Tabletting composition containing semeglutide

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a tablet composition containing semeglutide, which contains semeglutide, polyglycerol-3 diisostearate, SNAC (Sodium Nitrogen Amino Cellulose) and pharmaceutically acceptable auxiliary materials. The composition has high bioavailability and high stability, is beneficial to solving the problems of large coefficient of variation and low bioavailability of a semeglutide oral preparation, is simple and convenient in preparation process, and is expected to realize industrial production.

Description

Technical Field

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

[0002] Semaglutide (also known as semaglutide) was first developed by Novo Nordisk. Its structural formula is shown below. It is the fourth GLP-1 analogue for once-weekly administration to be marketed after dulaglutide, albiglutide and exenatide. It is known as the world's best GLP-1 agonist product and was approved by the FDA on December 5, 2017 for the injection form for the treatment of type 2 diabetes. It was later approved on September 20, 2019 for the tablet form.

[0003]

[0004] Original research of Simeglutide oral preparation The macromolecular delivery technology based on absorption enhancers uses the absorption enhancer 8-(2-hydroxybenzamido) sodium caprylate (SNAC). SNAC is a small molecule fatty acid derivative that causes a short-term local increase in the pH value of the gastric mucosal surface in the stomach, thereby inactivating pepsin and preventing drug degradation. At the same time, the local lipophilicity of the stomach is increased, which improves the solubility of the main drug and promotes trans-passive cell permeability, making it easier for semaglutide to pass through the cell membrane and enter the blood.

[0005] The recommended dosing condition is to take the drug with 120 ml of water at least 30 minutes before fasting under fasting conditions. However, the absorption site of semaglutide is in the stomach. Due to gastric emptying, the time that semaglutide stays in the stomach is limited, which reduces the bioavailability of semaglutide and increases the coefficient of variation.

[0006] The semaglutide compositions disclosed in patents CN103260608A and CN105963685B contain 5 to 20 mg semaglutide and 300 mg SNAC; CN104203266B and CN107812181B disclose semaglutide compositions comprising first-type particles and second-type particles, wherein the first-type particles contain N-(8-(2-hydroxybenzoyl)amino)caprylate and do not contain semaglutide, and the second-type particles contain semaglutide and do not contain N-(8-(2-hydroxybenzoyl)amino)caprylate, wherein the first-type particles in the optimal formulation F are composed of SNAC, magnesium stearate, and microcrystalline cellulose, and the second-type particles are composed of semaglutide, microcrystalline cellulose, and poly(vinyl alcohol). The solid pharmaceutical composition disclosed in CN115461044A comprises 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 needs to be improved; the pharmaceutical composition disclosed in CN112153979A comprises semaglutide, a salt of NAC and a hydrotropic agent nicotinamide or resorcinol, and the provided composition exhibits accelerated absorption, so that the active pharmaceutical ingredient can be taken quickly and effectively.

[0007] CN104487056A claims to provide semaglutide tablets with improved bioavailability, but requires strict control of physical parameters of the tablets such as density, porosity and / or crushing strength, which are not easy to control subjectively and are not suitable for industrial scale-up production; CN111683676B provides a semaglutide pharmaceutical composition composed of semaglutide, SNAC and a lubricant, which accelerates absorption within 15-30 minutes after administration, thereby improving the exposure of the GLP-1 agonist through oral administration.

[0008] CN118234504A discloses a composition of semaglutide, SNAC and sodium decanoate, which significantly improves the oral bioavailability of semaglutide compared to the composition of semaglutide and SNAC. However, the composition requires semaglutide, SNAC and sodium decanoate and other optional excipients to be dissolved in water, freeze-dried and then pressed into tablets. The preparation process is not simple, and different freeze-drying parameters will affect the product quality. WO2023084118A discloses a solid composition of semaglutide containing a penetration enhancer acylated amino acid AC-aa or a salt thereof, which is similar to Compared with arginine, sucrose stearate and semaglutide tablets with slow disintegration properties in gastric juice were prepared in WO2019193204A1, and arginine and sodium decanoate-containing semaglutide capsules achieved an absolute oral bioavailability of 3.1%.

[0009] CN116549656A relates to a composition for improving the stability of semaglutide in the intestine, using glycine dipeptide and citric acid as stabilizers for semaglutide. CN116159027A discloses a semaglutide freeze-dried pharmaceutical composition, which is added with citric acid and its sodium salt for adjusting the pH value, and adopts a freeze-drying process to solve the problem of low-temperature storage and transportation, and improve the adverse effects of the preparation on high temperature.

[0010] The human stomach contains a lot of gastric acid and pepsin. Peptide drugs have low resistance to enzymes and are easily degraded by gastrointestinal digestive enzymes and hydrolases in body fluids, thus losing their activity. Their oral bioavailability is extremely low, and their clinical application is difficult. Through analysis of the prior art, it is found that a large amount of N-(8-(2-hydroxybenzoyl)amino) caprylate, i.e., SNAC, needs to be added to the oral preparation of the peptide drug semaglutide to increase the pH in the stomach, reduce the activity of pepsin, and reduce the degradation of drugs by enzymes. However, SNAC is a small molecule fatty acid derivative with low solubility under acidic conditions. Therefore, a large amount of SNAC needs to be added to improve the stability and bioavailability of semaglutide. For example, in the original patent, at least 300 mg of SNAC is added to the semaglutide preparation with a tablet weight of 400 mg. In addition, the same amount of SNAC has a relatively large effect on different individuals, resulting in low bioavailability and a large coefficient of variation of semaglutide preparations.

[0011] In the prior art, oral preparations of semaglutide still have shortcomings such as large oral coefficient of variation, poor stability, and low bioavailability. It is still necessary to continuously study the prescription and preparation process, and to conduct in-depth research on its biodistribution and clearance mechanism in the body, so as to provide a more clinically suitable, high-quality oral preparation of semaglutide. Summary of the invention

[0012] In view of the fact that the oral preparations of semaglutide in the prior art still have the problems of large oral variation coefficient, poor stability and low bioavailability, the present invention provides a tablet composition containing semaglutide. The composition has high bioavailability and high stability, which is conducive to solving the problems of large variation coefficient and low bioavailability of oral preparations of semaglutide. At the same time, the preparation process is simple and it is expected to achieve industrial production.

[0013] Since the raw materials of semaglutide are sensitive to pH and humidity, most of the raw materials are emptied into the intestines after the tablet form slowly dissolves in the stomach, resulting in low bioavailability of the drug and causing intestinal side effects. The inventors considered that if the raw materials of semaglutide are dispersed in polyglycerol-3 diisostearate, the barrier effect of polyglycerol-3 diisostearate on moisture can be used to reduce the sensitivity of API to pH and humidity, while simply dispersing the drug in the oil phase polyglycerol-3 diisostearate is not conducive to improving the bioavailability of API, so further research on the prescription and preparation process is needed to overcome the above technical problems.

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

[0015] A tabletting composition containing semaglutide, wherein the composition contains semaglutide, polyglycerol-3 diisostearate, SNAC and pharmaceutically acceptable excipients.

[0016] Preferably, in the composition, the mass ratio of semaglutide, polyglycerol-3 diisostearate and SNAC is 10-14:10-20:100-300.

[0017] Preferably, in the composition, the pharmaceutically acceptable excipients are water-soluble carriers, fillers, disintegrants, phosphate buffer salts and lubricants.

[0018] Further preferably, in the composition, the water-soluble carrier is mannitol 160C.

[0019] More preferably, in the composition, the mass ratio of semaglutide to the water-soluble carrier is 10-14:20-170.

[0020] Further preferably, in the composition, the filler is selected from one or more of microcrystalline cellulose, sucrose, lactose, sorbitol and pregelatinized starch; more preferably, the filler is microcrystalline cellulose or sorbitol.

[0021] More preferably, in the composition, the mass ratio of semaglutide to filler is 10-14:15-50.

[0022] Further preferably, in the composition, the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.

[0023] More preferably, in the composition, the mass ratio of semaglutide to disintegrant is 10-14:3-12.

[0024] Preferably, in the composition, the phosphate buffer is disodium hydrogen phosphate buffer.

[0025] Further preferably, in the composition, the lubricant is selected from one or more of talc, magnesium stearate, micro powder silica gel and calcium stearate.

[0026] More preferably, in the composition, the mass ratio of semaglutide to lubricant is 10-14:1-10.

[0027] Further preferably, in the composition, each unit preparation contains the following components:

[0028] Semaglutide 10-14 mg, polyglyceryl-3 diisostearate 10-20 mg, SNAC 100-300 mg, mannitol 160C 20-170 mg, microcrystalline cellulose or sorbitol 15 mg-50 mg, disintegrant 3-12 mg, phosphate buffer salt 100-300 mg and lubricant 2-10 mg.

[0029] The present invention also provides a method for preparing the above-mentioned semaglutide tablet composition, comprising the following steps:

[0030] a. Add semaglutide to phosphate buffer and stir to dissolve;

[0031] b. Add the prescribed amount of polyglycerol-3 diisostearate, part of the prescribed amount of SNAC, a disintegrant to step a, and prepare a suspension with a grinder;

[0032] c. spraying the suspension onto a water-soluble carrier using a spray freeze dryer to obtain semaglutide particles;

[0033] d. Add the remaining SNAC, filler and lubricant and mix them evenly with a three-dimensional motion mixer;

[0034] e. Prepare semaglutide tablets using a rotary tablet press.

[0035] Preferably, in the preparation method, the amount of SNAC in the partial prescription in step b is 1 / 2 to 1 / 4.

[0036] Preferably, in the preparation method, the phosphate buffer is a mixed aqueous solution of disodium hydrogen phosphate, hydrochloric acid and sodium hydroxide, with a pH of 6.5-7.5; further preferably, the mass ratio of semaglutide to phosphate buffer is 10-14:100-300.

[0037] Compared with the prior art, the present invention has the following outstanding advantages:

[0038] 1. In the tablets prepared by the present invention, semaglutide is wrapped by a polyglycerol-3 diisostearate oil film, which reduces the sensitivity of semaglutide to humidity and pH and improves its stability;

[0039] 2. The tablets prepared by the present invention dissolve in the stomach, and the released semaglutide exists in the form of self-microemulsified oil droplets, which can not only adhere to the stomach wall, but also have nano-scale dispersion, with better penetration effect and significantly improved bioavailability;

[0040] 3. The preparation method of the present invention is simple and easy to operate, and is expected to achieve industrial production. DETAILED DESCRIPTION

[0041] The following specific implementation modes are listed to further illustrate the present invention, but do not limit the scope of the present invention in any way. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0042] Example 1

[0043]

[0044]

[0045] Preparation method:

[0046] a. Add semaglutide to pH 6.5-7.5 phosphate buffer and stir to dissolve;

[0047] b. Add the prescribed amount of polyglycerol-3 diisostearate, 1 / 2 the prescribed amount of SNAC, and the disintegrant crospovidone to step a, and prepare a suspension with a grinder;

[0048] c. Spray the suspension onto mannitol 160C using a spray freeze dryer to obtain semaglutide particles;

[0049] d. Add the remaining SNAC, the prescribed amount of filler microcrystalline cellulose, and lubricant talc, and mix them evenly with a three-dimensional motion mixer;

[0050] e. Prepare semaglutide tablets using a rotary tablet press.

[0051] Example 2

[0052]

[0053] Preparation method:

[0054] a. Add semaglutide to pH 6.5-7.5 phosphate buffer and stir to dissolve.

[0055] b. Add the prescribed amount of polyglycerol-3 diisostearate, 1 / 4 the prescribed amount of SNAC, and a disintegrant cross-linked carboxymethyl cellulose to step a, and prepare a suspension using a grinder;

[0056] c. Spray the suspension onto mannitol 160C using a spray freeze dryer to obtain semaglutide particles;

[0057] d. Add the remaining SNAC, the prescribed amount of fillers sorbitol and sucrose, and the lubricant magnesium stearate, and mix them evenly with a three-dimensional motion mixer;

[0058] e. Prepare semaglutide tablets using a rotary tablet press.

[0059] Example 3

[0060]

[0061] Preparation method:

[0062] a. Add semaglutide to pH 6.5-7.5 phosphate buffer and stir to dissolve;

[0063] b. Add the prescribed amount of polyglycerol-3 diisostearate, 1 / 3 the prescribed amount of SNAC, a disintegrant sodium carboxymethyl starch and a low-substituted hydroxypropyl cellulose to step a, and prepare a suspension with a grinder;

[0064] c. Spray the suspension onto mannitol 160C using a spray freeze dryer to obtain semaglutide particles;

[0065] d. Add the remaining SNAC, the prescribed amount of filler lactose and pregelatinized starch, lubricant micropowder silica gel and calcium stearate, and mix evenly with a three-dimensional motion mixer;

[0066] e. Prepare semaglutide tablets using a rotary tablet press.

[0067] Example 4

[0068]

[0069]

[0070] Preparation method:

[0071] a. Add semaglutide to pH 6.5-7.5 phosphate buffer and stir to dissolve;

[0072] b. Add the prescribed amount of polyglycerol-3 diisostearate, 1 / 2 the prescribed amount of SNAC, and the disintegrant crospovidone to step a, and prepare a suspension with a grinder;

[0073] c. Spray the suspension onto mannitol 160C using a spray freeze dryer to obtain semaglutide particles;

[0074] d. Add the remaining SNAC, the prescribed amount of filler microcrystalline cellulose, and lubricant talc, and mix them evenly with a three-dimensional motion mixer;

[0075] e. Prepare semaglutide tablets using a rotary tablet press.

[0076] Example 5

[0077]

[0078] Preparation method:

[0079] a. Add semaglutide to pH 6.5-7.5 phosphate buffer and stir to dissolve;

[0080] b. Add the prescribed amount of polyglycerol-3 diisostearate, 1 / 2 the prescribed amount of SNAC, and the disintegrant crospovidone to step a, and prepare a suspension with a grinder;

[0081] c. Spray the suspension onto mannitol 160C using a spray freeze dryer to obtain semaglutide particles;

[0082] d. Add the remaining SNAC, the prescribed amount of filler microcrystalline cellulose, and lubricant talc, and mix them evenly with a three-dimensional motion mixer;

[0083] e. Prepare semaglutide tablets using a rotary tablet press.

[0084] Comparative Example 1

[0085]

[0086] Preparation method:

[0087] a. Add semaglutide to pH 6.5-7.5 phosphate buffer and stir to dissolve;

[0088] b. adding 1 / 2 of the prescribed amount of SNAC and the prescribed amount of the disintegrant cross-linked polyvinylpyrrolidone to step a, and preparing a suspension with a grinder; c. spraying the suspension onto mannitol 160C with a spray freeze dryer to obtain semaglutide particles;

[0089] d. Add the remaining SNAC, the prescribed amount of filler microcrystalline cellulose, and lubricant talc, and mix them evenly with a three-dimensional motion mixer;

[0090] e. Prepare semaglutide tablets using a rotary tablet press.

[0091] Comparative Example 2

[0092]

[0093] Preparation method:

[0094] a. Add semaglutide to pH 6.5-7.5 phosphate buffer and stir to dissolve;

[0095] b. Add the prescribed amount of polyglycerol-3 diisostearate and disintegrant crospovidone to step a, and prepare a suspension with a grinder;

[0096] c. Spray the suspension onto mannitol 160C using a spray freeze dryer to obtain semaglutide particles;

[0097] d. The prescribed amount of filler microcrystalline cellulose and lubricant talc are mixed evenly with a three-dimensional motion mixer;

[0098] e. Prepare semaglutide tablets using a rotary tablet press.

[0099] Comparative Example 3

[0100]

[0101] Preparation method:

[0102] The prescribed amount of semaglutide, polyglycerol-3 diisostearate, SNAC, mannitol 160C, filler microcrystalline cellulose, and disintegrant cross-linked polyvinylpyrrolidone were added into a three-dimensional motion mixer, mixed evenly, and then lubricant talc was added, and the powder was directly compressed to prepare semaglutide tablets.

[0103] Comparative Example 4

[0104]

[0105] Preparation method:

[0106] a. Add semaglutide to 200 mg pH 6.5-7.5 phosphate buffer and stir to dissolve.

[0107] b. Add the prescribed amount of polyglycerol-3 diisostearate, SNAC, and disintegrant crospovidone to step a, and prepare a suspension using a grinder.

[0108] c. Spray the suspension onto mannitol 160°C using a spray freeze dryer to obtain semaglutide particles.

[0109] d. Add the prescribed amount of filler microcrystalline cellulose and lubricant talc and mix evenly with a three-dimensional motion mixer;

[0110] e. Prepare semaglutide tablets using a rotary tablet press.

[0111] Comparative Example 5

[0112]

[0113] Preparation method: SNAC and niacinamide are mixed in a mixer and added to an extruder (7min, 25rpm). The temperature is set to 200°C to 105°C for melt extrusion, and passed through a circular die with a diameter of 2mm. The extrudate is sieved using a 350 to 149μm mesh. The melt-extruded particles are blended with semaglutide in a turbulent mixer (7min, 25rpm), and the prescribed amount of dibehenyl glyceride passed through a 125μm mesh is added to the blending in the turbulent mixer (2min, 25rpm). After mixing evenly, tablets are pressed to obtain the product.

[0114] Verification Example

[0115] Stability test

[0116] The stability test was carried out in accordance with the fourth part of the 2020 edition of the Chinese Pharmacopoeia <9001 Guidelines for Stability Testing of Raw Materials and Preparations>. Accelerated test: Take the tablets obtained in the examples and comparative examples and the commercially available reference preparations (14 mg), placed at 40°C ± 2°C, 75% RH ± 5% RH, and sampled after 6 months for HPLC testing. (14 mg), placed under high humidity conditions of 90% RH ± 5% RH, sampled after 10 days and tested for moisture.

[0117] Table 1 Stability test results

[0118]

[0119] The results show that the moisture content and total impurity content of the tablets obtained in each embodiment are relatively small. In the prescription of Comparative Example 1, polyglycerol-3 diisostearate was not added, and its API was not wrapped by the oil film, and the moisture content of the obtained tablets was large and the total impurity content was high; in the prescription of Comparative Example 2, polyglycerol-3 diisostearate was contained and SNAC was not added, and the moisture content was small, and the total impurity content was slightly higher than that of the embodiment; Comparative Example 3 used a preparation method different from that of the embodiment, and its API was not wrapped by the oil film, and the moisture content of the obtained tablets was large and the total impurity content was high; in Comparative Example 4, when preparing tablets, the moisture and impurity content were slightly higher than that of the embodiment, possibly due to the hygroscopicity and uneven dispersion of SNAC; in Comparative Example 5, the moisture content and total impurity content of the obtained tablets were high using the prescription and preparation method in the prior art.

[0120] Pharmacokinetic studies

[0121] Male healthy Beagle dogs weighing 12.5±0.7 kg, 5 dogs in each group. The Beagle dogs were adapted to the new environment for 1 week before the experiment. Each group was given the Example, Comparative Example and commercially available semaglutide tablets (3.0 mg / kg) with water. Tablets, 5min, 10min, 15min, 20min, 25min, 30min after administration, about 3mL of blood was collected from the subcutaneous vein of the forelimb, placed in a heparinized test tube, and the blood drug concentration was measured, and the AUC was calculated. The pharmacokinetic data of semaglutide tablets in the examples and comparative examples were compared with those of commercially available semaglutide tablets. The results are shown in Table 2.

[0122] Table 2 Pharmacokinetic test results

[0123]

[0124] As shown in Table 2, the semaglutide tablets prepared in the embodiments of the present invention have significantly improved bioavailability. In Comparative Example 1, polyglycerol-3 diisostearate was not added, and its API was not wrapped by the oil film, and no nanoemulsion was formed, and the bioavailability of the obtained tablets was greatly reduced; the prescription of Comparative Example 2 contained polyglycerol-3 diisostearate and no SNAC was added, and the bioavailability decreased; in Comparative Example 3, different preparation methods were used, and the bioavailability of the obtained tablets was also greatly reduced; in Comparative Example 4, when preparing the tablets, the bioavailability may be slightly reduced due to uneven dispersion of SNAC; in Comparative Example 5, the prescription and preparation method in the prior art were used, and the bioavailability of the obtained tablets was low.

Claims

1. A tabletting composition containing semaglutide, characterized in that: The composition contains semaglutide, polyglycerol-3 diisostearate, SNAC and pharmaceutically acceptable excipients.

2. The composition according to claim 1, characterized in that The mass ratio of semaglutide, polyglycerol-3 diisostearate and SNAC in the composition is 10-14:10-20:100-300.

3. The composition according to claim 1, characterized in that The pharmaceutically acceptable excipients in the composition are water-soluble carriers, fillers, disintegrants, phosphate buffer salts and lubricants.

4. The composition according to claim 3, characterized in that In the composition, the water-soluble carrier is mannitol 160C.

5. The composition according to claim 3, characterized in that The mass ratio of semaglutide to the water-soluble carrier in the composition is 10-14:20-170.

6. The composition according to claim 3 or 5, characterized in that The mass ratio of semaglutide to filler in the composition is 10-14:15-50.

7. The composition according to claim 3, characterized in that The disintegrant in the composition is selected from one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.

8. The composition according to claim 3 or 7, characterized in that The mass ratio of semaglutide to disintegrant in the composition is 10-14:3-12.

9. A method for preparing the composition according to claim 3, characterized in that: The preparation method comprises the following steps: a. Add semaglutide to phosphate buffer and stir to dissolve; b. Add polyglycerol-3 diisostearate, part of SNAC, and a disintegrant to step a, and prepare a suspension using a grinder; c. spraying the suspension onto a water-soluble carrier using a spray freeze dryer to obtain semaglutide particles; d. Add the remaining SNAC, filler and lubricant and mix them evenly with a three-dimensional motion mixer; e. Prepare semaglutide tablets using a rotary tablet press.

10. The preparation method according to claim 9, characterized in that: In the preparation method, the SNAC in step b is 1 / 2 to 1 / 4 of the prescribed dosage.

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