A perampanel oral suspension and its preparation method

Abstract

This invention discloses a perampanel oral suspension and its preparation method. The preparation method of this invention includes the following steps: S1, adding microcrystalline cellulose sodium carboxymethyl cellulose co-treatment material to water for homogenization to obtain a first dispersion; S2, adding sorbitol, an antibacterial agent, and a pH adjuster to the first dispersion to obtain a second dispersion; S3, pulverizing perampanel and sieving it to control the particle size D. 90 The sample size is 10–15 μm; S4, the perampanel obtained in step S3 is subjected to antistatic treatment; S5, the perampanel treated in step S4, defoamer, and polyoxyethylene hydrogenated castor oil are added to the second dispersion to obtain the third dispersion; S6, water is added to the third dispersion to bring it to a final volume, and homogenization is performed to obtain the perampanel oral suspension. This method can significantly improve the dissolution rate, long-term stability, and control level of drug-related substances at day 0, and improve the uniformity of content.

Description

Technical Field

[0001] This invention belongs to the field of oral suspension manufacturing technology, specifically relating to a perampanel oral suspension and its preparation method. Background Technology

[0002] Perampanel is a selective, non-competitive AMPA (α-amino-3-hydroxy-5-methyl-4-isozolium acid) receptor antagonist that effectively controls partial and generalized tonic-clonic seizures by inhibiting glutamate-mediated neuronal overexcitation. Since its approval in tablet form (trade name: Fycompa®) in 2012, the use of perampanel has been limited by the unique characteristics of epilepsy, including swallowing difficulties, the high cost of solid dispersion technology, and cumbersome administration procedures during seizures.

[0003] Perampanel is a highly hydrophobic and poorly soluble drug, prone to static electricity. Its poor solubility leads to low oral bioavailability, and traditional formulation technologies struggle to achieve rapid dissolution and stable dispersion. After air jet milling, it is highly susceptible to adsorption and agglomeration, resulting in non-uniformity of the active pharmaceutical ingredient (API) content in the formulation. Existing technology CN119523951A, a perampanel pharmaceutical composition and its formulation, mentions preparing perampanel as an orally disintegrating film, but the processing of the API using only air jet milling fails to address the problem of electrostatic adsorption after milling, thus failing to guarantee the uniformity of the API content in the formulation. CN117919169A, a perampanel nasal delivery formulation, requires specialized commercial production equipment for orally disintegrating films and nasal sprays, resulting in high costs and significantly limiting commercial production capacity, failing to meet patients' actual payment needs and national medical insurance strategies. CN119015244A contains perampanel... The pharmaceutical composition mentions a method to improve the stability of perampanel, but this method is still a tablet dosage form and fails to solve the problem of difficulty in swallowing tablets during epileptic seizures; CN118615253A describes a perampanel microsphere based on a re-emulsification process and its preparation method, but because its main design direction is long-acting formulation, it cannot rationally guide medication according to the characteristics of epileptic seizures; CN116650483A describes a perampanel composition, mentioning a method for preparing a suspension using poloxamer 188 and the phenomenon of easy bubble generation during the preparation process, but does not propose a solution to remove the bubbles, and this patent ultimately prepares an orally disintegrating film from the suspension.

[0004] To address the aforementioned issues, existing technologies have not fundamentally solved the following core problems: Electrostatic adsorption of active pharmaceutical ingredients (APIs): Using only air jet milling as the API processing method cannot guarantee the uniformity of API content in the formulation; Insufficient dissolution rate: In CN107536805A, the existing dry suspension of perampanel and its preparation method shows a dissolution rate of only 74.0%–90.5% in 0.1 mol / L hydrochloric acid within 15 minutes, which is insufficient to meet the requirement for rapid onset of action; Long-term stability defects: Accelerated testing (30℃, RH 35%) shows a significant increase in total impurities within 6 months, and a significant decrease in dissolution rate; Industrial production bottlenecks: Solid dispersion technology, orally disintegrating film formulations, and nasal spray formulations have high equipment requirements, making large-scale application difficult. High precision control of process parameters leads to batch-to-batch quality fluctuations and high production costs. Therefore, there is an urgent need to provide a perampanel oral suspension with uniform content, rapid dissolution, long-term stability, simple preparation process, and improved patient compliance. Summary of the Invention

[0005] To address at least one of the aforementioned technical problems, the present invention aims to provide a method for preparing perampanel oral suspension. This method can significantly improve the dissolution rate, long-term stability, and control level of drug-related substances at day 0, as well as improve content uniformity. It is suitable for large-scale production and has better application prospects.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides a method for preparing a perampanel oral suspension, wherein the raw materials for preparing the perampanel oral suspension include perampanel, a co-treated microcrystalline cellulose sodium carboxymethyl cellulose, polyoxyethylene hydrogenated castor oil, sorbitol, a pH adjuster, an antibacterial agent, an antifoaming agent, and water, and the method comprises the following steps: S1. Add the microcrystalline cellulose sodium carboxymethyl cellulose co-treatment product to water and homogenize it to obtain the first dispersion; S2. Sorbitol, antibacterial agent and pH adjuster are added to the first dispersion to obtain the second dispersion; S3. After pulverizing the perampanel, sieve it to control the particle size D. 90 It is 10–15 μm; S4. Perform static electricity removal treatment on the perampanel obtained after step S3. S5. Add the perampanel, defoamer, and polyoxyethylene hydrogenated castor oil treated in step S4 to the second dispersion to obtain the third dispersion. S6. Add water to the third dispersion to the total volume, and homogenize to obtain the perampanel oral suspension.

[0008] Based on the above technical solutions, this invention, by using the original drug formulation and domestically available raw and excipient materials, improves the dissolution rate of oral suspensions, ensures long-term stability and control of 0-day related substances, and improves content uniformity by optimizing the particle size control of raw materials, the combination of excipients and adjusting the dispersion process. Moreover, this method is highly operable and more practical.

[0009] Regarding the particle size of the raw material, the inventors discovered that by controlling the particle size of perampanel (D... 90 A particle size of 10–15 μm eliminates electrostatic adsorption and agglomeration, achieving good dispersion of the active pharmaceutical ingredient without affecting the dissolution of the formulation, ensuring that the dissolution of this product meets requirements. However, when the particle size is too small or too large and no electrostatic removal treatment is performed, it significantly impacts dissolution and content uniformity, leading to non-compliance with dissolution requirements and poor content uniformity. Therefore, the particle size D of perampanel is crucial. 90 Preferably 10–15 μm, such as 11.6–14.5 μm, 11.6 μm, or 14.5 μm.

[0010] In at least one embodiment of the present invention, the concentration of perampanel in the perampanel oral suspension is 0.05% to 0.1% g / mL, such as 0.05% g / mL; The concentration of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated compound in the perampanel oral suspension is 2.0% to 2.5% g / mL, such as 2.2% g / mL; The concentration of the polyoxyethylene hydrogenated castor oil in the perampanel oral suspension is 0.5% to 1.0% g / mL, such as 0.8% g / mL; The concentration of sorbitol in the perampanel oral suspension is 15%–20% g / mL, such as 18% g / mL; The concentration of the pH adjuster in the perampanel oral suspension is 0.1% to 0.3% g / mL, such as 0.2% g / mL; The concentration of the antibacterial agent in the perampanel oral suspension is 0.1% to 0.2% g / mL, such as 0.12% g / mL; The concentration of the defoamer in the perampanel oral suspension is 0.01% to 0.03% g / mL, such as 0.02% g / mL.

[0011] In other words, the mass-volume percentage (w / v) of each raw material, expressed in g / mL, is as follows: perampanel: 0.05%–0.1%; the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product: 2.0%–2.5%; polyoxyethylene hydrogenated castor oil: 0.5%–1.0%; sorbitol: 15%–20%; pH adjuster: 0.1%–0.3%; antibacterial agent: 0.1%–0.2%; defoamer: 0.01%–0.03%; water: balance to 100%.

[0012] In at least one embodiment of the present invention, the perampanel is in a 3 / 4 hydrate crystal form. The present invention uses the same crystal form as the reference preparation, which is beneficial for subsequent static electricity removal treatment and suspension preparation.

[0013] In at least one embodiment of the present invention, the labeled percentage content of sodium carboxymethyl cellulose in the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is 8% to 13%, such as 11.1%. The labeled percentage content is calculated using the formula: percentage content x labeled amount = (actual measured amount × substance content) / (labeled amount of microcrystalline cellulose sodium carboxymethyl cellulose co-treated product) × 100%. That is, the 8% to 13% indicates that every 100g of labeled microcrystalline cellulose sodium carboxymethyl cellulose co-treated product contains 8 to 13g of sodium carboxymethyl cellulose.

[0014] In at least one embodiment of the present invention, the viscosity range of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is 39–91 mPa·s. The inventors have found that when the viscosity of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is too high, such as 96 mPa·s, the formulation viscosity is too high, resulting in a slow dissolution rate. Conversely, when the viscosity of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is too low, its ability to form a three-dimensional network structure as a suspending agent is insufficient, leading to accelerated particle settling speed, easy irreversible aggregation, and affecting redispersibility and content uniformity. Furthermore, to achieve the same suspending effect, the amount of low-viscosity co-treated product needs to be increased, which contradicts the economics of commercial production. Therefore, in the present invention, the viscosity range of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is selected as 39–91 mPa·s, such as 49–63 mPa·s, 49 mPa·s, or 63 mPa·s.

[0015] In at least one embodiment of the present invention, the defoamer is selected from one or more of simethicone and ethanol.

[0016] In at least one embodiment of the present invention, the polyoxyethylene hydrogenated castor oil is selected from one or more of polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (54) hydrogenated castor oil, and polyoxyethylene (60) hydrogenated castor oil.

[0017] In at least one embodiment of the present invention, the pH adjuster is selected from one or more of anhydrous citric acid and tartaric acid.

[0018] In at least one embodiment of the present invention, the antibacterial agent is selected from one or more of sodium benzoate, potassium sorbate, and ethylparaben.

[0019] In at least one embodiment of the present invention, the homogenization conditions in steps S1 and S6 are as follows: rotation speed 2300–2600 rpm, homogenization time 50–60 min, such as cyclic homogenization at 2600 rpm for 60 min. The inventors have found that the homogenization speed and time directly affect the rheological profile, thixotropic ring, and content uniformity of the formulation. When the homogenization speed and time are too low, such as 2000 rpm for 30 min, the thixotropy and content uniformity are poor; when the homogenization time is too long, such as 90 min, the rheological profile and content uniformity decrease, and the time required is longer. Therefore, to further improve the thixotropy and content uniformity of the formulation, the present invention selects the above-mentioned homogenization conditions. Preferably, the homogenization process uses a pipeline dispersion emulsification pump. Using pipeline homogenization technology can reduce production costs and operational complexity. In step S1, the method further includes a step of continuous stirring for 10–15 min before homogenization. The homogenization method for co-processing microcrystalline cellulose sodium carboxymethyl cellulose and the homogenization method for the liquid after weight determination provided by the present invention can not only effectively complete the dissolution and dispersion of excipients, but also greatly reduce foaming after liquid preparation, shorten the production waiting cycle, and reduce energy consumption in the production workshop.

[0020] In at least one embodiment of the present invention, in step S3, the pulverization is carried out by air jet pulverization and passing through a 40-mesh metal sieve.

[0021] In at least one embodiment of the present invention, in step S4, the absolute value of the electrostatic potential on the surface of perampanel after the electrostatic removal treatment is less than 500V. Preferably, an ionization electrostatic removal channel equipped with an array of ion bars is used, and the treatment time is 5-10 seconds. The electrostatic removal treatment can eliminate agglomeration caused by electrostatic adsorption and improve the uniformity of the oral suspension content.

[0022] In at least one embodiment of the present invention, in step S4, the perampanel is added to the second dispersion in two parts. First, half of the prescribed amount of perampanel, defoamer, and polyoxyethylene hydrogenated castor oil are added and stirred until the polyoxyethylene hydrogenated castor oil is dissolved. Then, the remaining perampanel is added while maintaining the stirring state.

[0023] In this invention, during the final filling process of the preparation method, the liquid medicine is poured into a polyester bottle, capped, and the capped medicine is conveyed to the outer packaging via a conveyor belt.

[0024] In at least one embodiment of the present invention, the water is purified water.

[0025] Secondly, the present invention provides a perampanel oral suspension obtained by any of the preparation methods described above.

[0026] Compared with the prior art, the present invention has the following beneficial effects: This invention, through extensive experimental exploration, optimized raw material pretreatment methods and controlled particle size, excipient combination, and adjusted dispersion processes, significantly reducing the content of related substances in the initial product and improving content uniformity. In 0.1 mol / L hydrochloric acid medium, the dissolution rate is ≥85% within 15 minutes, ensuring rapid onset of action for patients experiencing symptoms. It also improves the long-term stability of the product; in long-term stability tests, there were no significant changes in related substances within 12 months, and the dissolution rate remained ≥95%. The process described in this invention is easy to widely apply. It is ready to use immediately without reconstitution, suitable for children and patients with swallowing difficulties, improving patient compliance. Attached Figure Description

[0027] Figure 1A This is a particle size diagram of the active pharmaceutical ingredient in Example 1.

[0028] Figure 1B The particle size distribution of the active pharmaceutical ingredient in Comparative Example 1 is shown.

[0029] Figure 2 The rheological curves for the aqueous dispersions of microcrystalline cellulose co-treated with sodium carboxymethyl cellulose from Example 1, Comparative Examples 4 and 5 are shown below. The curves are labeled as follows: ┄▲┄: Example 1 (2600 rpm, 60 min), A: 2000.3 Pa / s, A_rel = 400.66 Pa / (s·cm) 2 ); ─▲─:Comparative Example 4 (2000 rpm, 30 min), A: 1793.3 Pa / s, A_rel=358.66 Pa / (s·cm) 2 ); ─△─: Comparative Example 5 (2300 rpm, 90 min), A: 1797.4 Pa / s, A_rel = 359.47 Pa / (s·cm) 2 ).

[0030] Figure 3 The rheological curves for the formulations of Example 1, Comparative Examples 4 and 5 are shown below. The curves are labeled as follows: ─▲─: Example 1 (2600 rpm, 60 min), A: 858.73 Pa / s, A_rel = 171.75 Pa / (s·cm) 2 ); ┄▲┄: Comparative Example 4 (2000 rpm, 30 min), A: 591.1 Pa / s, A_rel = 118.22 Pa / (s·cm) 2); ─○─: Comparative Example 5 (2300 rpm, 90 min), A: 634.5 Pa / s, A_rel = 126.9 Pa / (s·cm) 2 ). Detailed Implementation

[0031] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0032] Unless otherwise specified, the methods used in the following embodiments are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available.

[0033] Example 1: Preparation of perampanel oral suspension I. Prescription The perampanel oral suspension in this embodiment is prepared from the following raw materials, expressed as a percentage by weight (w / v): Perampanel: 0.05%; Microcrystalline cellulose and sodium carboxymethyl cellulose co-treated product: 2.2%; Polyoxyethylene hydrogenated castor oil: 0.8%; Sorbitol: 18%; pH adjuster (anhydrous citric acid): 0.2%; Antibacterial agent (sodium benzoate): 0.12%; Defoamer (simethicone): 0.02%; Purified water: Bring to 100%.

[0034] II. Preparation Method (1) Add microcrystalline cellulose sodium carboxymethyl cellulose co-treatment material (viscosity 63 mPa·s, sodium carboxymethyl cellulose content 11.1%) to purified water, stir continuously for 15 min, and circulate homogenize for 60 min using a pipeline dispersion emulsification pump (speed 2600 rpm) to obtain the first dispersion; (2) Sorbitol, sodium benzoate and anhydrous citric acid were added to the first dispersion. Sorbitol was added sequentially by stirring in the center and the temperature was continuously raised until all the sorbitol was dissolved. After cooling, sodium benzoate and anhydrous citric acid were added to obtain the second dispersion. (3) Add half the prescribed amount of perampanel active pharmaceutical ingredient (API) that has been air-jet pulverized and passed through a 40-mesh metal sieve to the second dispersion. The API is first subjected to ionization and destatic treatment before addition: an ionization and destatic treatment channel equipped with an array of ionizer bars is used, the treatment time is 5–10 s, and the absolute value of the surface electrostatic potential is below ±500V, to eliminate electrostatic adsorption. The perampanel API (3 / 4 hydrate crystal form, particle size D) after the above steps is obtained. 90 14.5μm, Figure 1A Add simethicone and polyoxyethylene (40) hydrogenated castor oil, turn on the center stirrer until the polyoxyethylene (40) hydrogenated castor oil is completely dissolved, and while maintaining the stirring state, add the remaining treated perampanel raw material and continue stirring to obtain the third dispersion; (4) Add purified water to the third dispersion to the total volume, and control the central stirring speed, the transfer pump speed (1100 rpm), and the pipeline dispersion emulsification pump (speed 2600 rpm) to circulate and homogenize for 60 min.

[0035] Example 2: Compared with Example 1, the only difference in this embodiment is that the active pharmaceutical ingredient is processed to a particle size of D. 90 11.6μm.

[0036] Example 3: The only difference between this embodiment and Example 1 is that the viscosity of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated material was adjusted to 49 mPa·s.

[0037] Comparative Example 1 The only difference between this comparative example and Example 1 is that the pretreatment method of the active pharmaceutical ingredient (API) perampanel was adjusted. It was processed using only an air jet mill, without sieving or ionization / static removal, to achieve a particle size of D. 90 5.81μm ( Figure 1B ).

[0038] Comparative Example 2 The only difference between this comparative example and Example 1 is that the pretreatment method of the active pharmaceutical ingredient (API) perampanel was adjusted. It was processed using only an air jet mill, without sieving or ionization / static removal, to achieve a particle size of D. 90 30.9μm.

[0039] Comparative Example 3 The only difference between this comparative example and Example 1 is that the viscosity of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is 96 mPa·s.

[0040] Comparative Example 4 The only difference between this comparative example and Example 1 is that the homogenization method of the microcrystalline cellulose sodium carboxymethyl cellulose co-treatment material and the homogenization parameters of the liquid after gradation are: rotation speed 2000 rpm, homogenization for 30 min.

[0041] Comparative Example 5 The only difference between this comparative example and Example 1 is that the homogenization method of the microcrystalline cellulose sodium carboxymethyl cellulose co-treatment material and the homogenization parameters of the liquid after gradation are: rotation speed 2300 rpm, homogenization for 90 min.

[0042] Performance Test Example 1 Stability tests were conducted on Example 1 and the reference formulation of perampanel oral suspension (specification 340mL:170mg, batch number: 137254, Weiketai®). The related substances, content, viscosity, dissolution curve, and sedimentation volume ratio were compared over a long period of 12M. The results are recorded in the table below.

[0043] The testing methods for each project are as follows: Sedimentation volume ratio: According to Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0123 (Sedimentation volume ratio); Dissolution: Determined according to the method for determination of dissolution and release (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method II, Paddle Method); Content: determined by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512); Related substances: determined by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, 0512); Viscosity: Determined according to the viscosity determination method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0633, Method III); Dissolution profile: determined according to the method for determination of dissolution and release (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method II, Paddle Method).

[0044] Table 1. Performance comparison between Example 1 and the reference formulation

[0045] The comparison results between Experimental Example 1 and the reference preparation in Table 1 show that, after 12 months of long-term storage, all test items of Example 1 met the proposed standards; compared with the results at day 0, there were no significant changes in any test item; overall, the stability trends of Example 1 and the reference preparation were basically consistent under long-term conditions. The dissolution curve similarity factor (f2) of the oral suspension obtained in Example 1 was >50, and the dissolution rate reached over 90% at 15 min, indicating that the in vitro dissolution was consistent with the reference preparation.

[0046] In Example 1 and the reference formulation, after being stored under long-term conditions for 12 months, the dissolution rate in 0.1 mol / L hydrochloric acid medium was greater than 85% within 15 minutes, indicating rapid dissolution. In pH 4.5 medium, the dissolution rate did not reach 50% within 120 minutes, but reached a dissolution plateau at 30 minutes. Compared with the results on day 0, f2 was greater than 50, and the dissolution trend did not change significantly. Moreover, the dissolution trends of the generic formulation and the reference formulation were basically consistent.

[0047] Performance Test Example 2 Examples 1, 2, and Comparative Examples 1 and 2 were prepared into formulations using raw materials with different particle sizes. The viscosity, dissolution curves, sedimentation volume ratios, and content uniformity of the formulations were compared. The results are recorded in the table below.

[0048] The testing methods for each project are as follows: Content uniformity: Take the upper, middle and lower layers of the homogenized solution from the mixing tank, and test them using the same method as the content method [determined by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512)].

[0049] The testing methods for the remaining items are the same as those in Performance Test Example 1.

[0050] Table 2. Comparison results of each item between Examples 1 and 2 and Comparative Examples 1 and 2.

[0051] The comparison results between Example 1 and Comparative Example 1 in Table 2 show that in pH 4.5 and pH 1.0 media, the dissolution of raw material in Comparative Example 1 is significantly faster than that in Example 1, indicating that in acidic media, as the particle size of the active pharmaceutical ingredient (API) decreases, the dissolution of the formulation increases. Similarly, the comparison results of Comparative Example 2 show that in the same medium, as the particle size of the API increases, the dissolution of the formulation decreases. These dissolution results suggest that after air jet milling, the particle size D of the raw material... 90 A particle size below 10 μm or above 15 μm will result in the formulation not meeting dissolution requirements; in the example, the raw material particle size D after passing through a 40-mesh metal sieve is... 90 The particle size was between 10 and 15 μm, and the dissolution profile was consistent with the reference formulation. The results of Examples 1 and 2 indicate that the particle size met the 10–15 μm requirement, and the formulation met the quality requirements.

[0052] In Comparative Example 1, perampanel exhibited significant agglomeration after air jet milling, and showed marked electrostatic adsorption during the mixing process. This resulted in the perampanel easily forming clumps that floated on the liquid surface and tank walls, leading to a higher content of active pharmaceutical ingredient (API) in the upper layer, poor content uniformity, and reduced formulation viscosity. In Comparative Example 2, due to the larger particle size of the raw material, it easily settled to the bottom of the suspension during mixing, resulting in a higher content of API in the lower layer, poor content uniformity, and a lower sedimentation volume ratio, indicating decreased physical stability. In Example 1, the API, after passing through a 40-mesh metal sieve, eliminated electrostatic adsorption. No significant adsorption or agglomeration was observed during the mixing process. After feeding, it dispersed rapidly, and the content uniformity (RSD%) met the requirements. Particle size differences had no significant effect on the viscosity of the formulation.

[0053] Performance Test Example 3 The formulations prepared from microcrystalline cellulose sodium carboxymethyl cellulose co-treated with different viscosities in Examples 1, 3 and Comparative Example 3 were compared in terms of viscosity, dissolution curves and sedimentation volume ratios. The results are recorded in the table below.

[0054] The testing methods for each project are the same as those in Performance Test Example 2.

[0055] Table 3. Comparison results of each item between Example 1, Example 3 and Comparative Example 3.

[0056] The comparison results between Example 1 and Comparative Example 3 in Table 3 show that after using sodium carboxymethyl cellulose microcrystalline cellulose with a viscosity of 96 mPa·s, the viscosity of Comparative Example 3 was significantly higher than that of Example 1, the dissolution rate was slower, and the dissolution curve showed good fitting. There was no significant effect on the sedimentation volume ratio of the formulation. The results of Examples 1 and 3 indicate that the viscosity of the microcrystalline cellulose co-treated with sodium carboxymethyl cellulose meets the requirements of 39–91 mPa·s, and the formulation meets the quality requirements.

[0057] Performance Test Example 4 The rheological curves of the aqueous dispersion, formulation rheological curves, and content uniformity of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product were compared by controlling different homogenization times and rotation speeds in Example 1, Comparative Example 4, and Comparative Example 5. The results are recorded in the table below.

[0058] The testing methods for each project are as follows: Rheological profile / thixotropy: Shear rate gradually increased from 0 to 100 s. -1 Constant at 100S -1 0.5–2 min, then from 100 s -1 Gradually decrease to 0.

[0059] Table 4. Comparison results of each item between Example 1 and Comparative Examples 4 and 5

[0060] The comparison results in Table 4 between Example 1 and Comparative Examples 4 and 5 show that the thixotropy of the microcrystalline cellulose-sodium carboxymethyl cellulose aqueous dispersions and formulations prepared by continuous homogenization for 30 min and 60 min using pipeline homogenizers at speeds of 2000 rpm and 2600 rpm increases with increasing homogenization speed and time. Example 1, prepared at 2600 rpm for 60 min, produced a homogeneous slurry with uniform properties. Comparative Example 4, prepared at 2000 rpm for 30 min, showed significantly worse rheological curves for both the microcrystalline cellulose-sodium carboxymethyl cellulose aqueous dispersion and the formulation compared to Example 1, exhibiting heterogeneous properties, layering, and insufficient content uniformity. Comparative Example 5, prepared at 2300 rpm for 90 min, also showed significantly worse rheological curves for both the microcrystalline cellulose-sodium carboxymethyl cellulose aqueous dispersion and the formulation compared to Example 1, achieving the required content uniformity, but requiring a longer homogenization time.

[0061] The homogenization time in the preparation process of microcrystalline cellulose-sodium carboxymethyl cellulose aqueous dispersion affects the thixotropy of microcrystalline cellulose-sodium carboxymethyl cellulose (as indicated by rheological curves). The homogenization time in the whole formulation preparation process affects the thixotropy of the formulation (as indicated by rheological curves). The rheological curves of the microcrystalline cellulose-sodium carboxymethyl cellulose aqueous dispersion, the rheological curves of the formulation, and the content uniformity show that, in Example 1, controlling the homogenization time to 60 min and the homogenization speed to 2600 rpm has a significant impact on the quality of the formulation.

[0062] This demonstrates that the present invention controls the particle size D of the raw material. 90 Not less than 10μm (10~15μm), the excipient combination is specified as: perampanel (3 / 4 hydrate crystal form), microcrystalline cellulose sodium carboxymethyl cellulose co-processed product (labeled viscosity limit 60%~140%; sodium carboxymethyl cellulose labeled percentage content 8%~13%), polyoxyethylene (40) hydrogenated castor oil, sorbitol, anhydrous citric acid, sodium benzoate; the pretreatment method of the active pharmaceutical ingredient is specified as air jet milling, passing through a 40-mesh metal sieve and undergoing static electricity removal treatment; the homogenization parameters are specified as rotation speed 2300~2600 rpm, homogenization for 50~60min, which can significantly improve the quality and stability of oral suspension.

[0063] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including modifications made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. A method for preparing a perampanel oral suspension, characterized in that, The raw materials for preparing the perampanel oral suspension include perampanel, microcrystalline cellulose sodium carboxymethyl cellulose co-treated product, polyoxyethylene hydrogenated castor oil, sorbitol, pH adjuster, antibacterial agent, defoamer, and water, and include the following steps: S1. Add the microcrystalline cellulose sodium carboxymethyl cellulose co-treatment product to water and homogenize it to obtain the first dispersion; S2. Sorbitol, antibacterial agent and pH adjuster are added to the first dispersion to obtain the second dispersion; S3. After pulverizing the perampanel, sieve it to control the particle size D. 90 It is 10–15 μm; S4. Perform static electricity removal treatment on the perampanel obtained after step S3. S5. Add the perampanel, defoamer, and polyoxyethylene hydrogenated castor oil treated in step S4 to the second dispersion to obtain the third dispersion. S6. Add water to the third dispersion to the total volume, and homogenize to obtain the perampanel oral suspension.

2. The preparation method according to claim 1, characterized in that: The concentration of perampanel in the perampanel oral suspension is 0.05%–0.1% g / mL; The concentration of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated compound in the perampanel oral suspension was 2.0%–2.5% g / mL; The concentration of the polyoxyethylene hydrogenated castor oil in the perampanel oral suspension is 0.5%–1.0% g / mL; The concentration of sorbitol in the perampanel oral suspension is 15%–20% g / mL; The concentration of the pH adjuster in the perampanel oral suspension is 0.1%–0.3% g / mL; The concentration of the antibacterial agent in the perampanel oral suspension is 0.1%–0.2% g / mL; The concentration of the defoamer in the perampanel oral suspension is 0.01% to 0.03% g / mL.

3. The preparation method according to any one of claims 1 to 2, characterized in that: The pyrampanel is in the 3 / 4 hydrate crystal form.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The labeled percentage content of sodium carboxymethyl cellulose in the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is 8% to 13%; And / or, the viscosity range of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is 39–91 mPa·s.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The defoamer is selected from one or more of simethicone and ethanol; And / or, the polyoxyethylene hydrogenated castor oil is selected from one or more of polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (54) hydrogenated castor oil, and polyoxyethylene (60) hydrogenated castor oil; And / or, the pH adjuster is selected from one or more of anhydrous citric acid and tartaric acid; And / or, the antibacterial agent is selected from one or more of sodium benzoate, potassium sorbate, and ethylparaben.

6. The preparation method according to any one of claims 1 to 5, characterized in that: In steps S1 and S6, the homogenization conditions are as follows: rotation speed 2300-2600 rpm, homogenization time 50-60 min; preferably, the homogenization process uses an inline dispersion emulsification pump.

7. The preparation method according to any one of claims 1 to 6, characterized in that: In step S3, the pulverization is performed by air jet pulverization and passing through a 40-mesh metal sieve.

8. The preparation method according to any one of claims 1 to 7, characterized in that: In step S4, the absolute value of the electrostatic potential on the surface of pirampanel after the electrostatic removal treatment is less than 500V.

9. The preparation method according to any one of claims 1 to 8, characterized in that: In step S4, the perampanel is added to the second dispersion in two parts. First, half of the prescribed amount of perampanel, defoamer, and polyoxyethylene hydrogenated castor oil are added and stirred until the polyoxyethylene hydrogenated castor oil dissolves. Then, the remaining perampanel is added while stirring.

10. The perampanel oral suspension obtained by any one of claims 1 to 9.

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