Stable perampanel oral suspension and preparation method thereof

Abstract

The invention provides a stable perampanel oral suspension and a preparation method thereof, the oral suspension adopts carboxylated nanocellulose (CNF) as a suspending aid and octadecanol as a defoaming agent, and adopts a high-shear dispersion mode in the preparation process, so that the stability, uniformity, suspension effect and dissolution rate of active ingredients in the suspension can be effectively improved, and the stability, the uniformity, the suspension effect and the dissolution rate of the perampanel oral suspension are improved. The pharmaceutical composition has the advantages of being good in suspension effect, high in content uniformity, high in dissolution speed, low in content of related substances, good in stability, high in bioavailability, convenient to take, capable of improving patient compliance and the like, and the preparation method is simple, high in operability and suitable for large-scale industrial production.

Description

Technical Field

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

[0002] Perampanel is a non-competitive antagonist of the ionic α-amino-3-hydroxy-5-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor on postsynaptic neurons. Glutamate is a major excitatory neurotransmitter in the central nervous system and is associated with many neurological disorders caused by neuronal overexcitation. Activation of AMPA receptors by glutamate is considered the cause of the fastest excitatory synaptic transmission in the brain. In in vitro studies, perampanel does not compete with AMPA for binding to AMPA receptors, but its binding is replaced by non-competitive AMPA receptor antagonists, indicating that perampanel is a non-competitive AMPA receptor antagonist. In vitro, perampanel inhibits AMPA-induced (but not NMDA-induced) increases in intracellular calcium. In vivo, perampanel significantly prolongs seizure latency in an AMPA-induced seizure model.

[0003] Perampanel oral suspension is indicated for the treatment of partial seizures (with or without secondary generalized seizures) in adults and children aged 4 years and older, and as adjunctive therapy for partial seizures (with or without secondary generalized seizures) in patients aged 12 years and older. Developed by Eisai Co., Ltd. of Japan, it was first approved for marketing in the European Union on July 23, 2012. In April 2016, the U.S. Food and Drug Administration (FDA) approved perampanel oral suspension for marketing.

[0004] Perampanel, chemically known as 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one (3 / 4) hydrate, has the molecular formula C2. 23 H 15 N3O·3 / 4H2O, with a molecular weight of 374.83, has the following chemical structural formula:

[0005]

[0006] Perampanel is readily soluble in N-methylpyrrolidone, sparingly soluble in acetonitrile and acetone, slightly soluble in methanol, ethanol, and ethyl acetate, very slightly soluble in 1-octanol and diethyl ether, and insoluble in heptane and water. (Based on the US marketed product information for perampanel tablets...) The product information states that perampanel is insoluble in water and is classified as a low-solubility drug. Furthermore, the active pharmaceutical ingredient is prone to aggregation and adhesion, which is detrimental to drug production and long-term storage, posing a significant challenge to the formulation process.

[0007] Currently, oral tablets containing perampanel are the most commonly known dosage form for the treatment of partial-onset seizures in children aged 4 years and older (with or without secondary generalized seizures). Most perampanel tablets available domestically and internationally are in two strengths: 2 mg and 4 mg, taken once daily at bedtime. This dosage form is known to contain a large amount of excipients, making it challenging for children and patients with poor medication compliance due to weak swallowing ability.

[0008] Therefore, it is essential to develop a formulation that has good content uniformity, high bioavailability, good stability, convenient administration, improved patient compliance, and is suitable for commercial production. Summary of the Invention

[0009] The purpose of this invention is to address the problems of poor suspension effect, stability, and content uniformity of the active ingredient perampanel, which is characterized by poor solubility, easy aggregation and adsorption, which are not conducive to drug production and long-term storage. This results in a perampanel oral suspension that simultaneously satisfies high stability and suspension effect, making it suitable for children and patients with swallowing difficulties. It uses carboxylated nanocellulose (CNF) as a suspending agent, octadecanol as an antifoaming agent, and a high-shear dispersion method during preparation, which effectively improves the stability, uniformity, suspension effect, and dissolution rate of the active ingredient in the suspension. It has advantages such as good suspension effect, high content uniformity, fast dissolution rate, low content of related substances, good stability, high bioavailability, convenient administration, and improved patient compliance.

[0010] Another objective of this invention is to provide a method for preparing the above-mentioned perampanel oral suspension, which is simple, highly operable, and suitable for large-scale industrial production.

[0011] The technical solution of the present invention is as follows:

[0012] A stable oral suspension of perampanel comprises perampanel, a suspending agent and an antifoaming agent, wherein the suspending agent is carboxylated nanocellulose and the antifoaming agent is octadecyl alcohol.

[0013] For the purposes of this invention, the weight ratio of perampanel, carboxylated nanocellulose, and octadecyl alcohol is 0.1-0.3:3.5-7.5:0.05-0.2; preferably 0.17:4.08-6.8:0.068-0.17.

[0014] In one embodiment, the stable perampanel oral suspension provided by this invention is mainly composed of perampanel, a suspending agent, a flavoring agent, a wetting agent, an antibacterial agent, a pH adjuster, an antifoaming agent, and purified water. The suspending agent is carboxylated nanocellulose, and the flavoring agent is sorbitol solution, a commercially available product, for example, sorbitol solution containing D-sorbitol (C6H4O3). 14O6) shall not be less than 64.0% (g / g); the wetting agent is poloxamer, preferably poloxamer 188; the antibacterial agent is one or more of sodium benzoate, methylparaben or ethylparaben, preferably sodium benzoate; the pH adjuster is anhydrous citric acid; the defoamer is octadecyl alcohol.

[0015] In a preferred embodiment, the stable perampanel oral suspension provided by the present invention is mainly composed of the following components in parts by weight: 0.1-0.3 parts perampanel, 3.5-7.5 parts carboxylated nanocellulose, 75-95 parts sorbitol solution, 1-3 parts poloxamer 188, 0.3-0.8 parts sodium benzoate, 0.5-1.5 parts anhydrous citric acid, and 0.05-0.2 parts octadecyl alcohol.

[0016] In a more preferred embodiment, the stable perampanel oral suspension provided by the present invention is mainly composed of the following components in parts by weight: 0.17 parts perampanel, 4.08-6.8 parts carboxylated nanocellulose, 80-90 parts sorbitol solution, 1.5-2 parts poloxamer 188, 0.4-0.6 parts sodium benzoate, 0.8-0.9 parts anhydrous citric acid, and 0.068-0.17 parts octadecyl alcohol.

[0017] In a particularly preferred embodiment, the stable perampanel oral suspension provided by the present invention is mainly composed of the following components in parts by weight: 0.17 parts perampanel, 4.08-6.8 parts carboxylated nanocellulose, 85 parts sorbitol solution, 1.7 parts poloxamer 188, 0.51 parts sodium benzoate, 0.85 parts anhydrous citric acid, and 0.068-0.17 parts octadecyl alcohol.

[0018] For example, the stable perampanel oral suspension provided by the present invention is mainly composed of the following components in parts by weight: 0.17 parts perampanel, 4.08 parts carboxylated nanocellulose, 85 parts sorbitol solution, 1.7 parts poloxamer 188, 0.51 parts sodium benzoate, 0.85 parts anhydrous citric acid, and 0.102 parts octadecyl alcohol.

[0019] For example, the stable perampanel oral suspension provided by the present invention is mainly composed of the following components in parts by weight: 0.17 parts perampanel, 5.1 parts carboxylated nanocellulose, 85 parts sorbitol solution, 1.7 parts poloxamer 188, 0.51 parts sodium benzoate, 0.85 parts anhydrous citric acid, and 0.102 parts octadecyl alcohol.

[0020] For example, the stable perampanel oral suspension provided by the present invention is mainly composed of the following components in parts by weight: 0.17 parts perampanel, 6.8 parts carboxylated nanocellulose, 85 parts sorbitol solution, 1.7 parts poloxamer 188, 0.51 parts sodium benzoate, 0.85 parts anhydrous citric acid, and 0.102 parts octadecyl alcohol.

[0021] For example, the stable perampanel oral suspension provided by the present invention is mainly composed of the following components in parts by weight: 0.17 parts perampanel, 5.1 parts carboxylated nanocellulose, 85 parts sorbitol solution, 1.7 parts poloxamer 188, 0.51 parts sodium benzoate, 0.85 parts anhydrous citric acid, and 0.068 parts octadecyl alcohol.

[0022] For example, the stable perampanel oral suspension provided by the present invention is mainly composed of the following components in parts by weight: 0.17 parts perampanel, 5.1 parts carboxylated nanocellulose, 85 parts sorbitol solution, 1.7 parts poloxamer 188, 0.51 parts sodium benzoate, 0.85 parts anhydrous citric acid, and 0.17 parts octadecyl alcohol.

[0023] The present invention also provides a method for preparing the above-mentioned perampanel oral suspension, comprising the following steps:

[0024] (1) Solution I: Dissolve carboxylated nanocellulose in a portion of purified water, stir to disperse evenly, then add sorbitol solution and sodium benzoate, and continue stirring until completely dissolved to obtain solution I;

[0025] (2) Solution II: Dissolve poloxamer 188 in part of purified water, then add perampanel, stir well, and then perform high-shear dispersion on the resulting mixed solution to obtain solution II;

[0026] (3) Mix solution I from step (1) and solution II from step (2), and perform high-shear dispersion on the resulting mixed solution;

[0027] (4) Add octadecyl alcohol to the dispersion obtained in step (3), stir to defoam, add anhydrous citric acid, stir to disperse, add the remaining purified water to make up the volume, and stir evenly to obtain an oral suspension.

[0028] In this invention, in step (1), the amount of purified water added is 50-70% of its total amount, preferably 60%.

[0029] In this invention, in step (2), the amount of purified water added is 5 to 15% of its total amount, preferably 10%.

[0030] In step (2), during high-speed shear dispersion, the high-speed shear rotation speed is 3.0-6.0 k rpm, preferably 4.0 k rpm; the high-speed shear time is 20-40 min, preferably 30 min.

[0031] In this invention, during step (3), the high-speed shearing and dispersion is performed at a rotation speed of 3.0-6.0 k rpm, preferably 4.0 k rpm; and the high-speed shearing time is 20-40 min, preferably 30 min.

[0032] The advantages of using the technical solution of this invention are as follows:

[0033] This invention utilizes carboxylated nanocellulose (CNF) as a suspending agent, octadecanol as an antifoaming agent, and a high-shear dispersion method during preparation. This addresses the problems of poor suspension effect, stability, and content uniformity in perampanel oral suspensions due to its poor solubility, easy aggregation, and adsorption, which hinder drug production and long-term storage. The invention provides a perampanel oral suspension that simultaneously achieves high stability and suspension effect, suitable for children and patients with swallowing difficulties. It effectively improves the stability, uniformity, suspension effect, and dissolution rate of the active ingredient in the suspension. It offers advantages such as good suspension effect, high content uniformity, fast dissolution rate, low content of related substances, good stability, high bioavailability, convenient administration, and improved patient compliance. Furthermore, the preparation method is simple, highly operable, and suitable for large-scale industrial production. Detailed Implementation

[0034] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0035] Examples 1-5

[0036] A stable oral suspension of perampanel is made from the following components by weight, the specific components and weights of Examples 1-10 are shown in Table 1.

[0037] Table 1. Components and Dosage

[0038]

[0039]

[0040] The preparation method of the stable perampanel oral suspension in Examples 1-5 includes the following steps:

[0041] (1) Solution I: Dissolve carboxylated nanocellulose (CNF) in 60% of purified water, stir to disperse evenly, add sorbitol solution and sodium benzoate, and continue stirring until completely dissolved to obtain solution I;

[0042] (2) Solution II: Poloxamer 188 was dissolved in 10% of purified water, and then perampanel was added. After stirring evenly, the resulting mixed solution was subjected to high-shear dispersion to obtain Solution II; the high-shear speed was 4.0 k rpm and the high-shear time was 30 min.

[0043] (3) Mix solution I from step (1) and solution II from step (2), and perform high-shear dispersion on the resulting mixed solution; the high-shear rotation speed is 4.0 k rpm and the high-shear time is 30 min;

[0044] (4) Add octadecyl alcohol to the dispersion obtained in step (3), stir to defoam for 15 min, then add anhydrous citric acid, stir to disperse for 15 min, add the remaining purified water to make up to 340 mL, stir evenly to obtain oral suspension.

[0045] In the preparation process, compared with Example 1, the difference between Examples 2-5 lies in the amount of carboxylated nanocellulose or octadecyl alcohol used.

[0046] Comparative Example 1

[0047] A stable perampanel oral suspension is prepared from the following components by weight:

[0048]

[0049] The method for preparing the stable perampanel oral suspension in Comparative Example 1 includes the following steps:

[0050] (1) Solution I: Dissolve the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product in 60% of the total amount of purified water, stir and disperse evenly, then add sorbitol solution and sodium benzoate, and continue stirring until completely dissolved to obtain solution I;

[0051] (2) Solution II: Poloxamer 188 was dissolved in 10% purified water, and then perampanel was added. After stirring evenly, the resulting mixed solution was dispersed by high-speed shear to obtain solution II; the high-speed shear speed was 4.0 k rpm and the high-speed shear time was 30 min.

[0052] (3) Mix solution I from step (1) and solution II from step (2), and perform high-shear dispersion on the resulting mixed solution; the high-shear rotation speed is 4.0 k rpm and the high-shear time is 30 min;

[0053] (4) Add octadecyl alcohol to the dispersion obtained in step (3), stir to defoam for 15 min, then add anhydrous citric acid, stir to disperse for 15 min, add the remaining purified water to make up to 340 mL, stir evenly to obtain oral suspension.

[0054] Comparative Example 2

[0055] A stable perampanel oral suspension is prepared from the following components by weight:

[0056]

[0057] The preparation method of the stable perampanel oral suspension in Comparative Example 2 includes the following steps:

[0058] (1) Solution I: Dissolve carboxylated nanocellulose (CNF) in 60% of purified water, stir to disperse evenly, add sorbitol solution and sodium benzoate, and continue stirring until completely dissolved to obtain solution I;

[0059] (2) Solution II: Poloxamer 188 was dissolved in 10% purified water, and then perampanel was added. After stirring evenly, the resulting mixed solution was dispersed by high-speed shear to obtain solution II; the high-speed shear speed was 4.0 k rpm and the high-speed shear time was 30 min.

[0060] (3) Mix solution I from step (1) and solution II from step (2), and perform high-shear dispersion on the resulting mixed solution; the high-shear rotation speed is 4.0 k rpm and the high-shear time is 30 min;

[0061] (4) Add simethicone emulsion to the dispersion obtained in step (3), stir to defoam for 15 min, then add anhydrous citric acid, stir to disperse for 15 min, add the remaining purified water to make up to 340 mL, stir evenly to obtain oral suspension.

[0062] Comparative Example 3

[0063] A stable perampanel oral suspension is prepared from the following components by weight:

[0064]

[0065]

[0066] The preparation method of the stable perampanel oral suspension in Comparative Example 3 includes the following steps:

[0067] (1) Solution I: Dissolve carboxylated nanocellulose (CNF) in 60% of purified water, stir to disperse evenly, add sorbitol solution and sodium benzoate, and continue stirring until completely dissolved to obtain solution I;

[0068] (2) Solution II: Dissolve poloxamer 188 in 10% purified water, then add perampanel, stir well to obtain solution II;

[0069] (3) Mix solution I from step (1) and solution II from step (2) by stirring.

[0070] (4) Add octadecyl alcohol to the mixed solution obtained in step (3), stir to defoam for 15 min, then add anhydrous citric acid, stir to disperse for 15 min, add the remaining purified water to make up to 340 mL, stir evenly to obtain oral suspension.

[0071] The defoaming time of the oral suspensions obtained in the examples and comparative examples was investigated, as shown in Table 2.

[0072] Table 2 Defoaming time results

[0073]

[0074] As shown in Table 2, octadecyl alcohol was used as a defoamer in Examples 1-3 of the present invention, resulting in a shorter defoaming time and a better defoaming effect.

[0075] The properties, sedimentation volume ratio, and viscosity of the oral suspensions obtained in the examples and comparative examples were investigated, as shown in Table 3.

[0076] Table 3 Results of properties, sedimentation volume ratio and viscosity

[0077]

[0078]

[0079] As shown in Table 3, in Examples 1-3 of this invention, carboxylated nanocellulose (CNF) was used as a suspending agent, resulting in oral suspensions with better properties, sedimentation volume ratio, and viscosity, significantly improving the drug suspension effect. In Comparative Example 1, the use of microcrystalline cellulose and sodium carboxymethyl cellulose co-treatment as a suspending agent resulted in a significantly worse suspending effect than in the examples. In Comparative Example 2, the use of simethicone emulsion as an antifoaming agent also resulted in a significantly worse suspending effect than the use of octadecyl alcohol as an antifoaming agent in this application. In Comparative Example 3, high-speed shear dispersion was not performed during its preparation, resulting in a poor suspending effect.

[0080] The oral suspensions obtained in the examples and comparative examples were investigated for related substances, content, sodium benzoate content, and dissolution rate, as shown in Table 4.

[0081] Table 4. Results of relevant substances, content, sodium benzoate content, and dissolution rate.

[0082]

[0083] As shown in Table 4, in Examples 1-3 of this invention, carboxylated nanocellulose (CNF) was used as a suspending agent. The content of related substances in the resulting oral suspension was relatively low, and the content of sodium benzoate and sodium benzoate were maintained in the range of 99.0-101.0%. The dissolution rate was not less than 96%, which can ensure the stability and uniformity of the active ingredients in the entire suspension and the excellent dissolution rate.

[0084] The content uniformity of the oral suspensions obtained in the examples and comparative examples was investigated, as shown in Table 5.

[0085] Table 5 Results of content uniformity

[0086]

[0087] As shown in Table 5, in this invention, the use of carboxylated nanocellulose (CNF) as a suspending agent in Examples 1-3 significantly improved the suspending effect of perampanel, and the content uniformity data were significantly better than those of the comparative examples. In Comparative Example 1, when microcrystalline cellulose and sodium carboxymethyl cellulose co-treated material were used as the suspending agent, the content uniformity was poor. In Comparative Example 2, when simethicone emulsion was used as the defoamer, the content uniformity was also significantly worse than that of using octadecyl alcohol as the defoamer in this application. In Comparative Example 3, high-speed shear dispersion was not performed during its preparation, resulting in poor suspending effect and poor content uniformity.

[0088] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A stable pirfenidone oral suspension characterized in that, A suspension comprising pirfenidone, a suspending agent which is carboxylated nanocellulose, and an antifoaming agent which is octadecanol.

2. The stable pirfenidone oral suspension according to claim 1, wherein A suspension made mainly from pirfenidone, a suspending agent, a flavoring agent, a wetting agent, a bacteriostatic agent, a pH adjusting agent, an antifoaming agent, and purified water; the suspending agent is sorbitol solution; the wetting agent is poloxamer, preferably poloxamer 188; the bacteriostatic agent is one or several of sodium benzoate, hydroxymethylbenzoate or hydroxyethylbenzoate, preferably sodium benzoate; the pH adjusting agent is anhydrous citric acid.

3. The stable pirfenidone oral suspension according to claim 2, wherein The weight ratio of the pirfenidone, carboxylated nanocellulose and octadecanol is 0.1-0.3:3.5-7.5:0.05-0.2; preferably 0.17:4.08-6.8:0.068-0.

17.

4. The stable pirfenidone oral suspension according to claim 3, wherein Made mainly from the following components in weight parts: pirfenidone 0.1-0.3 parts, carboxylated nanocellulose 3.5-7.5 parts, sorbitol solution 75-95 parts, poloxamer 188 1-3 parts, sodium benzoate 0.3-0.8 parts, anhydrous citric acid 0.5-1.5 parts, octadecanol 0.05-0.2 parts.

5. The stable pirfenidone oral suspension according to claim 4, wherein Made mainly from the following components in weight parts: pirfenidone 0.17 parts, carboxylated nanocellulose 4.08-6.8 parts, sorbitol solution 80-90 parts, poloxamer 188 1.5-2 parts, sodium benzoate 0.4-0.6 parts, anhydrous citric acid 0.8-0.9 parts, octadecanol 0.068-0.17 parts.

6. The stable pirfenidone oral suspension according to claim 5, wherein Made mainly from the following components in weight parts: pirfenidone 0.17 parts, carboxylated nanocellulose 4.08-6.8 parts, sorbitol solution 85 parts, poloxamer 188 1.7 parts, sodium benzoate 0.51 parts, anhydrous citric acid 0.85 parts, octadecanol 0.068-0.17 parts.

7. The stable pirfenidone oral suspension according to claim 5, wherein Made mainly from the following components in weight parts: pirfenidone 0.17 parts, carboxylated nanocellulose 4.08 parts, sorbitol solution 85 parts, poloxamer 188 1.7 parts, sodium benzoate 0.51 parts, anhydrous citric acid 0.85 parts, octadecanol 0.102 parts; pirfenidone 0.17 parts, carboxylated nanocellulose 5.1 parts, sorbitol solution 85 parts, poloxamer 188 1.7 parts, sodium benzoate 0.51 parts, anhydrous citric acid 0.85 parts, octadecanol 0.102 parts; pirfenidone 0.17 parts, carboxylated nanocellulose 6.8 parts, sorbitol solution 85 parts, poloxamer 188 1.7 parts, sodium benzoate 0.51 parts, anhydrous citric acid 0.85 parts, octadecanol 0.102 parts; pirfenidone 0.17 parts, carboxylated nanocellulose 5.1 parts, sorbitol solution 85 parts, poloxamer 188 1.7 parts, sodium benzoate 0.51 parts, anhydrous citric acid 0.85 parts, octadecanol 0.068 parts; pirfenidone 0.17 parts, carboxylated nanocellulose 5.1 parts, sorbitol solution 85 parts, poloxamer 188 1.7 parts, sodium benzoate 0.51 parts, anhydrous citric acid 0.85 parts, octadecanol 0.17 parts.

8. A process for the preparation of the stable pirfenidone oral suspension of claim 1, characterized in that, Comprising the following steps: (1) Solution I: carboxylated nanocellulose is dissolved in partially purified water, after stirring and uniformly dispersing, sorbitol solution and sodium benzoate are added, continuous stirring until completely dissolved, to obtain solution I; (2) Solution II: poloxamer 188 is dissolved in partially purified water, then pirfenidone is added, after stirring and uniformly dispersing, the obtained mixed solution is subjected to high shear dispersion, to obtain solution II; (3) Solution I in step (1) and solution II in step (2) are mixed, and the obtained mixed solution is subjected to high shear dispersion; (4) To the dispersion solution obtained in step (3), stearyl alcohol is added, after stirring and defoaming, anhydrous citric acid is added, stirring and dispersing, then the remaining purified water is added to constant volume, stirring and uniformly dispersing to obtain an oral suspension.

9. The process for the preparation of stable pirfenidone oral suspension according to claim 8, characterized in that, In steps (2) and (3), during high shear dispersion, the high shear rotation speed is 3.0-6.0 k rpm, preferably 4.0 k rpm; The high shear time is 20-40 min, preferably 30 min.

10. The process for the preparation of stable pirfenidone oral suspension according to claim 8, characterized in that, In step (1), the amount of purified water added is 50-70% of the total amount, preferably 60%; in step (2), the amount of purified water added is 5-15% of the total amount, preferably 10%.

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