A highly stable solution of brivaracetam, its preparation method and its use

Abstract

The present application relates to a kind of high stability's bexontan solution, with 0.1-10% bexontan, 20-50% high molecular material and buffer solution in bexontan solution with mass volume percentage, wherein, the high molecular material is selected from any one or combination of polymethyl methacrylate, cyclodextrin, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, the buffer solution is selected from any one of citric acid buffer solution, phosphate buffer solution, malic acid buffer solution, succinic acid buffer solution, tartaric acid buffer solution, lactic acid buffer solution, acetic acid buffer solution, bexontan solution pH4-7.5.The bexontan solution of the present application significantly delays the diffusion of drug bitter taste in oral cavity and realizes taste masking, and has excellent stability, more optimal cost, quality controllable, good taste and the like advantages.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a high-stability brivaracetam solution, a preparation method thereof and application thereof. BACKGROUND

[0002] Epilepsy and epilepsy-related diseases seriously affect the quality of life and daily life (such as cooking, cleaning and driving) of patients, and become a burden to the families and society of patients, but there is no effective drug and treatment method for treating epilepsy.

[0003] The brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide) solution is used for treating epilepsy, patients with intractable partial-onset seizures, with or without secondary generalized seizures, adult epilepsy patients, progressive myoclonic epilepsy, symptomatic myoclonus and the like. The brivaracetam solution is degraded under the action of acid, alkali, high temperature, oxidation, epimerization and the like to generate degradation impurities such as hydroxyl amide and hydroxy acid, and the brivaracetam solution developed by the original research has relatively good stability only at pH 5.5±0.2. Therefore, a high-stability brivaracetam solution is urgently needed to ensure the safety and effectiveness of clinical medication. SUMMARY

[0004] The application aims to provide a high-stability brivaracetam solution, which contains 0.1-10% of brivaracetam, 20-50% of a high-molecular material and a buffer solution in terms of mass percentage, wherein the high-molecular material is selected from any one or a combination of polymethacrylate, beta-cyclodextrin, hydroxypropyl methyl cellulose (HPMC) and sodium carboxymethyl cellulose, the buffer solution is selected from any one of citric acid buffer solution, phosphate buffer solution, malic acid buffer solution, succinic acid buffer solution, tartaric acid buffer solution, lactic acid buffer solution and acetic acid buffer solution, and the pH of the brivaracetam solution is 4-7.5.

[0005] In a preferred technical scheme of the application, the high-molecular material is selected from a combination of polymethacrylate and sodium carboxymethyl cellulose, a combination of beta-cyclodextrin and sodium carboxymethyl cellulose, and a combination of hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose, wherein the mass ratio of any one of polymethacrylate, beta-cyclodextrin and hydroxypropyl methyl cellulose to sodium carboxymethyl cellulose is 50-100:1, and preferably 60-90:1.

[0006] In a preferred technical scheme of the application, the beta-cyclodextrin is selected from any one or a combination of hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin and sulfobutyl-beta-cyclodextrin.

[0007] In the preferred technical scheme of the present application, the solution of brivaracetam optionally contains any one of thickening agent, preservative, flavoring agent.

[0008] In the preferred technical scheme of the present application, the solution of brivaracetam contains 25-40% of thickening agent in mass volume percentage, and the thickening agent is selected from any one or combination of sorbitol and glycerol.

[0009] In the preferred technical scheme of the present application, the solution of brivaracetam contains 0.1-1% of preservative in mass volume percentage, and the preservative is selected from any one or combination of p-hydroxybenzoic acid ester, propyl paraben and ethyl paraben.

[0010] In the preferred technical scheme of the present application, the composition contains 1-10% of flavoring agent in mass volume percentage, and the flavoring agent is selected from any one or combination of sucralose, aspartame, saccharin, acesulfame potassium, steviol glycoside, menthol, menthylamide, mogroside, N-ethyl-p-menthyl-3-formamide, N,2,3-trimethyl-2-isopropylbutyramide, 2-(4-methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(thiophene-2-ylmethyl)acetamide, (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexylformamide and essence.

[0011] In the preferred technical scheme of the present application, the essence is selected from any one or combination of mint essence, lemon essence, peach essence, raspberry essence, orange essence, strawberry essence, red berry essence and cherry essence.

[0012] In the preferred technical scheme of the present application, the solution of brivaracetam has pH 4.5-7, preferably pH 5-7.

[0013] In the preferred technical scheme of the present application, the solution of brivaracetam contains 1% of brivaracetam, 30-45% of high molecular material, 0.35-0.4% of citric acid-sodium citrate, 30-35% of thickening agent, 1-10% of flavoring agent and 0.1-1% of preservative in mass volume percentage, and the solution of brivaracetam has pH 4-7.5.

[0014] In the preferred technical scheme of the present application, the composition contains 1% of brivaracetam, 45.5% of high molecular material, 17% of sorbitol, 15% of glycerol, 0.374% of citric acid-sodium citrate, 4% of sucralose, 0.1% of p-hydroxybenzoic acid ester and 0.56% of essence in mass volume percentage, and the solution of brivaracetam has pH 4-7.5, wherein the high molecular material is composed of Eudragit EPO and sodium carboxymethyl cellulose at a mass ratio of 90:1.

[0015] In the preferred technical scheme of the present application, the composition contains 1% of brivaracetam, 35.5% of high molecular material, 17% of sorbitol, 15% of glycerol, 0.384% of citric acid-sodium citrate, 4% of sucralose, 0.1% of p-hydroxy benzoic acid ester and 0.56% of essence, and the pH of the brivaracetam solution is 4-7.5, wherein the high molecular material is composed of Eudragit L100 and sodium carboxymethyl cellulose at a mass ratio of 70:1.

[0016] In the preferred technical scheme of the present application, the composition contains 1% of brivaracetam, 30.5% of high molecular material, 17% of sorbitol, 15% of glycerol, 0.395% of citric acid-sodium citrate, 4% of sucralose, 0.1% of p-hydroxy benzoic acid ester and 0.56% of essence, and the pH of the brivaracetam solution is 4-7.5, wherein the high molecular material is composed of hydroxypropyl-beta-cyclodextrin and sodium carboxymethyl cellulose at a mass ratio of 60:1.

[0017] In the preferred technical scheme of the present application, the pH of the brivaracetam solution is 5-7.

[0018] In the preferred technical scheme of the present application, the total impurities of the brivaracetam solution after being placed at 60℃ for 30 days are ≤2.5%, preferably ≤1.5%, more preferably ≤0.5%.

[0019] In the preferred technical scheme of the present application, the total impurities of the brivaracetam solution after being placed at 60℃ for 10 days are ≤1%, preferably ≤0.5%, more preferably not detected.

[0020] In the preferred technical scheme of the present application, the composition is an oral solution.

[0021] Another object of the present application is to provide a preparation method of a high-stability brivaracetam solution, wherein the brivaracetam solution contains 0.1-10% of brivaracetam, 20-50% of high molecular material and buffer solution, the high molecular material is selected from any one or combination of polymethacrylate, cyclodextrin, hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose, the buffer solution is selected from any one of citric acid buffer solution, phosphate buffer solution, malic acid buffer solution, succinic acid buffer solution, tartaric acid buffer solution and lactic acid buffer solution, the pH of the brivaracetam solution is 4-7.5, and the method comprises the following steps:

[0022] 1) weighing the required amount of brivaracetam and buffer solution, stirring to dissolve, and preparing a drug solution;

[0023] 2) adding the required amount of high molecular material to the drug solution prepared in step 1), stirring to dissolve, heating in a water bath at 50-100℃ for 10-15h, adding water to constant volume, and filtering, thereby obtaining the brivaracetam solution.

[0024] In the preferred technical scheme of the present application, the filtration is membrane filtration, preferably with a pore size of ≤ 45 μm, more preferably ≤ 40 μm.

[0025] Another object of the present application is to provide the use of the high-stability brivaracetam solution of the present application for preparing a medicament for treating epilepsy and its complications.

[0026] In the preferred technical scheme of the present application, the epilepsy is selected from any one of generalized seizures, partial / focal seizures, convulsive seizures, reflex seizures, or complications thereof.

[0027] In the preferred technical scheme of the present application, the generalized seizures are selected from any one of generalized tonic-clonic seizures, absence seizures, tonic seizures, clonic seizures, myoclonic seizures, atonic seizures, or complications thereof.

[0028] In the preferred technical scheme of the present application, the partial seizures are selected from any one of simple partial seizures, complex partial seizures, secondary generalized seizures, or complications thereof.

[0029] Another object of the present application is to provide a pharmaceutical composition containing brivaracetam, which is a combination of the high-stability brivaracetam solution of the present application and other antiepileptic drugs.

[0030] In the preferred technical scheme of the present application, the other antiepileptic drugs are selected from any one of sodium channel blockers, drugs that reduce neurotransmitter release, drugs that enhance gamma-aminobutyric acid (GABA)-mediated excitatory inhibition, N-methyl-D-aspartate (NMDA) receptor blockers, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, or combinations thereof.

[0031] In the preferred technical scheme of the present application, the sodium channel blockers are selected from any one of phenytoin sodium, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or combinations thereof.

[0032] In the preferred technical scheme of the present application, the drugs that reduce neurotransmitter release are selected from any one of ethosuximide, sodium valproate, lamotrigine, topiramate, levetiracetam, gabapentin, pregabalin, or combinations thereof.

[0033] In the preferred technical scheme of the present application, the drugs that enhance gamma-aminobutyric acid-mediated excitatory inhibition are selected from any one of phenobarbital, phenytoin, fosphenytoin, benzodiazepines, non-encefalons, sodium valproate, topiramate, tiagabine, vigabatrin, or combinations thereof.

[0034] The drug of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist is selected from any one of perampanel, zonisamide or a combination thereof.

[0035] Unless otherwise stated, when the present application relates to a percentage between liquids, the percentage is a volume / volume percentage; when the present application relates to a percentage between a liquid and a solid, the percentage is a volume / weight percentage; when the present application relates to a percentage between a solid and a liquid, the percentage is a weight / volume percentage; and the rest are weight / weight percentages.

[0036] Compared with the prior art, the present application detects the related substances by the following method:

[0037] Test solution: about 5 ml of brivaracetam oral solution was taken into a 50 ml volumetric flask, diluted to the mark with acetonitrile-water (35:65), shaken well, filtered, and the first 2 ml of the filtrate was discarded, and the subsequent filtrate was used as the test solution.

[0038] Control solution: 1 ml of the test solution was accurately measured and placed in a 100 ml volumetric flask, diluted to the mark with acetonitrile-water (35:65), shaken well, filtered, and the first 2 ml of the filtrate was discarded, and the subsequent filtrate was used as the control solution.

[0039] Chromatographic conditions: octadecylsilane-bonded silica gel was used as the filler (Thermo Hypersil GOLD C18 4.6 mm x 250 mm 5 µm or a chromatographic column with equivalent performance); the mobile phase was composed of phase A and phase B, phase A was acetonitrile, and phase B was a 0.1% phosphoric acid solution (1 ml of phosphoric acid was diluted to 1000 ml with water), gradient elution (the volume ratio of phase A to phase B was 5:95-75:25, elution time was 0-50 min). The detection wavelength was 210 nm; the column temperature was 40°C; the injection volume was 10 µl.

[0040] Determination method: 10 µl of the test solution and the control solution were accurately measured and injected into the liquid chromatograph, respectively, and the chromatogram was recorded.

[0041]

[0042] Compared with the prior art, the present application has the following beneficial effects:

[0043] 1. This invention scientifically screens the components and proportions of brivacertan solution, utilizing the hydrogen bonds, van der Waals forces, and electrostatic forces generated between polymer materials and brivacertan. The resulting brivacertan solution exhibits good stability over a wider pH range (pH 4-7.5, preferably pH 4.5-7), significantly improving the long-term stability of the drug. The brivacertan solution of this invention significantly reduces the contact between brivacertan and taste buds, delaying the diffusion of the bitter taste in the oral cavity and effectively masking the taste. The resulting drug solution has a good taste, significantly improving the problem of poor patient medication compliance caused by the bitter taste of the drug. It also has the advantages of controllable quality, high yield, better cost, and high patient compliance, providing patients with a convenient, low-cost, and ideal method of drug administration.

[0044] 2. The preparation method of the present invention has the advantages of simple operation, lower cost, green and environmentally friendly, and suitable for industrial production. Attached Figure Description

[0045] Figure 1 Experiment Example 2: Taste Evaluation Results Detailed Implementation

[0046] The present invention is described in detail through the following embodiments and test examples, but is for illustrative purposes only and not for limiting the scope of the invention.

[0047] Example 1 Preparation of buvasidan solution

[0048] Composition of buvacerostat solution:

[0049] Ingredient Amount (g) Bouvistane 1 Eudragit EPO: carboxymethylcellulose sodium in a mass ratio of 90:1 45.5 Sorbitol 17.0 Glycerol 15.0 Citric acid-sodium citrate (citric acid:sodium citrate in a mass ratio of 0.09:0.29) 0.374 Sucralose 4.0 Parabens 0.1 Raspberry flavour 0.56

[0050] The preparation of buvacerostat solution involves the following steps:

[0051] 1. Weigh the required amount of p-hydroxybenzoate, dissolve it in 60 ml of water under stirring, then add the required amounts of buvacertan, sodium citrate-citrate, glycerin, sucralose, sorbitol and raspberry flavor, and stir until dissolved to obtain the drug solution.

[0052] 2. Add the required amount of EPO and sodium carboxymethyl cellulose to the prepared drug solution, stir until dissolved, heat in a water bath at 60°C for 10 hours, add water to make up to 100 ml, stir until uniformly mixed, and filter through a 40 μm filter membrane to obtain the final product.

[0053] Example 2 Preparation of buvasidan solution

[0054] Composition of buvacerostat solution:

[0055] Ingredient Amount (g) Bouvistane 1 Eudragit L100: carboxymethylcellulose sodium in a mass ratio of 70:1 35.5 Sorbitol 17.0 Glycerol 15.0 Citric acid-sodium citrate (citric acid:sodium citrate in a mass ratio of 0.09:0.29) 0.384 Sucralose 4.0 Parabens 0.1 Lemon flavour 0.56

[0056] Preparation of the solution of brivaracetam includes the following steps:

[0057] 1. Weigh the required amount of p-hydroxybenzoate, and dissolve it in 60 ml of purified water under stirring. Then, add the required amount of brivaracetam, citric acid-sodium citrate, glycerol, sucralose, sorbitol and lemon flavor, and stir until dissolved to prepare the drug solution.

[0058] 2. Add the required amount of Eudragit L100 and sodium carboxymethyl cellulose to the prepared drug solution, and stir until dissolved. Then, heat in a water bath at 60°C for 10 h, add water to make up to 100 ml, and stir until uniformly mixed. Filter through a 40 μm filter to obtain the product.

[0059] Example 3 Preparation of the solution of brivaracetam

[0060] Composition of the solution of brivaracetam:

[0061] Ingredient Amount (g) Bouvistane 1 Hydroxypropyl-β-cyclodextrin: carboxymethylcellulose sodium in a mass ratio of 60:1 30.5 Sorbitol 17.0 Glycerol 15.0 Citric acid-sodium citrate (citric acid:sodium citrate in a mass ratio of 0.09:0.29) 0.395 Sucralose 4.0 Parabens 0.1 Apple flavour 0.56

[0062] Preparation of the solution of brivaracetam includes the following steps:

[0063] 1. Weigh the required amount of p-hydroxybenzoate, and dissolve it in 60 ml of purified water under stirring. Then, add the required amount of brivaracetam, citric acid-sodium citrate, glycerol, sucralose, sorbitol and apple flavor, and stir until dissolved to prepare the solution of brivaracetam.

[0064] 2. Add the required amount of hydroxypropyl-β-cyclodextrin and sodium carboxymethyl cellulose to the prepared solution of brivaracetam, and stir until dissolved. Then, heat in a water bath at 60°C for 10 h, add water to make up to 100 ml, and stir until uniformly mixed. Filter through a 40 μm filter to obtain the product.

[0065] Preparation of the solution of brivaracetam in Comparative Example 1

[0066] Composition of the solution of brivaracetam:

[0067] Ingredient Amount (g) Bouvistane 1.0 Sorbitol 17.0 Glycerol 15.2 Citric acid 0.0895 Sodium citrate dihydrate 0.294 Sucralose 4 Methyl paraben 0.1 Carboxymethylcellulose sodium 0.5 Raspberry flavour 0.56

[0068] Preparation of the solution of brivaracetam includes the following steps:

[0069] Weigh the required amount of glycerol and p-hydroxybenzoic acid methyl ester, and dissolve them in 60 ml of purified water under stirring. Then, add the required amount of sodium citrate dihydrate, citric acid, brivaracetam, and stir until completely dissolved. Add the required amount of sodium carboxymethyl cellulose, and stir until dissolved. Then, add the required amount of sucralose, sorbitol and red berry flavor, and stir until completely dissolved. Adjust the pH to 5.6, add water to make up to 100 ml, and filter through a 40 μm filter to obtain the product.

[0070] Test Example 1 Stability investigation of the solution of Boceprevir

[0071] The solution of Boceprevir prepared in Example 1 and Comparative Example 1 was placed at 60℃ and different pH conditions (pH 4, pH 5.5, pH 7, pH 7.5) for 10 days and 30 days, and the total amount of impurities was detected. The results are shown in Table 1. The solution of Boceprevir of the present application has good stability.

[0072] Table 1

[0073]

[0074]

[0075] Taste evaluation experiment of Test Example 2

[0076] The classic population taste evaluation method was used, and the "ranking + scoring method" (Integrated score evaluation method, ISEM) was used for analysis. ISEM uses single-blind, random method testing. After the volunteers taste the medicine, the bitterness level is arranged according to the subjective taste perception, and the "drug bitterness ranking score table" is filled out. The higher the score, the better the acceptability.

[0077] Five healthy young people were selected as subjects (subject 1 to subject 5), and the aqueous solution of Example 1 and the aqueous solution of Comparative Example 1 were taken respectively, and the test sample was tasted for 10s and then spit out, and the mouth was rinsed with pure water for 3 times, and the next batch of sample was tested after 10min. The bitterness evaluation standard is shown in Table 2, the bitterness is designed as 5 grades, each grade is given a certain bitterness score, the score is 1 to 5, the bitterness is weakened in turn, and the test results are shown in Figure 1 .

[0078] Table 2 Bitterness evaluation table

[0079]

[0080] The above description of specific embodiments of the present application does not limit the present application, and those skilled in the art can make various changes or modifications to the present application according to the present application, as long as they do not deviate from the spirit of the present application, and all should belong to the scope of protection of the claims of the present application.

Claims

1. A highly stable brivacertan solution, comprising, by mass-volume percentage, 0.1-10% brivacertan, 20-50% polymeric material and buffer solution, wherein, The polymeric material is composed of hydroxypropyl-β-cyclodextrin and sodium carboxymethyl cellulose in a mass ratio of 60-90:1, or the polymeric material is composed of EPO and sodium carboxymethyl cellulose in a mass ratio of 90:1, or the polymeric material is composed of L100 and sodium carboxymethyl cellulose in a mass ratio of 70:1; the buffer solution is selected from any one of citrate buffer solution, phosphate buffer solution, malic acid buffer solution, succinic acid buffer solution, tartaric acid buffer solution, lactic acid buffer solution, and acetate buffer solution, and the buvasidan solution has a pH of 4-7.

5.

2. The buvasidan solution of claim 1, wherein the buvasidan solution optionally contains any one of a thickener, a preservative, or a flavoring agent.

3. The buvasidan solution of claim 2, wherein the buvasidan solution contains 25-40% thickener by weight-volume percentage, said thickener being selected from any one or a combination of sorbitol, glycerol, or similar substances.

4. The buvasidan solution of claim 2, wherein the buvasidan solution contains 0.1-1% preservative by weight-volume percentage, said preservative being selected from any one or a combination of parabens, propylparaben, and ethylparaben.

5. The buvasidan solution of claim 2, wherein the buvasidan solution contains 1-10% flavoring agent by weight-volume percentage, said flavoring agent being selected from any one or a combination of sucralose, aspartame, saccharin, acesulfame potassium, steviol glycosides, menthol, mentholamide, mogrosides, N-ethyl-p-menthyl-3-carboxamide, N,2,3-trimethyl-2-isopropylbutyramide, 2-(4-methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide, (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexylcarboxamide, and flavorings.

6. The buvacerostat solution as described in claim 5, wherein the flavoring is selected from any one or a combination of peppermint flavoring, lemon flavoring, peach flavoring, raspberry flavoring, orange flavoring, strawberry flavoring, cranberry flavoring, and cherry flavoring.

7. The buvacerostat solution of claim 1, wherein the buvacerostat solution has a pH of 4.5-7.

8. The buvacertan solution of claim 7, wherein the buvacertan solution has a pH of 5-7.

9. The buvacerostatin solution as described in claim 2, wherein, by mass-volume percentage, the buvacerostatin solution contains 1% buvacerostatin, 30-45% polymeric material, 0.35-0.4% sodium citrate-citrate, 30-35% thickener, 1-10% flavoring agent, and 0.1-1% preservative, and the pH of the buvacerostatin solution is 4-7.

5.

10. The brivacertan solution as described in claim 1, wherein, by mass-volume percentage, the brivacertan solution contains 1% brivacertan, 45.5% polymer, 17% sorbitol, 15% glycerol, 0.374% sodium citrate-citrate, 4% sucralose, 0.1% paraben, and 0.56% fragrance; the brivacertan solution has a pH of 4-7.

5. The polymer material is composed of EPO and sodium carboxymethyl cellulose in a mass ratio of 90:

1.

11. The brivacertan solution as described in claim 1, wherein, by mass-volume percentage, the brivacertan solution contains 1% brivacertan, 35.5% polymeric material, 17% sorbitol, 15% glycerol, 0.384% sodium citrate-citrate, 4% sucralose, 0.1% parabens, and 0.56% fragrance; the pH of the brivacertan solution is 4-7.

5. The polymer material is composed of Utec L100 and sodium carboxymethyl cellulose in a mass ratio of 70:

1.

12. The brivacertan solution as described in claim 1, wherein, by mass-volume percentage, the brivacertan solution contains 1% brivacertan, 30.5% polymer, 17% sorbitol, 15% glycerol, 0.395% sodium citrate-citrate, 4% sucralose, 0.1% paraben, and 0.56% fragrance, and the pH of the brivacertan solution is 4-7.

5. The polymeric material is composed of hydroxypropyl-β-cyclodextrin and sodium carboxymethyl cellulose in a mass ratio of 60:

1.

13. The buvasidan solution according to any one of claims 1-12, wherein the total impurities % of the buvasidan solution after being stored at 60°C for 30 days are ≤2.5%.

14. The buvasidan solution as described in claim 13, wherein the total impurities ≤ 1.5% after being stored at 60°C for 30 days.

15. The buvasidan solution as described in claim 14, wherein the total impurities ≤ 0.5% after being stored at 60°C for 30 days.

16. The buvasidan solution according to any one of claims 1-12, wherein the total impurities % of the buvasidan solution after being placed at 60°C for 10 days are ≤1%.

17. The buvasidan solution as described in claim 16, wherein the total impurities ≤ 0.5% after being stored at 60°C for 10 days.

18. The buvasidan solution as described in claim 17, wherein total impurities were not detected after the buvasidan solution was placed at 60°C for 10 days.

19. The brivacertan solution according to any one of claims 1-12, wherein the brivacertan solution is an oral solution.

20. A method for preparing a highly stable buvacerostat solution according to any one of claims 1-19, the method comprising the following steps: 1) Weigh the required amount of brivacertan and buffer solution, stir until dissolved, and prepare the drug solution; 2) Add the required amount of polymer material to the drug solution obtained in step 1), stir until dissolved, heat in a water bath at 50℃-100℃ for 10-15 hours, add water to make up the volume, filter, and the drug is obtained.

21. The preparation method according to claim 20, wherein the filtration is membrane filtration and the membrane pore size is ≤45μm.

22. The preparation method according to claim 21, wherein the filtration is membrane filtration and the membrane pore size is ≤40μm.

23. The use of the highly stable brivacertan solution as described in any one of claims 1-19 in the preparation of a medicament for treating epilepsy and its complications.

24. The application as described in claim 23, wherein the epilepsy is selected from any one of generalized seizures, partial / focal seizures, epileptic spasms, reflex seizures, or their complications.

25. The application as described in claim 24, wherein the generalized seizure is selected from any one of generalized tonic-clonic seizures, absence seizures, tonic seizures, clonic seizures, myoclonic seizures, atonic seizures, or their complications.

26. The application as described in claim 24, wherein the partial seizure is selected from any one of simple partial seizures, complex partial seizures, secondary generalized seizures, or their complications.

27. A pharmaceutical composition comprising brivacertan, said pharmaceutical composition comprising a highly stable brivacertan solution as described in any one of claims 1-19 and other antiepileptic drugs.

28. The pharmaceutical composition of claim 27, wherein the other antiepileptic drug is selected from any one or a combination of sodium channel blockers, drugs that reduce neurotransmitter release, drugs that enhance γ-aminobutyric acid-mediated excitatory inhibition, N-methyl-D-aspartate receptor blockers, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonists.

29. The pharmaceutical composition of claim 28, wherein the sodium channel blocker is selected from any one or a combination of phenytoin sodium, carbamazepine, oxcarbazepine, lamotrigine, and lacosamide.

30. The pharmaceutical composition of claim 28, wherein the neurotransmitter-reducing agent is selected from any one or a combination of ethosuximide, sodium valproate, lamotrigine, topiramate, levetiracetam, gabapentin, and pregabalin.

31. The pharmaceutical composition of claim 28, wherein the drug that enhances γ-aminobutyric acid-mediated excitatory inhibition is selected from any one or a combination of phenobarbital, phenytoin, fosphenytoin, benzodiazepines, nonamino esters, sodium valproate, topiramate, tiagabine, and aminovinyl acetate.

32. The pharmaceutical composition of claim 28, wherein the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist is selected from any one of perampanel, zonisamide, or a combination thereof.

Images