Gefapison film-coated tablet and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and provides a gefapison film-coated tablet and a preparation method thereof, the gefapison film-coated tablet contains gefapison or salt thereof, a filler, a disintegrating agent, a flavoring agent, a wetting agent, a lubricant and coating powder, the gefapison film-coated tablet is prepared through a wet granulation process, and the prepared gefapison film-coated tablet is stable in process, qualified in content and good in quality.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a gefapixel film-coated tablet and a preparation method thereof. Background Art

[0002] Chronic cough (cough lasting more than 8 weeks) has an incidence rate of about 10% in adults worldwide. It troubles a large number of cough patients in clinical practice and is one of the intractable diseases that are difficult to cure in the respiratory field. It is estimated that 5%-10% of adults worldwide suffer from chronic cough. Some of these patients have refractory chronic cough (RCC) and unexplained chronic cough (UCC), which are more sensitive to various triggers that do not usually cause cough in healthy subjects. This includes daily activities (such as talking and laughing), temperature changes, and exposure to aerosols or food odors. To date, treatment options for these patients are extremely limited, and many patients have often not been relieved for many years.

[0003] Lyfnua (gefapixant) is the first drug to treat refractory chronic cough (RCC) or unexplained chronic cough (UCC).

[0004] Gefapixant is a novel oral selective P2X3 receptor antagonist. It inhibits extracellular ATP signaling through P2X3 receptors present on the C fibers of the vagus nerve in the airways, and reduces sensory nerve activation and coughing. Excessive activation of P2X3 receptors is believed to be related to the hypersensitivity of sensory neurons. Sensory neuron hypersensitivity occurs after damage or infection of the airways or lungs, causing persistent and frequent coughing. Summary of the invention

[0005] The present invention provides a gefapiroxen film-coated tablet and a preparation method thereof, which has stable quality, mature preparation technology and is suitable for industrial production.

[0006] The gefapiroxen film-coated tablets of the present invention comprise gefapiroxen or its salt, a filler, a disintegrant, a flavoring agent, a wetting agent, a lubricant, and a coating material.

[0007] Furthermore, the gefapiroxen salt includes but is not limited to citrate, succinate, lactate, and oxalate, preferably citrate.

[0008] Furthermore, the filler is one or two of D-mannitol, lactose, microcrystalline cellulose, and corn starch; the disintegrant is one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and microcrystalline cellulose, preferably cross-linked polyvinylpyrrolidone; the flavoring agent includes but is not limited to aspartame, acesulfame potassium, and oligosaccharides; the wetting agent includes but is not limited to hydroxypropyl cellulose, water, ethanol, and polyvinyl alcohol; the lubricant includes but is not limited to stearic acid, sodium stearyl fumarate, magnesium stearate, talc, sodium lauryl sulfate, and colloidal silicon dioxide; the coating material includes but is not limited to ethyl cellulose, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, and cellulose acetate, preferably triacetate.

[0009] Further, the lubricant includes an internal lubricant and an external lubricant.

[0010] Furthermore, the internal lubricant includes sodium stearyl fumarate, which can be purchased from Riedenmeier (Shanghai) Fiber Trading Co., Ltd.; the external lubricant includes magnesium stearate and colloidal silicon dioxide, wherein the colloidal silicon dioxide is purchased from Evonik Operations GmbH.

[0011] Furthermore, the gefapiroxen film-coated tablets contain 5%-20% gefapiroxen citrate, 30-75% filler, 10-35% disintegrant, 0.15-2.0% flavoring agent, 0.5-5% lubricant, and 1-10% coating material.

[0012] Furthermore, the preparation method of the gefapixel film-coated tablets is as follows: (1) The gefapiroxine or its salt, filler, disintegrant and internal lubricant were mixed and granulated using a wet granulator, wherein the stirring speed was 220 rpm and the shear speed was 1500 rpm; (2) uniformly mixing the prepared granules with additional auxiliary materials including an external lubricant; (3) Use Φ10 shallow concave stamping sheet; (4) Prepare the coating liquid, stir it with a stirring paddle for 30 minutes, and pass it through a 100-mesh sieve for coating. The material temperature should be 30-60°C, the spray speed should be 1.0-10.0rpm, and the air volume should be 20-60m 3 / h.

[0013] Furthermore, the amount of the wetting agent used in the wet granulation process is 20%-60% by weight of the added material, preferably 20%-50%, more preferably 20%-40%.

[0014] Embodiment 1 composition percentage Gefapixen citrate 10% D-Mannitol 50% Microcrystalline Cellulose 18% Oligosaccharides 0.5% Crospovidone 13% Purified water 30% of added materials Sodium stearyl fumarate 2% Colloidal Silica 0.5% Magnesium Stearate 1% Film coating premix 5% Preparation process (1) The gefapiroxine or its salt, filler, disintegrant and internal lubricant were mixed and granulated using a wet granulator, wherein the stirring speed was 220 rpm and the shear speed was 1500 rpm; (2) uniformly mixing the obtained particles with additional auxiliary materials including an external lubricant; (3) Use Φ10 shallow concave stamping sheet; (4) Prepare the coating liquid, stir it with a stirring paddle for 30 minutes, and pass it through a 100-mesh sieve for coating. The material temperature should be 30-60°C, the spray speed should be 1.0-10.0rpm, and the air volume should be 20-60m 3 / h.

[0015] Embodiment 2 composition percentage Gefapixen citrate 10% D-Mannitol 50% Microcrystalline Cellulose 17.5% Aspartame 1% Crospovidone 13% Purified water 40% of added materials Sodium stearyl fumarate 2% Colloidal Silica 0.5% Stearic acid 1% Film coating premix 5% Preparation process (1) The gefapiroxine or its salt, filler, disintegrant and internal lubricant were mixed and granulated using a wet granulator, wherein the stirring speed was 220 rpm and the shear speed was 1500 rpm; (2) uniformly mixing the obtained particles with additional auxiliary materials including an external lubricant; (3) Use Φ10 shallow concave stamping sheet; (4) Prepare the coating liquid, stir it with a stirring paddle for 30 minutes, and pass it through a 100-mesh sieve for coating. The material temperature should be 30-60°C, the spray speed should be 1.0-10.0rpm, and the air volume should be 20-60m 3 / h.

[0016] Embodiment 3 composition percentage Gefapixen citrate 10% D-Mannitol 50% Microcrystalline Cellulose 17.5% Acesulfame K 1% Crospovidone 13% Purified water 30% of added materials Sodium stearyl fumarate 2% Colloidal Silica 0.5% talcum powder 1% Film coating premix 5% Preparation process (1) The gefapiroxine or its salt, filler, disintegrant and internal lubricant were mixed and granulated using a wet granulator, wherein the stirring speed was 220 rpm and the shear speed was 1500 rpm; (2) uniformly mixing the obtained particles with additional auxiliary materials including an external lubricant; (3) Use Φ10 shallow concave stamping sheet; (4) Prepare the coating liquid, stir it with a stirring paddle for 30 minutes, and pass it through a 100-mesh sieve for coating. The material temperature should be 30-60°C, the spray speed should be 1.0-10.0rpm, and the air volume should be 20-60m 3 / h.

[0017] Comparative Example 1 composition percentage Gefapixen citrate 10% D-Mannitol 50% Microcrystalline Cellulose 18% Oligosaccharides 0.5% Croscarmellose Sodium 13% Purified water 30% of added materials Sodium stearyl fumarate 2% Colloidal Silica 0.5% Magnesium Stearate 1% Film coating premix 5% Preparation process (1) The gefapiroxine or its salt, filler, disintegrant and internal lubricant were mixed and granulated using a wet granulator, wherein the stirring speed was 220 rpm and the shear speed was 1500 rpm; (2) uniformly mixing the obtained particles with additional auxiliary materials including an external lubricant; (3) Use Φ10 shallow concave stamping sheet; (4) Prepare the coating liquid, stir it with a stirring paddle for 30 minutes, and pass it through a 100-mesh sieve for coating. The material temperature should be 30-60°C, the spray speed should be 1.0-10.0rpm, and the air volume should be 20-60m 3 / h.

[0018] Comparative Example 2 composition percentage Gefapixen citrate 10% D-Mannitol 50% Microcrystalline Cellulose 27% Oligosaccharides 0.5% Croscarmellose Sodium 4% Purified water 30% of added materials Sodium stearyl fumarate 2% Colloidal Silica 0.5% Magnesium Stearate 1% Film coating premix 5% Preparation process (1) The gefapiroxine or its salt, filler, disintegrant and internal lubricant were mixed and granulated using a wet granulator, wherein the stirring speed was 220 rpm and the shear speed was 1500 rpm; (2) uniformly mixing the obtained particles with additional auxiliary materials including an external lubricant; (3) Use Φ10 shallow concave stamping sheet; (4) Prepare the coating liquid, stir it with a stirring paddle for 30 minutes, and pass it through a 100-mesh sieve for coating. The material temperature should be 30-60°C, the spray speed should be 1.0-10.0rpm, and the air volume should be 20-60m 3 / h.

[0019] The samples prepared in the above examples were subjected to dissolution testing in the main medium of water + 0.5% SDS medium at 50 rpm. The results are as follows: Time (min) Embodiment 1 Embodiment 2 Embodiment 3 Comparative Example 1 Comparative Example 2 5 47.63% 46.60% 48.97% 36.64% 38.57% 10 91.92% 92.92% 90.35% 65.96% 71.14% 15 97.22% 99.54% 92.22% 79.02% 84.15% 20 98.10% 100.01% 94.34% 85.42% 91.10% 30 96.90% 100.18% 95.62% 90.78% 94.97% 45 98.67% 100.60% 96.30% 93.87% 98.93% 60 97.30% 100.80% 96.57% 95.16% 99.60% 90 98.10% 101.56% 96.45% 97.01% 101.60% It can be seen from the above test results that the dissolution rate of the drugs in Examples 1-3 reached more than 85% in 15 minutes, which is a very rapid dissolution, while the drugs in Comparative Examples 1-2 did not achieve a very rapid dissolution. According to the content determination method, the samples prepared in the above embodiment were placed under 40°C, RH 75% and 25°C, RH 60% for three months, and the samples were tested for related substances, content and dissolution. The results are as follows: Related substances (%) Detection items Embodiment 1 Embodiment 2 Embodiment 3 Comparative Example 1 Comparative Example 2 Day 0 0.31 0.29 0.35 0.40 0.39 Accelerate March 0.40 0.41 0.43 0.61 0.63 Long March 0.33 0.31 0.35 0.55 0.52 Content (%) Investigation Detection items Embodiment 1 Embodiment 2 Embodiment 3 Comparative Example 1 Comparative Example 2 Day 0 100.1 100.3 99.9 100.1 99.9 Accelerate March 99.9 98.8 97.9 97.3 96.3 Long March 100.1 100.0 99.8 98.1 97.5 Accelerated March sample dissolution test results Time (min) Embodiment 1 Embodiment 2 Embodiment 3 Comparative Example 1 Comparative Example 2 5 45.18% 49.97% 40.42% 37.52% 44.33% 10 88.33% 87.35% 90.03% 59.74% 65.29% 15 95.13% 92.22% 93.15% 70.04% 74.24% 20 96.52% 94.34% 95.80% 87.08% 85.42% 30 94.88% 95.62% 96.65% 90.31% 87.37% 45 96.42% 96.30% 97.68% 92.64% 91.60% 60 97.05% 96.57% 98.08% 94.15% 93.28% 90 98.28% 96.45% 98.61% 94.93% 96.34% Long-term three-month sample dissolution test results Time (min) Embodiment 1 Embodiment 2 Embodiment 3 Comparative Example 1 Comparative Example 2 5 48.43% 48.36% 45.36% 38.57% 43.52% 10 90.51% 90.66% 89.95% 71.14% 67.16% 15 96.41% 96.48% 92.74% 79.15% 78.98% 20 96.87% 96.37% 95.66% 83.10% 82.97% 30 97.12% 98.13% 96.38% 87.97% 86.49% 45 97.59% 98.54% 97.57% 92.93% 91.26% 60 98.35% 98.82% 97.96% 94.60% 94.09% 90 98.45% 98.72% 98.29% 96.26% 97.75% It can be seen from the above test results that the samples of Examples 1-3 are relatively stable, while the related substances of Comparative Example 1-2 increase greatly under accelerated conditions, the content decreases slightly, and the stability is poor. In summary, the gefapixel film-coated tablets of the present invention have stable process, qualified content and good quality. The above embodiments are intended to illustrate the present invention, not to limit the present invention. Any solution that is a simple transformation of the present invention belongs to the protection scope of the present invention.

Claims

1. A gefapiroxen film-coated tablet and a preparation method thereof, comprising gefapiroxen or its salt, a filler, a disintegrant, a flavoring agent, a wetting agent, a lubricant and a coating powder, granulated by a wet granulation process, and then compressed into tablets and coated.

2. The gefapiroxen film-coated tablet according to claim 1, characterized in that: The gefapiroxen salts include, but are not limited to, citrate, succinate, lactate, and oxalate.

3. The gefapiroxen film-coated tablet according to claim 1, characterized in that: The filler includes one or two of D-mannitol, lactose, microcrystalline cellulose, and corn starch; the disintegrant includes but is not limited to cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and microcrystalline cellulose; the flavoring agent includes but is not limited to aspartame, acesulfame potassium, and oligosaccharides; the wetting agent includes but is not limited to hydroxypropyl cellulose, water, ethanol, and polyvinyl alcohol; the lubricant includes but is not limited to stearic acid, sodium stearyl fumarate, magnesium stearate, talc, sodium lauryl sulfate, and colloidal silicon dioxide; the coating material includes but is not limited to ethyl cellulose, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, and cellulose acetate.

4. The gefapixel film-coated tablet according to claim 1, wherein the lubricant comprises an internal lubricant and an external lubricant.

5. The gefapixen film-coated tablet according to claim 1, wherein the internal lubricant comprises sodium stearate, which can be purchased from Riedenmeier (Shanghai) Fiber Trading Co., Ltd.; and the external lubricant comprises colloidal silicon dioxide, wherein the colloidal silicon dioxide is purchased from Evonik Operations GmbH.

6. The gefapixen film-coated tablets according to claim 1, wherein the prescription percentage composition is: 。 7. The gefapiroxen film-coated tablet according to claim 1, wherein the preparation method is as follows: (1) The gefapiroxine or its salt, filler, disintegrant and internal lubricant were mixed and granulated using a wet granulator, wherein the stirring speed was 220 rpm and the shear speed was 1500 rpm; (2) uniformly mixing the prepared granules with additional auxiliary materials including an external lubricant; (3) Use Φ10 shallow concave stamping sheet; (4) Prepare the coating liquid, stir it with a stirring paddle for 30 minutes, and pass it through a 100-mesh sieve for coating. The material temperature should be 30-60°C, the spray speed should be 1.0-10.0rpm, and the air volume should be 20-60m 3 / h.

8. The gefapixen film-coated tablet according to claims 1-7, wherein the additional excipients may contain 0-15% microcrystalline cellulose or no microcrystalline cellulose.

9. The gefapixen film-coated tablets according to claims 1-8, wherein the amount of the wetting agent added is 20%-60% by weight of the added material.