Method for improving stability of topiramate preparation

Abstract

The invention provides a method for improving the stability of a topiramate preparation, a method for preparing the topiramate preparation, the prepared topiramate preparation and application of the topiramate preparation in preparation of medicines for treating epilepsy. The content of sulfamate in the topiramate is less than 0.02%, and the content of sulfate in the topiramate is less than 0.02%. By further controlling the content of sulfamate and sulfate in topiramate and controlling the particle size of topiramate, the obtained topiramate preparation is good in stability, the dissolution property of the topiramate preparation is similar to that of a reference preparation, and the topiramate preparation has a good application prospect.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a method for improving the stability of a topiramate preparation, a method for preparing the preparation, and the topiramate preparation prepared thereby and uses thereof. Background Art

[0002] Topiramate is a new, broad-spectrum anti-epileptic drug developed by Janssen Pharms and first approved for marketing in the UK in 1995 under the trade name Topamax. Topiramate is approved for use as an anti-epileptic drug, as an adjunctive treatment for patients with partial-onset epilepsy or primary generalized tonic-clonic epilepsy, and for the prevention of migraine. Currently, the marketed topiramate preparations include tablets, capsules, sustained-release capsules, and solutions.

[0003] The chemical name of topiramate is 2,3:4,5-bis-O-(1-methylethylidene)-β-D-pyranose sulfamate, which is a white crystalline powder with a bitter taste. It is easily degraded in a hot and humid environment. Its degradation can be easily judged by the change in physical appearance (turning brown or black), and its degree of degradation can also be confirmed by detecting degradation products (aminosulfonates or sulfates). The conventional solution to this problem is to apply a coating to reduce the contact between topiramate and the external environment when making topiramate into a preparation, or to improve the stability of the preparation by replacing the excipients.

[0004] Patent application CN103417501A discloses a topiramate pharmaceutical composition, in which pregelatinized starch is added to increase the stability of the active ingredient of topiramate. However, the dissolution rate of the composition is slow, with about 60% dissolving in 5 minutes, and the dissolution rate is lower than that of commercially available topiramate tablets, which is not conducive to the efficacy of the drug.

[0005] In addition, in order to maintain the quality of the tablets, the topiramate tablets are packaged in high-density polyethylene (HDPE) bottles containing desiccant or in blister packages containing desiccant. Patent application WO01 / 89445 discloses a topiramate blister package that does not contain desiccant and maintains the stability of the active ingredient. The blister package includes a disc-shaped sheet for placing a cavity for pre-dried topiramate tablets and a cover for sealing the disc-shaped sheet. The package is expensive and requires drying the topiramate tablets before packaging, which increases production costs.

[0006] Therefore, there is an urgent need for a method for improving the stability of a topiramate preparation and a topiramate preparation with high stability. Summary of the invention

[0007] The present invention aims to provide a method for improving the stability of a topiramate preparation, wherein the aminosulfonate content of the topiramate is less than 0.02%, and the sulfate content is less than 0.02%.

[0008] In the preferred technical solution of the present invention, the aminosulfonate content in the topiramate is less than 0.005%, and the sulfate content is less than 0.005%.

[0009] In the preferred technical solution of the present invention, aminosulfonate and sulfate are not detected in the topiramate.

[0010] In a preferred technical solution of the present invention, the method for detecting the contents of aminosulfonate and sulfate in topiramate is high performance liquid chromatography.

[0011] In the preferred technical scheme of the present invention, the chromatographic conditions of the high performance liquid chromatography are: using an anion exchange chromatography column (4.6mm×150mm, 5μm); using 0.08% p-hydroxybenzoic acid aqueous solution (adjusting the pH to 9.9±0.1 with sodium hydroxide test solution)-methanol (97.5:2.5) as the mobile phase; the flow rate is 2.0mL per minute; the column temperature is 40°C; the detection wavelength is 310nm; and the detector polarity is negative.

[0012] In a preferred technical solution of the present invention, the topiramate particle size D90 value is 15 to 200 μm.

[0013] In a preferred technical solution of the present invention, the topiramate particle size D90 value is 60 to 150 μm.

[0014] Another object of the present invention is to provide a method for purifying topiramate, which comprises the following steps:

[0015] The topiramate to be purified is mixed with a mixed solvent consisting of an organic solvent and water, heated and stirred until dissolved and clarified, cooled to 35-40°C and stirred, then cooled to 5±5°C for crystallization, filtered with suction, and the filter cake is dried to obtain the product.

[0016] In a preferred technical solution of the present invention, the mass volume ratio of the topiramate to be purified to the mixed solvent is 1:1 to 1:5 g / mL, preferably 1:2 to 1:3 g / mL.

[0017] In a preferred technical solution of the present invention, the organic solvent is selected from one of methanol, ethanol, isopropanol or a combination thereof.

[0018] In a preferred technical solution of the present invention, the volume ratio of the organic solvent to water is 1:2-1:4.

[0019] In the preferred technical solution of the present invention, the heating temperature is 75-85°C.

[0020] In a preferred technical solution of the present invention, the temperature is lowered to 35-40° C. and stirred for 0.5-1 hour.

[0021] In a preferred technical solution of the present invention, the temperature is lowered to 5±5° C. for crystallization for 1-5 hours.

[0022] In a preferred technical solution of the present invention, the drying condition is reduced pressure drying at 50-60° C. for 2-5 hours.

[0023] Another object of the present invention is to provide topiramate, which is prepared by the above purification method, wherein the aminosulfonate content in the topiramate is less than 0.02%, and the sulfate content is less than 0.02%; preferably, the aminosulfonate content is less than 0.005%, and the sulfate content is less than 0.005%; more preferably, the aminosulfonate content is not detected and the sulfate content is not detected.

[0024] Another object of the present invention is to provide a pharmaceutical composition, which comprises topiramate and pharmaceutically acceptable excipients.

[0025] In the preferred technical solution of the present invention, the aminosulfonate content in the topiramate is less than 0.02%, and the sulfate content is less than 0.02%; preferably, the aminosulfonate content in the topiramate is less than 0.005%, and the sulfate content is less than 0.005%; more preferably, the aminosulfonate content and the sulfate content in the topiramate are not detected;

[0026] In a preferred technical solution of the present invention, the topiramate particle size D90 value is 15 to 200 μm; preferably, the topiramate particle size D90 value is 60 to 150 μm.

[0027] In a preferred technical solution of the present invention, the pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants and lubricants.

[0028] In the preferred technical solution of the present invention, the pharmaceutical composition comprises the following components in percentage by weight:

[0029]

[0030] In the preferred technical solution of the present invention, the pharmaceutical composition comprises the following components in percentage by weight:

[0031]

[0032] In a preferred technical solution of the present invention, the filler 1 is selected from one or a combination of lactose, sucrose, microcrystalline cellulose, mannitol, sorbitol, xylitol, glucose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, calcium chloride, aluminum chloride, sodium chloride, calcium oxide, zinc oxide, and magnesium oxide.

[0033] In a preferred technical solution of the present invention, the filler 2 is selected from one of lactose, sucrose, microcrystalline cellulose, mannitol, sorbitol, xylitol, glucose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, calcium chloride, aluminum chloride, sodium chloride, calcium oxide, zinc oxide, and magnesium oxide, or a combination thereof.

[0034] In a preferred technical solution of the present invention, the adhesive is selected from one of pregelatinized starch, polyvinyl pyrrolidone, gelatin, xanthan gum, dextrin, polyvinyl alcohol, carboxymethyl cellulose or a combination thereof.

[0035] In a preferred technical solution of the present invention, the disintegrant is selected from one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, or a combination thereof.

[0036] In the preferred technical solution of the present invention, the lubricant is selected from one of talc, micropowder silica gel, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, hydrogenated vegetable oil or a combination thereof.

[0037] In the preferred technical solution of the present invention, the pharmaceutical composition comprises the following components in percentage by weight:

[0038]

[0039] In a preferred technical solution of the present invention, the dosage form of the pharmaceutical composition is selected from tablets, pills or capsules.

[0040] Another object of the present invention is to provide a method for preparing a pharmaceutical composition, wherein the composition comprises topiramate and a pharmaceutically acceptable excipient, comprising the following steps:

[0041] (1) crushing topiramate with a crusher to a D90 value of 15 to 200 μm, preferably to a D90 value of 60 to 150 μm;

[0042] (2) mixing the crushed topiramate with filler 2, disintegrant, and part of lubricant, and then adding filler 1 and binder, and sieving. After sieving, the materials are further mixed to obtain premixed powder;

[0043] (3) granulating the premixed drug powder using a dry granulator, adding the remaining lubricant, and mixing to obtain a total mixed drug powder;

[0044] (4) Compressing the total mixed drug powder into tablets and coating the tablets to obtain the product.

[0045] In a preferred technical solution of the present invention, in step (2), the mixing time is 5 to 10 minutes.

[0046] In a preferred technical solution of the present invention, in step (2), the amount of the lubricant added is 37.5-40% of the total weight of the lubricant.

[0047] In a preferred technical solution of the present invention, in step (2), a granulator is used for screening, and the sieve size of the granulator is 0.8 to 1.5 mm, preferably 1 to 2 mm.

[0048] In the preferred technical solution of the present invention, in step (3), the screen size of the dry granulator is 0.8-1.5 mm, the feeding speed is 20-40 rpm, the roller speed is 5-7 rpm, and the granulation speed is 80-100 rpm; preferably, the screen size is 1-2 mm.

[0049] In a preferred technical solution of the present invention, in step (3), the mixing time is 3 to 10 minutes.

[0050] In the preferred technical solution of the present invention, in step (4), the tableting hardness is 25 to 90N.

[0051] In the preferred technical solution of the present invention, in step (4), the coating is performed using a coating solution having a solid content of 8.0% prepared by using a film coating premix and 80% ethanol.

[0052] Another object of the present invention is to provide use of the pharmaceutical composition in preparing drugs for treating epilepsy.

[0053] Compared with the prior art, the present invention has the following beneficial effects:

[0054] The United States Pharmacopoeia USP2022 discloses the quality standard of topiramate, which limits aminosulfonate to ≤0.1% and sulfate to ≤0.1%, and has no limit on particle size. The present invention controls the content of aminosulfonate and sulfate in topiramate to less than 0.02% (for example, less than 0.005%, or not detected), and controls the particle size of topiramate to 60-150 μm, which can slow down the degradation rate of topiramate and significantly improve the stability of the topiramate preparation.

[0055] The topiramate preparation prepared by the present invention has good stability, and its dissolution property is similar to that of the reference preparation, and has good application prospects.

[0056] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0057] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0058] The topiramate to be purified used in the specific embodiment of the present invention can be obtained by purchasing commercially available products.

[0059] Example 1 Purification of Topiramate

[0060] Weigh 1.0 kg of topiramate to be purified (D90 235 μm), add 2 L of ethanol and water (ethanol: water = 1:2, V / V) solution, heat to 80±5°C and stir to dissolve, cool to 35-40°C and stir for 0.5 hour, then slowly cool to 5±5°C for crystallization for 2 hours, filter, and dry the filter cake under reduced pressure at 55±5°C for 3 hours to obtain 920.5 g of purified topiramate. Yield 92%.

[0061] The particle size D90 value of topiramate after purification was determined by a particle size analyzer to be 254 μm.

[0062] Example 2 Purification of Topiramate

[0063] Weigh 1.0 kg of topiramate to be purified (D90 235 μm), add 3 L of ethanol and water (ethanol: water = 1:4, V / V) solution, heat to 80±5°C and stir to dissolve, cool to 35-40°C and stir for 0.5 hour, then slowly cool to 5±5°C for crystallization for 2 hours, filter, and dry the filter cake under reduced pressure at 55±5°C for 4 hours to obtain 930.0 g of purified topiramate. Yield 93%.

[0064] The particle size D90 value of topiramate after purification was determined by a particle size analyzer to be 280 μm.

[0065] Example 3 Purification of Topiramate

[0066] Weigh 100g of topiramate to be purified (D90 235μm), add 1L of ethanol and water (ethanol: water = 1:1, V / V) solution, heat to 80±5℃, stir to dissolve, cool to 35-40℃, stir for 0.5 hours, then slowly cool to 5±5℃ for crystallization for 2 hours, filter, and dry the filter cake under reduced pressure at 55±5℃ for 2 hours to obtain 86.2g of purified topiramate. Yield 86.2%.

[0067] The particle size D90 value of topiramate after purification was determined by a particle size analyzer to be 269 μm.

[0068] Example 4 Purification of Topiramate

[0069] Weigh 100g of topiramate to be purified (D90 is 235μm), add 1L of ethanol and water (ethanol: water = 3:1, V / V) solution, heat to 80±5℃, stir to dissolve, clarify, filter while hot, lower the internal temperature to 35-40℃, stir for 0.5 hours, then slowly cool to 5±5℃ for crystallization for 4 hours, filter by suction, and dry the filter cake under reduced pressure at 55±5℃ for 3 hours to obtain 79.5g of purified topiramate. Yield 79.5%.

[0070] The particle size D90 value of topiramate after purification was determined by a particle size analyzer to be 240 μm.

[0071] The method for detecting the aminosulfonate and sulfate content in topiramate is as follows:

[0072] Weigh the topiramate to be tested, add the mobile phase to dissolve and dilute to make a solution containing 30 mg of topiramate per 1 mL as the test solution; take an appropriate amount of aminosulfonic acid and sodium sulfate, accurately weigh, add the mobile phase to dissolve and quantitatively dilute to make a mixed solution containing about 60 μg of aminosulfonic acid and 90 μg of sodium sulfate per 1 mL as the reference solution. Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Four General Rules 0512). Use an anion exchange column (Hamilton PRP X100, 4.6 mm × 150 mm, 5 μm); 0.08% p-hydroxybenzoic acid aqueous solution (adjust pH to 9.9 ± 0.1 with sodium hydroxide test solution)-methanol (97.5: 2.5) as the mobile phase; the flow rate is 2.0 mL per minute; the column temperature is 40 ° C; the detection wavelength is 310 nm; the detector polarity is negative; the injection volume is 100 μL. Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. If there is an impurity peak with the same retention time as the aminosulfonate peak and sulfate peak in the chromatogram of the test solution, aminosulfonate (NH2SO3 ﹣ Calculate by external standard method by multiplying the peak area by 0.99, sulfate (as SO4 2﹣ (Calculated by external standard method by multiplying the peak area by 0.68) and shall not exceed 0.2% of the labeled amount of topiramate.

[0073] The test results are shown in Table 1.

[0074] Table 1 Test results of aminosulfonate and sulfate content in topiramate

[0075] Test product Sulfamate Sulfate Topiramate to be purified 0.08％ 0.07％ Topiramate after purification (Example 1) 0.005％ Not detected Topiramate after purification (Example 2) Not detected Not detected Topiramate after purification (Example 3) 0.02％ 0.02％ Topiramate after purification (Example 4) 0.04％ 0.05％

[0076] Example 5-12 Preparation of Topiramate Preparation

[0077] The topiramate preparation was prepared according to the prescription shown in Table 2, batch size: 1000 tablets.

[0078] Table 2 Prescription of topiramate preparations

[0079]

[0080]

[0081] Preparation method:

[0082] (1) The purified topiramate in Examples 6-9 and 12 was crushed with a hammer mill to a D90 value of 150 μm; the purified topiramate in Example 10 was crushed with a hammer mill to a D90 value of 60 μm; the purified topiramate in Examples 5 and 11 was crushed with a hammer mill to a D90 value of 25 μm;

[0083] (2) According to the prescription in Table 2, topiramate, microcrystalline cellulose, sodium starch glycolate, and part of magnesium stearate (0.6 g) were added to a three-dimensional mixer and mixed for 5 min at a frequency of 30.34 Hz. Lactose and pregelatinized starch were added and mixed for 5 min at a frequency of 30.42 Hz. The premixed powder was passed through a 2.0 mm sieve of a granulator at a frequency of 20 Hz. After sieving, the materials were mixed for 10 min at a frequency of 30.47 Hz to obtain a premixed powder.

[0084] (3) The premixed powder was granulated using a dry granulator, using a 1.0 mm screen, a feeding speed of 40 rpm, a roller speed of 7 rpm, and a granulation speed of 100 rpm. The remaining magnesium stearate (1.0 g) was added and mixed for 5 min at a frequency of 30.17 Hz to obtain a total mixed powder;

[0085] (4) Using a 9.5 mm diameter round punch, tablets are compressed according to a theoretical tablet weight of 320 mg ± 5.0% and a hardness of 60-90 N. The obtained plain tablets are coated with a coating solution having a solid content of 8.0% prepared by using a film coating premix and 80% ethanol.

[0086] Comparative Example 1 Preparation of Topiramate Preparation (Batch: 1000 Tablets)

[0087]

[0088] The preparation method is the same as Example 9.

[0089] Comparative Example 2 Preparation of Topiramate Preparation (Batch: 1000 Tablets)

[0090]

[0091] The preparation method is the same as Example 9.

[0092] Comparative Example 3 Preparation of Topiramate Preparation (Batch: 1000 Tablets)

[0093]

[0094]

[0095] The preparation method is the same as Example 9.

[0096] Test 1 Stability test of topiramate preparation

[0097] The topiramate preparations prepared in Examples 5-12 of the present invention and Examples 1-3 and the reference preparation were placed at 60° C. for 30 days and compared with the data of the samples from the same batch at day 0. The results are shown in Table 3.

[0098] Table 3 Stability test results of topiramate preparations

[0099]

[0100] As shown in Table 3, when neither sulfamate nor sulfate was detected in topiramate, and the particle size D90 of topiramate was in the range of 60-150 μm, the obtained topiramate preparation had good stability, and the degree of degradation was the least after being placed at 60°C for 30 days (Examples 6-10, 12), which was better than the reference preparation; when the particle size D90 of topiramate was 25 μm (Examples 5, 11), the obtained topiramate preparation was placed at 60°C for 30 days, and the degree of degradation was greater than that of the topiramate preparation with a particle size D90 of 60-150 μm (Examples 6-10, 12), proving that a smaller particle size is not conducive to the storage of the topiramate preparation; when both sulfamate and sulfate in topiramate were ≥0.02%, significant degradation occurred after being placed at 60°C for 30 days (Comparative Examples 1-3), and the higher the content of sulfamate and sulfate, the greater the degree of degradation.

[0101] Test 2 In vitro dissolution test of topiramate preparation

[0102] According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method), the in vitro dissolution of the topiramate preparation prepared in Example 9 was investigated. The results are shown in Table 4.

[0103] Table 4 Dissolution test results

[0104]

[0105]

[0106] According to the results in Table 4, the topiramate preparation prepared by the method of the present invention has a dissolution rate of more than 85% in pH 1.2, pH 4.5, pH 6.8 and aqueous media within 15 minutes, which is similar to the reference preparation.

[0107] In summary, the present invention further controls the contents of aminosulfonate and sulfate in topiramate and controls the particle size of topiramate, so that the obtained topiramate preparation has good stability and a dissolution property similar to that of the reference preparation, and has good application prospects.

Claims

1. A method for improving the stability of a topiramate preparation, characterized in that: The aminosulfonate content of the topiramate is less than 0.02%, and the sulfate content is less than 0.02%; preferably, the aminosulfonate content of the topiramate is less than 0.005%, and the sulfate content is less than 0.005%; more preferably, the aminosulfonate and sulfate in the topiramate are not detected; the topiramate particle size D90 value is 15 to 200 μm; preferably, the topiramate particle size D90 value is 60 to 150 μm.

2. A method for purifying topiramate, characterized in that: The steps include: Mix the topiramate to be purified with a mixed solvent consisting of an organic solvent and water, heat and stir until dissolved and clarified, cool to 35-40°C and stir, cool to 5±5°C and crystallize, filter with suction, and dry the filter cake to obtain; Preferably, the mass volume ratio of the topiramate to be purified to the mixed solvent is 1:1 to 1:5 g / mL, more preferably 1:2 to 1:3 g / mL; Preferably, the organic solvent is selected from one of methanol, ethanol, isopropanol or a combination thereof; Preferably, the volume ratio of the organic solvent to water is 1:2-1:4; Preferably, the heating temperature is 75-85°C; Preferably, the drying condition is reduced pressure drying at 50-60° C. for 2-5 hours.

3. Topiramate prepared by the purification method according to claim 2, characterized in that: The aminosulfonate content of the topiramate is less than 0.02%, and the sulfate content is less than 0.02%; preferably, the aminosulfonate content is less than 0.005%, and the sulfate content is less than 0.005%; more preferably, the aminosulfonate content and the sulfate content are not detected.

4. A pharmaceutical composition, characterized in that The composition comprises the topiramate according to claim 3 and a pharmaceutically acceptable excipient; preferably, the pharmaceutically acceptable excipient is selected from a filler, a binder, a disintegrant and a lubricant; preferably, the dosage form of the pharmaceutical composition is selected from a tablet, a pill or a capsule.

5. The pharmaceutical composition according to claim 4, characterized in that The composition comprises the following weight percentages: Topiramate 20-40% Filler 1 30-50% Filler 2 10-30% Adhesive 0.5-5% Disintegrant 0.5-10% Lubricant 0.1-1%; Preferably, the pharmaceutical composition comprises the following components in percentage by weight: Topiramate 30-35% Filler 1 38-47% Filler 2 15-24% Adhesive 1-3% Disintegrant 1-7% Lubricant 0.1-0.5%.

6. The pharmaceutical composition according to claim 5, characterized in that The filler 1 is selected from one of lactose, sucrose, microcrystalline cellulose, mannitol, sorbitol, xylitol, glucose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, calcium chloride, aluminum chloride, sodium chloride, calcium oxide, zinc oxide, and magnesium oxide, or a combination thereof; Preferably, the filler 2 is selected from one of lactose, sucrose, microcrystalline cellulose, mannitol, sorbitol, xylitol, glucose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, calcium chloride, aluminum chloride, sodium chloride, calcium oxide, zinc oxide, magnesium oxide, or a combination thereof; Preferably, the adhesive is selected from one or a combination of pregelatinized starch, polyvinyl pyrrolidone, gelatin, xanthan gum, dextrin, polyvinyl alcohol, and carboxymethyl cellulose; Preferably, the disintegrant is selected from one or a combination of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch; Preferably, the lubricant is selected from one or a combination of talc, micropowdered silica gel, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, and hydrogenated vegetable oil.

7. The pharmaceutical composition according to any one of claims 4 to 6, characterized in that The composition comprises the following weight percentages: Topiramate 31.25% Lactose 38-47% Microcrystalline cellulose 15-24% Pregelatinized starch 1-3% Sodium carboxymethyl starch 1-7% Magnesium stearate 0.1-0.5%.

8. The method for preparing the pharmaceutical composition according to any one of claims 4 to 7, characterized in that: The steps include: (1) crushing topiramate with a crusher to a D90 value of 15 to 200 μm, preferably to a D90 value of 60 to 150 μm; (2) mixing the crushed topiramate with filler 2, disintegrant, and part of lubricant, and then adding filler 1 and binder, and sieving. After sieving, the materials are further mixed to obtain premixed powder; (3) granulating the premixed drug powder using a dry granulator, adding the remaining lubricant, and mixing to obtain a total mixed drug powder; (4) Compressing the total mixed drug powder into tablets and coating the tablets to obtain the product.

9. The method according to claim 8, characterized in that In step (2), the mixing time is 5 to 10 minutes; Preferably, in step (2), the amount of the lubricant added is 37.5-40% of the total weight of the lubricant; Preferably, in step (2), a granulator is used for sieving, and the sieve size of the granulator is 0.8 to 1.5 mm, more preferably 1 to 2 mm; Preferably, in step (3), the screen size of the dry granulator is 0.8-1.5 mm, the feeding speed is 20-40 rpm, the roller speed is 5-7 rpm, and the granulation speed is 80-100 rpm; more preferably, the screen size is 1-2 mm; Preferably, in step (3), the mixing time is 3 to 10 minutes; Preferably, in step (4), the tableting hardness is 25 to 90N; Preferably, in step (4), the coating is performed using a coating solution having a solid content of 8.0% prepared by using a film coating premix and 80% ethanol.

10. Use of the pharmaceutical composition according to any one of claims 4 to 7 in the preparation of a drug for treating epilepsy.

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