Perampanel pharmaceutical composition and preparation thereof

Abstract

The invention belongs to the technical field of perampanel medicines, and particularly relates to a perampanel medicine composition and a preparation thereof. The perampanel pharmaceutical composition provided by the invention comprises perampanel, Tween 80, a flavoring agent, a plasticizer and a film forming material, the pharmaceutical preparation of the perampanel pharmaceutical composition is a perampanel oral soluble film, and the preparation method of the perampanel oral soluble film comprises the following steps: mixing perampanel, first Tween 80 and an ethanol aqueous solution, performing vacuum freeze drying, and crushing to obtain freeze-dried powder; heating the freeze-dried powder to 20-30 DEG C, performing vacuum freeze-drying, and crushing to obtain secondary freeze-dried powder; mixing second Tween 80 with water, adding the secondary freeze-dried powder, a flavoring agent, a plasticizer and a film-forming material, and stirring to obtain slurry; and carrying out vacuum defoaming on the slurry, then coating a base material with the slurry, and drying to obtain the perampanel oral soluble film. The oral soluble film provided by the invention has the advantages of excellent content uniformity and stability, high dissolution rate and good flexibility.

Description

Technical Field

[0001] The invention belongs to the technical field of perampanel drugs, and specifically relates to a perampanel drug composition and a preparation thereof. Background Art

[0002] Perampanel (CAS No. 380917-97-5) is a highly selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptor antagonist. It reduces neuronal overexcitation by non-competitively binding to AMPA receptors, thereby preventing and treating epilepsy.

[0003] Currently, most of the dosage forms of Perampanel on the market are Perampanel tablets. Perampanel tablets have many advantages, such as easy to carry and transport tablet dosage forms, accurate dosage, and the surface of the tablets is generally coated for protection, and light, air, moisture, etc. have little effect on them. However, Perampanel tablets also have their disadvantages. One of the biggest disadvantages is that oral administration is inconvenient, and the user needs to swallow it and take it with water. Therefore, the researchers used it as an orodispersible film, that is, the Perampanel orodispersible film. The orodispersible film has the characteristics of instant dissolution on the tongue and no need to take it with water. At the same time, compared with dosage forms such as oral suspensions, it is more convenient to carry and store.

[0004] However, perampanel is hydrophobic and has low solubility in water, and the preparation process of the orodispersible film requires the participation of water, which makes the content uniformity of the prepared orodispersible film poor, thereby affecting the stability of the orodispersible film. In order to solve the above problems, researchers generally add surfactants during the preparation process of the orodispersible film to increase the water-soluble effect of perampanel. Tween 80, as a non-ionic surfactant, has good solubility and can be dissolved not only in water but also in organic solvents such as ethanol. At the same time, it has good stability to acids, alkalis and salts at room temperature and is widely used in food, cosmetics, medicine and other fields. However, researchers found that directly adding Tween 80 as a surfactant still has limited effect on the improvement of the content uniformity and stability of the orodispersible film. Summary of the invention

[0005] Therefore, the technical problem to be solved by the present invention is to overcome the defect that Tween 80 is directly added as a surfactant in the preparation process of perampanel orodispersible film, which has limited effect on the uniformity and stability of the content of the orodispersible film, and further provide a perampanel pharmaceutical composition and a preparation thereof, and further provide a method for preparing the perampanel orodispersible film.

[0006] In order to solve the above problems, the scheme of the present invention is as follows:

[0007] A perampanel pharmaceutical composition comprises perampanel, Tween 80, a flavoring agent, a plasticizer and a film-forming material.

[0008] The present invention also provides a perampanel pharmaceutical preparation, which comprises the perampanel pharmaceutical composition described above.

[0009] Optionally, the pharmaceutical preparation is a perampanel orosoluble film.

[0010] The present invention also provides a method for preparing a perampanel orodispersible film, comprising the following steps:

[0011] 1) mixing perampanel, the first Tween 80 and an ethanol aqueous solution, and then performing vacuum freeze drying and crushing to obtain a freeze-dried powder;

[0012] 2) heating the freeze-dried powder to 20-30° C., and then freeze-drying and crushing the freeze-dried powder again to obtain a secondary freeze-dried powder;

[0013] 3) mixing the second Tween 80 with water, and then adding the secondary freeze-dried powder prepared in step 2), a flavoring agent, a plasticizer, and a film-forming material, and stirring to obtain a slurry;

[0014] 4) vacuum degassing the slurry, then coating the degassing slurry on a base material, and drying to obtain the perampanel orosoluble film.

[0015] Preferably, the mass ratio of the perampanel, the first Tween 80, the second Tween 80, the flavoring agent, the plasticizer, the film-forming material and water is 1: (0.1-0.2): (0.05-0.13): (0.04-0.2): (1.0-2.2): (4.2-4.8): (28-35).

[0016] Preferably, the mass ratio of the perampanel, the first Tween 80, the second Tween 80, the flavoring agent, the plasticizer, the film-forming material and water is 1:0.15:0.1:0.1:1.2:4.5:30.

[0017] Preferably, in step 1), the vacuum freeze drying temperature is -50°C to -65°C, the vacuum freeze drying time is 10-30h, and the vacuum degree is 10-20Pa;

[0018] In step 2), the vacuum freeze drying temperature is -50°C to -65°C, the vacuum freeze drying time is 10-30h, and the vacuum degree is 10-20Pa.

[0019] Preferably, the particle size D90 of the perampanel is 5-12 μm;

[0020] The mass ratio of perampanel to the ethanol aqueous solution is 1:10-20, and the mass fraction of ethanol in the ethanol aqueous solution is 15-30%;

[0021] In step 2), the heating rate is 5-10°C / min;

[0022] In step 3), the stirring speed is 1000-2000 rpm and the stirring time is 20-40 min.

[0023] Preferably, the drying in step 4) is vacuum drying, the vacuum drying temperature is 60-70° C., and the vacuum drying time is 20-60 min;

[0024] The base material is a PET release film;

[0025] Step 4) also includes the steps of cutting and packaging the film obtained after drying.

[0026] Preferably, the flavoring agent is selected from at least one of sucralose, acesulfame potassium, and saccharin sodium;

[0027] The plasticizer is selected from at least one of glycerol, sorbitol, and polyethylene glycol 400;

[0028] The film-forming material is selected from at least one of xanthan gum, polyvinyl alcohol, hydroxypropyl methylcellulose and gelatin.

[0029] The technical solution of the present invention has the following advantages:

[0030] The preparation method of the perampanel orosoluble film provided by the present invention comprises the following steps: firstly, perampanel, part of Tween 80 and an ethanol aqueous solution are mixed, and then the mixture is subjected to vacuum freeze drying; through vacuum freeze drying, perampanel and Tween 80 are mixed together in a solid state; then the freeze-dried powder is heated; during the heating process, Tween 80 gradually melts and adheres to the surface of perampanel; then vacuum freeze drying is performed again to obtain a secondary freeze-dried powder; finally, the remaining Tween 80, water, the secondary freeze-dried powder, a flavoring agent, a plasticizer and a film-forming material are mixed and stirred to obtain a slurry; the slurry is subjected to vacuum degassing, coating and drying to obtain the perampanel orosoluble film. The invention firstly mixes part of Tween 80 with perampanel and ethanol aqueous solution before adding perampanel, and then performs vacuum freeze drying. Through vacuum freeze drying, perampanel and Tween 80 are mixed together in a solid state to complete preliminary solid-state mixing. Then, the temperature is raised again. During the heating process, Tween 80 gradually melts and adheres to the surface of perampanel. Then, vacuum freeze drying is performed again to coat Tween 80 on the surface of perampanel. Finally, the formed secondary freeze-dried powder is mixed with other raw materials. The orally dissolving film prepared by the method has excellent content uniformity and stability, high dissolution and good flexibility.

[0031] The orally dissolving film provided by the invention has good stability, a smooth surface, uniform drug loading, a simple preparation process, and is suitable for industrial production. DETAILED DESCRIPTION

[0032] The following examples are provided for further understanding of the present invention, but are not intended to limit the best mode of implementation and do not limit the scope of protection of the present invention.

[0033] The experimental steps or conditions not specified in the following embodiments of the present invention can be implemented according to the conventional experimental steps and conditions used in the existing literature in the field. The reagents or instruments used without specifying the manufacturer are all conventional reagents or instruments that can be purchased commercially.

[0034] Example 1

[0035] This embodiment provides a method for preparing a perampanel orodispersible film, comprising the following steps:

[0036] 1) mixing 1 g of perampanel (particle size D90: 12 μm), 0.15 g of Tween 80 and 15 g of ethanol aqueous solution (ethanol mass fraction: 20%), and then performing vacuum freeze drying at a vacuum freeze drying temperature of -55°C, a vacuum freeze drying time of 10 h, a vacuum degree of 20 Pa, and pulverizing to obtain a freeze-dried powder;

[0037] 2) heating the freeze-dried powder to 25° C. at a heating rate of 5° C. / min, and then freeze-drying it again under vacuum at a temperature of −55° C., a vacuum freeze-drying time of 10 h, and a vacuum degree of 20 Pa, and crushing to obtain a secondary freeze-dried powder;

[0038] 3) 0.1 g of Tween 80 and 30 g of water were mixed, and then the secondary freeze-dried powder prepared in step 2), 0.1 g of sucralose, 1.2 g of glycerol, and 4.5 g of hydroxypropyl methylcellulose were added, and stirred at a stirring speed of 1500 rpm for 30 min to obtain a slurry;

[0039] 4) vacuum degassing the slurry in a vacuum degassing mixer, coating the degassing slurry on a PET release film, vacuum drying at 65° C. for 30 min, and then cutting and packaging the dried film to obtain the perampanel orosoluble film.

[0040] Example 2

[0041] This embodiment provides a method for preparing a perampanel orodispersible film, comprising the following steps:

[0042] 1) mixing 1 g of perampanel (particle size D90: 12 μm), 0.15 g of Tween 80 and 15 g of ethanol aqueous solution (ethanol mass fraction: 25%), and then performing vacuum freeze drying at a vacuum freeze drying temperature of -55°C, a vacuum freeze drying time of 15 h, a vacuum degree of 15 Pa, and pulverizing to obtain a freeze-dried powder;

[0043] 2) heating the freeze-dried powder to 25° C. at a heating rate of 10° C. / min, and then freeze-drying it again under vacuum at a temperature of −55° C., a vacuum freeze-drying time of 15 h, and a vacuum degree of 15 Pa, and crushing to obtain a secondary freeze-dried powder;

[0044] 3) 0.1 g of Tween 80 and 30 g of water were mixed, and then the secondary freeze-dried powder prepared in step 2), 0.1 g of sucralose, 1.2 g of glycerol, and 4.5 g of hydroxypropyl methylcellulose were added, and stirred at a stirring speed of 1500 rpm for 30 min to obtain a slurry;

[0045] 4) vacuum degassing the slurry in a vacuum degassing mixer, coating the degassing slurry on a PET release film, vacuum drying at 65° C. for 30 min, and then cutting and packaging the dried film to obtain the perampanel orosoluble film.

[0046] Example 3

[0047] This embodiment provides a method for preparing a perampanel orodispersible film, comprising the following steps:

[0048] 1) mixing 1 g of perampanel (particle size D90: 12 μm), 0.15 g of Tween 80 and 15 g of ethanol aqueous solution (ethanol mass fraction: 25%), and then performing vacuum freeze drying at a vacuum freeze drying temperature of -60°C, a vacuum freeze drying time of 10 h, a vacuum degree of 15 Pa, and pulverizing to obtain a freeze-dried powder;

[0049] 2) heating the freeze-dried powder to 20° C. at a heating rate of 8° C. / min, and then freeze-drying it again under vacuum at a temperature of −60° C., a vacuum freeze-drying time of 10 h, and a vacuum degree of 15 Pa, and crushing to obtain a secondary freeze-dried powder;

[0050] 3) 0.1 g of Tween 80 and 30 g of water were mixed, and then the secondary freeze-dried powder prepared in step 2), 0.1 g of sucralose, 1.2 g of glycerol, and 4.5 g of hydroxypropyl methylcellulose were added, and stirred at a stirring speed of 1800 rpm for 40 min to obtain a slurry;

[0051] 4) vacuum degassing the slurry in a vacuum degassing mixer, coating the degassing slurry on a PET release film, vacuum drying at 65° C. for 30 min, and then cutting and packaging the dried film to obtain the perampanel orosoluble film.

[0052] Example 4

[0053] This embodiment provides a method for preparing a perampanel orodispersible film, comprising the following steps:

[0054] 1) mixing 1 g of perampanel (particle size D90: 12 μm), 0.15 g of Tween 80 and 15 g of ethanol aqueous solution (ethanol mass fraction: 25%), and then performing vacuum freeze drying at a vacuum freeze drying temperature of -65°C, a vacuum freeze drying time of 20 h, a vacuum degree of 15 Pa, and pulverizing to obtain a freeze-dried powder;

[0055] 2) heating the freeze-dried powder to 20° C. at a heating rate of 8° C. / min, and then freeze-drying it again under vacuum at a temperature of −65° C., a vacuum freeze-drying time of 20 h, and a vacuum degree of 15 Pa, and crushing to obtain a secondary freeze-dried powder;

[0056] 3) 0.1 g of Tween 80 and 30 g of water were mixed, and then the secondary freeze-dried powder prepared in step 2) was added, 0.1 g of sucralose, 1.2 g of glycerol, and 4.5 g of hydroxypropyl methylcellulose were stirred at a stirring speed of 2000 rpm for 40 min to obtain a slurry;

[0057] 4) vacuum degassing the slurry in a vacuum degassing mixer, coating the degassing slurry on a PET release film, vacuum drying at 65° C. for 40 min, and then cutting and packaging the dried film to obtain the perampanel orosoluble film.

[0058] Comparative Example 1

[0059] This comparative example provides a method for preparing a perampanel orodispersible film, comprising the following steps:

[0060] 1) 1 g of perampanel (particle size D90: 12 μm), 0.25 g of Tween 80 and 30 g of water were mixed, and then 0.1 g of sucralose, 1.2 g of glycerol and 4.5 g of hydroxypropyl methylcellulose were added, and stirred at a stirring speed of 1500 rpm for 30 min to obtain a slurry;

[0061] 2) vacuum degassing the slurry in a vacuum degassing mixer, coating the degassing slurry on a PET release film, vacuum drying at 65° C. for 30 min, and then cutting and packaging the dried film to obtain the perampanel orosoluble film.

[0062] Comparative Example 2

[0063] This comparative example provides a method for preparing a perampanel orodispersible film, comprising the following steps:

[0064] 1) mixing 1 g of perampanel (particle size D90: 12 μm), 0.15 g of Tween 80 and 15 g of ethanol aqueous solution (ethanol mass fraction: 20%), and then performing vacuum freeze drying at a vacuum freeze drying temperature of -55°C, a vacuum freeze drying time of 10 h, a vacuum degree of 20 Pa, and pulverizing to obtain a freeze-dried powder;

[0065] 2) 0.1 g of Tween 80 and 30 g of water were mixed, and then the freeze-dried powder prepared in step 1), 0.1 g of sucralose, 1.2 g of glycerol, and 4.5 g of hydroxypropyl methylcellulose were added, and stirred at a stirring speed of 1500 rpm for 30 min to obtain a slurry;

[0066] 3) vacuum degassing the slurry in a vacuum degassing mixer, coating the degassing slurry on a PET release film, vacuum drying at 65° C. for 30 min, and then cutting and packaging the dried film to obtain the perampanel orosoluble film.

[0067] Test Example 1

[0068] The film-forming effect, flexibility, dissolution and content uniformity of the orally dissolving films prepared in the above embodiments and comparative examples were tested, wherein the content uniformity was tested with reference to the general rule "0941 Content Uniformity Test Method" of the 2020 edition of the Chinese Pharmacopoeia, and the test results are shown in Table 1.

[0069] Table 1

[0070]

[0071]

[0072] Test Example 2

[0073] The orally dissolving film samples prepared in Example 1 and Comparative Examples 1-2 were placed at 40° C. and 75% RH for 6 months and then tested for related substances. The test results are shown in Table 2.

[0074] Table 2

[0075]

[0076] Obviously, for ordinary technicians in the field, other modifications can be made based on the above embodiments, and the obvious modifications brought about by these modifications are still within the protection scope of the present invention.

Claims

1. A perampanel pharmaceutical composition, characterized in that: The perampanel pharmaceutical composition comprises perampanel, Tween 80, a flavoring agent, a plasticizer and a film-forming material.

2. A perampanel pharmaceutical preparation, characterized in that: The pharmaceutical preparation comprises the perampanel pharmaceutical composition according to claim 1.

3. The perampanel pharmaceutical preparation according to claim 1, characterized in that The pharmaceutical preparation is a perampanel orosoluble film.

4. A method for preparing a perampanel orodispersible film, characterized in that: The steps include: 1) mixing perampanel, the first Tween 80 and an ethanol aqueous solution, and then performing vacuum freeze drying and crushing to obtain a freeze-dried powder; 2) heating the freeze-dried powder to 20-30° C., and then freeze-drying and crushing the freeze-dried powder again to obtain a secondary freeze-dried powder; 3) mixing the second Tween 80 with water, and then adding the secondary freeze-dried powder prepared in step 2), a flavoring agent, a plasticizer, and a film-forming material, and stirring to obtain a slurry; 4) vacuum degassing the slurry, then coating the degassing slurry on a base material, and drying to obtain the perampanel orosoluble film.

5. The method for preparing the perampanel orosoluble film according to claim 4, characterized in that: The mass ratio of the perampanel, the first Tween 80, the second Tween 80, the flavoring agent, the plasticizer, the film-forming material and water is 1: (0.1-0.2): (0.05-0.13): (0.04-0.2): (1.0-2.2): (4.2-4.8): (28-35).

6. The method for preparing the perampanel orosoluble film according to claim 4, characterized in that: The mass ratio of the perampanel, the first Tween 80, the second Tween 80, the flavoring agent, the plasticizer, the film-forming material and water is 1:0.15:0.1:0.1:1.2:4.5:

30.

7. The method for preparing the perampanel orosoluble film according to claim 4, characterized in that: In step 1), the vacuum freeze drying temperature is -50°C to -65°C, the vacuum freeze drying time is 10-30h, and the vacuum degree is 10-20Pa; In step 2), the vacuum freeze drying temperature is -50°C to -65°C, the vacuum freeze drying time is 10-30h, and the vacuum degree is 10-20Pa.

8. The method for preparing the perampanel orosoluble film according to claim 4, characterized in that: The particle size D90 of the perampanel is 5-12 μm; The mass ratio of perampanel to the ethanol aqueous solution is 1:10-20, and the mass fraction of ethanol in the ethanol aqueous solution is 15-30%; In step 2), the heating rate is 5-10°C / min; In step 3), the stirring speed is 1000-2000 rpm and the stirring time is 20-40 min.

9. The method for preparing the perampanel orosoluble film according to claim 4, characterized in that: The drying in step 4) is vacuum drying, the vacuum drying temperature is 60-70° C., and the vacuum drying time is 20-60 min; The base material is a PET release film; Step 4) also includes the steps of cutting and packaging the film obtained after drying.

10. The method for preparing the perampanel orosoluble film according to claim 4, characterized in that: The flavoring agent is selected from at least one of sucralose, acesulfame potassium, and saccharin sodium; The plasticizer is selected from at least one of glycerol, sorbitol, and polyethylene glycol 400; The film-forming material is selected from at least one of xanthan gum, polyvinyl alcohol, hydroxypropyl methylcellulose and gelatin.

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