remaining sorbitol, and magnesium stearate to obtain mixture 2; c. Transfer mixture 2 to a tabletting machine, pre-press, and press the tablet core; d. Transfer mixture 1 to the tabletting machine to prepare the outer layer of the tablet, obtaining semaglutide sandwich tablets.

[0057] Preparation method 2: a. Weigh the prescribed amounts of vonoprazan fumarate, sodium carboxymethyl starch, 1 / 2 of the prescribed amount of sorbitol, and 1 / 2 of the prescribed amount of magnesium stearate, and mix them thoroughly to obtain mixture 1; b. Thoroughly mix the prescribed amounts of semaglutide, SNAC, copovidone, the remaining sorbitol, and magnesium stearate to obtain mixture 2; c. Transfer mixtures 1 and 2 to the tabletting machine to prepare a bilayer tablet.

[0058] Example 4

[0059]

[0060] Preparation method 1: a. Weigh the prescribed amounts of vonoprazan fumarate, crospovidone, 1 / 2 of the prescribed amount of lactose, and 1 / 2 of the prescribed amount of sodium stearyl fumarate, and mix them thoroughly to obtain mixture 1; b. Thoroughly mix the prescribed amounts of semaglutide, SNAC, copovidone, the remaining lactose, and sodium stearyl fumarate to obtain mixture 2; c. Transfer mixture 2 to the tabletting machine, pre-press, and press the tablet core; d. Transfer mixture 1 to the tabletting machine to prepare the outer layer of the tablet, obtaining semaglutide sandwich tablets.

[0061] Preparation method 2: a. Weigh the prescribed amounts of vonoprazan fumarate, crospovidone, 1 / 2 of the prescribed amount of lactose, and 1 / 2 of the prescribed amount of sodium stearyl fumarate, and mix them thoroughly to obtain mixture 1; b. Thoroughly mix the prescribed amounts of semaglutide, SNAC, copovidone, the remaining lactose, and sodium stearyl fumarate to obtain mixture 2; c. Transfer mixtures 1 and 2 to the tabletting machine to prepare a bilayer tablet.

[0062] Example 5

[0063]

[0064]

[0065] Same as the preparation method of the sandwich tablets in Example 1.

[0066] Example 6

[0067]

[0068] Same as the preparation method of the sandwich tablets in Example 1.

[0069] Example 7

[0070]

[0071] Same as the preparation method of the sandwich tablets in Example 1.

[0072] Example 8

[0073]

[0074]

[0075] Same as the preparation method of the sandwich tablets in Example 1.

[0076] Example 9

[0077]

[0078] Same as the preparation method of the sandwich tablets in Example 1.

[0079] Example 10

[0080]

[0081] Preparation method 1: a. Weigh the prescribed amounts of voroprevir fumarate, mannitol, low-substituted hydroxypropyl cellulose, and 1 / 2 of the prescribed amount of talc powder, and mix them thoroughly to obtain mixture 1; b. Mix the prescribed amounts of semaglutide, SNAC, polyvinylpyrrolidone, microcrystalline cellulose, and the remaining talc powder thoroughly to obtain mixture 2; c. Feed mixture 2 into a tabletting machine, pre-press, and press the tablet core; d. Feed mixture 1 into the tabletting machine to prepare the outer layer of the tablet, obtaining the semaglutide sandwich tablet.

[0082] Example 11

[0083]

[0084] Mix all the components in the prescribed amounts thoroughly and then directly press them into tablets to obtain the product.

[0085] Comparative Example 1

[0086]

[0087] Preparation method: a. Weigh the prescribed amounts of sodium bicarbonate, mannitol, low-substituted hydroxypropyl cellulose, and 1 / 2 of the prescribed amount of talc powder, and mix them thoroughly to obtain Mixture 1; b. Thoroughly mix the prescribed amounts of semaglutide, SNAC, copovidone, microcrystalline cellulose, and the remaining talc powder to obtain Mixture 2; c. Feed Mixture 2 into a tablet press, pre-press, and press the tablet core; d. Feed Mixture 1 into the tablet press to prepare the outer layer of the tablet, obtaining the semaglutide sandwich tablet.

[0088] Comparative Example 2

[0089]

[0090]

[0091] Preparation method: 1) First, screen each component through a #35 sieve; 2) Geometrically mix semaglutide and SNAC using a mortar and pestle; 3) Dissolve polyvinylpyrrolidone in water, and granulate the mixture of semaglutide and SNAC with the resulting solution; 4) Dry the granules at a temperature not exceeding 40 °C until the moisture content ≤ 4%; and 5) Grind the obtained dry granules through a #35 sieve; 6) Finally, mix the granules with Avicel PH 102 and magnesium stearate, and press the final mixture into tablets, where the pressing is carried out at approximately 4.4 kN.

[0092] Comparative Example 3

[0093]

[0094] Preparation method: Pass the magnesium stearate for the first granule fraction through a 355 μm sieve. Manually mix the magnesium stearate and SNAC in a stainless steel bowl of the corresponding volume. Apply two cycles of geometric dilution by mixing for about 60 s until the mixture is visually homogeneous. Transfer the remaining amount of SNAC to the mixer and pre-mix it at 25 rpm for 2 min. Add the pre-mixture of SNAC and magnesium stearate to the mixer and mix it at 25 rpm for 20 min. Geometrically dilute the microcrystalline cellulose with the SNAC and magnesium stearate mixed in the mixer by manually mixing it for at least 60 s until visually homogeneous. Then add the pre-mixture to the mixed SNAC and magnesium stearate. Complete the mixing step by mixing at 25 rpm in the mixer for 10 min. Roll the mixture.

[0095] Weigh semaglutide, microcrystalline cellulose (Avicel PH 101), and povidone (Kollidon90F) for the second granulation fraction directly into a stainless-steel bowl in the order of decreasing amounts, manually mix for at least 3 min until visually homogeneous, and then transfer the premix to a 500 mL Duma bottle. Seal the Duma bottle with a lid and manually invert it in a Turbula-like motion for at least 1 min. Roll the mixture.

[0096] Add the two types of granules to the mixing container in the order of decreasing content and mix at 32 rpm for 5 min. Manually mix the magnesium stearate outside the granules with the granule mixture by using volume doubling, and then mix in the mixer at 32 rpm for 30 s, followed by tabletting.

[0097] Comparative Example 4

[0098]

[0099] Preparation method: Dissolve semaglutide and histidine in water at a concentration of 2% w / w. Spray-dry the solution with the aspirator set to 100%, an inlet temperature of about 120 °C, an outlet temperature of about 45 °C, and a solution feed flow rate of about 6 g / min to obtain co-spray-dried semaglutide-histidine. Use a mixer to premix microcrystalline cellulose, povidone, and magnesium stearate of the second granule at 25 rpm for 30 min. Weigh the granules of SNAC, microcrystalline cellulose, and magnesium stearate for the first granule onto a weighing pan. On top of it, weigh the granules of microcrystalline cellulose and povidone premixed with magnesium stearate of the second granule. Finally, weigh the co-spray-dried semaglutide-histidine onto the top of the other components in the weighing pan. Then manually mix the components and directly transfer them to the tabletting die cavity of a tabletting machine. Compress the mixture in the die cavity into oval-shaped tablets with dimensions of 7.5 x 13 mm at a die table rotation speed of 20 rpm and a compression force of about 9 kN.

[0100] Comparative Example 5

[0101]

[0102]

[0103] Preparation method: Weigh the prescribed amounts of dapagliflozin propylene glycol hydrate, semaglutide, and SNAC, and then manually mix them according to the geometric mixing principle. Mix the obtained blend in a mixer at 25 rpm for 7 min, then mix magnesium stearate into the blend, and remix the blend in the mixer at 25 rpm for another 2 min. Roll the mixture, and compress the mixture in the die cavity into oval-shaped tablets with dimensions of 7.5 x 12 mm at a die table rotation speed of 20 rpm and a compression force of about 9 kN.

[0104] Comparative Example 6

[0105]

[0106] Preparation method: Mix SNAC and nicotinamide in a mixer and add them to an extruder (7 min, 25 rpm). Set the temperature to melt and extrude at 200°C to 105°C, pass through a circular die with a diameter of 2 mm, use a final screen of 355 to 150 μm, manually screen the obtained extrudate into particles, and admix the molten extruded particles with semaglutide and dapagliflozin propylene glycol hydrate in a turbulent mixer (7 min, 25 rpm). Sieve magnesium stearate through a 355-μm sieve and admix it in a mixer (2 min, 25 rpm) for addition, and press the mixture in the mold cavity into tablets at a mold table speed of 20 rpm and a compression force of about 9 kN.

[0107] Verification Example

[0108] Stability test

[0109] Refer to the "Guidelines for Stability Testing of Raw Drugs and Preparations" in Part IV of the Chinese Pharmacopoeia 2020 Edition <9001> for stability investigation. Accelerated test: Take the tablets obtained from the examples, comparative examples, and commercially available reference preparations (14 mg), place them under the conditions of 40°C ± 2°C and 75% RH ± 5% RH, sample after 3 months of placement, and detect by HPLC. Conduct three parallel tests and take the average of the results.

[0110] Table 1 Results of stability test

[0111]

[0112]

[0113] Pharmacokinetic test

[0114] Male healthy Beagle dogs weighing 12.5 ± 0.7 Kg, 5 in each group. The Beagle dogs underwent a 1-week adaptation period in a new environment before the experiment. Each group was given the tablets of the examples, comparative examples, and commercially available semaglutide tablets by taking them with clear water (3.0 mg / Kg), and about 3 ml of blood was collected from the subcutaneous vein on the inner side of the forelimb at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, 8.5 h, 9 h, 10 h, 11 h, 12 h, 16 h, 20 h, 24 h after administration, placed in a heparinized test tube, and the blood drug concentration was measured. Calculate C max, AUC, and compare the pharmacokinetic data of semaglutide tablets in the examples and comparative examples with commercially available semaglutide tablets for comparison. The results are shown in Table 2.

[0115] Table 2 Determination results of pharmacokinetic experiments

[0116]

[0117]

[0118] As can be seen from Table 2, the semaglutide tablets of the present application have high bioavailability, and both C max and AUC are significantly higher than those of commercially available semaglutide tablets and the prior art.

Claims

1. A semaglutide pharmaceutical composition, characterized in that: include Each unit of preparation contains the following components: semaglutide 3mg-14mg, vonoprazan fumarate 5mg-20mg, sodium N-(8-(2-hydroxybenzoyl)amino)caprylate 20-50mg, copovidone 3mg-20mg, filler 50-200mg, disintegrant 2mg-10mg, and lubricant 2mg-8mg; The composition is a double-layer tablet or a sandwich tablet; The preparation method of the semaglutide pharmaceutical composition in the form of a sandwich chip comprises the following steps: a. Weigh the prescribed amount of vonoprazan fumarate, a disintegrant, part of the prescribed amount of filler and part of the lubricant, mix thoroughly to obtain a mixture of 1; b. The prescribed amount of semaglutide, sodium N-(8-(2-hydroxybenzoyl)amino) caprylate, copovidone, the remaining filler and the remaining lubricant were thoroughly mixed to obtain a mixture 2; c. The mixture 2 was fed to a tablet press, pre-compressed, and pressed into tablet cores; the mixture 1 was fed to a tablet press to prepare the outer layer of the tablet, and the semaglutide sandwich chip was obtained; The preparation method of the semaglutide pharmaceutical composition in the form of a double-layer tablet comprises the following steps: a. Weigh the prescribed amount of vonoprazan fumarate, a disintegrant, part of the prescribed amount of filler and part of the lubricant, mix thoroughly to obtain a mixture of 1; b. The prescribed amount of semaglutide, sodium N-(8-(2-hydroxybenzoyl)amino) caprylate, copovidone, the remaining filler and the remaining lubricant were thoroughly mixed to obtain a mixture 2; c. Mixtures 1 and 2 are placed in a tablet press to prepare bilayer tablets, thereby obtaining semaglutide bilayer tablets.

2. The semaglutide pharmaceutical composition according to claim 1, characterized in that The filler is selected from one or more of lactose, starch, microcrystalline cellulose, sorbitol, and mannitol; the disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; and the lubricant is selected from one or more of magnesium stearate, calcium stearate, talc, and sodium stearyl fumarate.

Images