Briracetam sustained release tablet and preparation method thereof

Abstract

The invention discloses a briracetam sustained-release tablet and a preparation method thereof, belongs to the field of pharmaceutical preparations, and aims to solve the problems of food effect, unstable release and process formability of the briracetam sustained-release tablet. According to the technical scheme, a tablet-in-tablet structure is adopted, a sustained-release core contains composite hydroxypropyl methylcellulose (high / medium viscosity mixture) and micronized ethyl cellulose, and a quick-release outer layer contains a disintegrating agent; the preparation method comprises the steps of ethanol granulation and pressing. The invention has the technical effects that the 24-hour stable drug release is realized, and the postprandial / empty stomach release difference is 1t; and meanwhile, the flowability and the hardness are improved by 53%, and the preparation method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a brivaracetam sustained-release tablet and a preparation method thereof. BACKGROUND

[0002] Epilepsy is a common chronic neurological disease characterized by abnormality and excessive synchronization of brain neuron discharge. Brivaracetam is a new generation of high-selectivity and high-affinity synaptic vesicle protein 2A (SV2A) ligand, which can effectively control seizures. At present, all the brivaracetam on the market in the world are ordinary immediate-release tablets, which need to be taken twice a day.

[0003] This twice-a-day administration regimen has inherent defects: first, the blood drug concentration of the patient presents a clear "peak-valley" phenomenon, the peak concentration is easy to cause adverse reactions such as dizziness and sleepiness, and the valley concentration may increase the risk of "breakthrough" seizures due to being lower than the effective therapeutic window; second, multiple daily dosing reduces the medication compliance of patients, especially for patients with epilepsy who need long-term treatment. Therefore, it has great clinical value to develop a brivaracetam sustained-release preparation which only needs to be taken once a day.

[0004] In the development of sustained-release preparations, hydrophilic gel matrix technology, such as the use of high-viscosity hydroxypropyl methylcellulose (HPMC) alone, is a common means. However, the drug release behavior of such single matrix is extremely susceptible to the gastrointestinal environment (such as pH, peristalsis intensity) and food. In particular, a high-fat diet can significantly change the physiological state of the gastrointestinal tract, which may lead to a large amount of drug release in a short time, i.e. "dose dumping", which is a serious safety hazard for anti-epileptic drugs with a narrow therapeutic window.

[0005] To solve this problem, some technicians attempt to simply compound hydrophobic matrix materials (such as ethyl cellulose, EC) with HPMC. However, such simple physical mixing often fails to form a uniform and stable matrix structure. The difference in properties of the two materials may cause local aggregation or stratification during granulation or tabletting, resulting in uneven internal structure of the tablet, and further leading to large differences in drug release behavior between tablets and batches, and difficulty in ensuring the uniformity of product quality. In addition, when the drug load and the total amount of matrix material are high, new technical problems may also arise, i.e. poor flowability of powder and poor compressibility, leading to phenomena such as sticking, cracking and loose tablets during tabletting, and the physical properties such as hardness and friability of the tablets are difficult to meet the standards, which poses a challenge to industrialized production.

[0006] In summary, there is an urgent need in the art for a new type of brivaracetam sustained-release preparation, which not only can achieve 24-hour stable drug release and overcome the food effect, but also should have excellent formulation forming properties and stable batch quality to meet the requirements of clinical needs and industrialized production. SUMMARY

[0007] The present application aims to overcome the deficiencies of the prior art, and provides a brivaracetam sustained-release tablet and a preparation method thereof.

[0008] The object of the present application can be achieved by the following technical solutions. A brivaracetam sustained-release tablet, which is in a tablet-in-tablet structure and comprises a sustained-release core and a rapid-release outer layer covering the sustained-release core. The sustained-release core is made of the following raw materials by weight: Brivaracetam: 40-100 parts; Composite hydrogel matrix material: 30-80 parts; Micronized hydrophobic inert matrix material: 10-50 parts; Filling agent: 20-60 parts; Lubricant: 0.5-2 parts; The composite hydrogel matrix material is a mixture of high-viscosity hypromellose and medium-viscosity hypromellose at a mass ratio of (3-5): 1. The micronized hydrophobic inert matrix material is ethyl cellulose with an average particle size of less than 20 μm. The rapid-release outer layer is made of the following raw materials by weight: Brivaracetam: 10-25 parts; Filling agent: 30-90 parts; Disintegrant: 2-10 parts; Binder: 1-5 parts; Lubricant: 0.5-2 parts.

[0009] Further, the high-viscosity hypromellose has a viscosity of 80000-120000 mPa·s, and the medium-viscosity hypromellose has a viscosity of 10000-20000 mPa·s.

[0010] Further, the filling agent in the sustained-release core and the rapid-release outer layer is selected from one or more of microcrystalline cellulose, lactose, and calcium hydrogen phosphate.

[0011] Further, the disintegrant in the rapid-release outer layer is selected from one or more of croscarmellose sodium, crospovidone, and low-substitution hydroxypropyl cellulose.

[0012] Further, the adhesive in the immediate release outer layer is selected from one of povidone K30, hydroxypropyl cellulose.

[0013] Further, the lubricant in the sustained release core and the immediate release outer layer is selected from one or both of magnesium stearate, silicon dioxide.

[0014] Further, the present application also provides a preparation method of the above-mentioned brivaracetam sustained release tablet, comprising the following steps: (1) Preparation of the sustained release core: uniformly premix the prescription amount of high viscosity hydroxypropyl methyl cellulose and medium viscosity hydroxypropyl methyl cellulose to obtain a composite hydrophilic gel skeleton material, then mix the prescription amount of brivaracetam, the composite hydrophilic gel skeleton material, micronized hydrophobic inert skeleton material and filler to obtain a dry mixed material, then add 75% by volume of ethanol aqueous solution to the dry mixed material to granulate, pass through a 20 mesh sieve to obtain wet granules, then fluidized bed dry the wet granules at 50-60°C, control the weight loss of the granules to be less than 2.0%, then use a 18-24 mesh sieve to size the dried granules, add the prescription amount of lubricant, and total mix in a three-dimensional mixer for 5-10 minutes to obtain sustained release core granules, then use a tablet press to pre-press the sustained release core granules into a sustained release core; (2) Preparation of the immediate release outer layer powder: mix the prescription amount of brivaracetam, filler, disintegrant and adhesive, then add the lubricant and mix to obtain the immediate release outer layer powder; (3) Compression into tablets: place the sustained release core in the center of half of the total amount of the immediate release outer layer powder, then fill in the remaining immediate release outer layer powder, and compress to obtain the brivaracetam sustained release tablet.

[0015] Further, the amount of the 75% by volume of ethanol aqueous solution is 35%-45% of the total weight of the dry mixed material.

[0016] The present application has the following advantages: (1) Industrial production advantage: the present application solves the process problem under high drug loading (flowability ↑ 32%, compressibility ↑ 44%) by the cooperation of composite HPMC and micronized EC, the tablet hardness is increased by 53% (compared with the worst comparative example), the friability is reduced by 83%, and the large-scale production requirements are met.

[0017] (2) Breakthrough in quality controllability: the micronized EC of the present application ensures the uniformity of the skeleton structure, and the release batch difference is significantly lower than the prior art (the fluctuation range of comparative examples 2 / 3 is >25%).

[0018] (3) Upgrade of clinical safety: the unique "dual-phase regulation microporous composite skeleton" of the present application completely overcomes the food effect (postprandial / fasting release difference <3%), avoids the risk of dose dumping, and provides safety guarantee for anti-epileptic drugs with narrow therapeutic window.

[0019] In summary, the present application overcomes the three bottlenecks of poor process performance, uncontrollable release behavior and food effect in the prior art by the disruptive innovation of material selection (composite HPMC + micronized EC) and structural design (tablet-in-tablet), and has great value in industrialization and clinical application. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application. Meanwhile, the raw materials, reagents or devices used in the following embodiments can be obtained from conventional commercial channels if not specifically stated, and part of the main raw material specifications and sources are as follows: (1) Brivaracetam: purity > 99.5%, Zhejiang Huahai Pharmaceutical Co., Ltd.

[0021] (2) Hydroxypropyl Methylcellulose K100M (HPMC K100M): Dow Chemical Company, viscosity 100000 mPa·s.

[0022] (3) Hydroxypropyl Methylcellulose K15M (HPMC K15M): Dow Chemical Company, viscosity 15000 mPa·s.

[0023] (4) Ethylcellulose (EC, Ethocel TM 10 FP Premium): Dow Chemical Company, micronized grade, D 90 <20 μm.

[0024] (5) Ethylcellulose (EC, Ethocel TM 10 Premium): Dow Chemical Company, standard particle grade.

[0025] (6) Microcrystalline cellulose (MCC, Avicel® PH102): FMC Corporation, USA.

[0026] (7) Crosscarmellose sodium (Ac-Di-Sol®): FMC Corporation, USA.

[0027] (8) Polyvinylpyrrolidone K30 (PVP K30): BASF, Germany.

[0028] (9) Magnesium stearate: commercially available.

[0029] Example 1

[0030] This embodiment provides a 100mg / tablet brucetam extended-release tablet, each tablet containing 100mg brucetam (20mg immediate-release layer and 80mg extended-release core). 1000 tablets are prepared.

[0031] 1. Preparation of sustained-release core: (1) Prescription: Buriceran 80g, HPMC K100M 45g, HPMC K15M 15g, micronized ethyl cellulose (Ethocel) TM 10 FP Premium) 25g, Microcrystalline cellulose 35g, Magnesium stearate 2g.

[0032] (2) Preparation steps: a. Place 45g HPMC K100M and 15g HPMC K15M in a mixer and premix for 10 minutes.

[0033] b. Add 80g bricetan, 25g micronized ethyl cellulose and 35g microcrystalline cellulose, and dry mix in a high-efficiency wet granulation machine for 10 minutes.

[0034] c. Slowly add 80g of 75% ethanol aqueous solution as a wetting agent and stir at low speed to form a soft material.

[0035] d. Granulate the soft material through a 20-mesh sieve and dry it in a fluidized bed at 60°C until the LOD of the particles is less than 2.0%.

[0036] e. Use a granulator to granulate through a 24-mesh sieve.

[0037] f. Add 2g of magnesium stearate and mix in a three-dimensional mixer for 5 minutes.

[0038] g. Using an 8mm round shallow concave punch, press the above particles into a sustained-release core weighing approximately 202mg and with a hardness of 40-60N.

[0039] 2. Preparation of the immediate-release outer layer: (1) Prescription: Brucetan 20g, lactose 70g, croscarmellose sodium 6g, povidone K30 4g, magnesium stearate 2g.

[0040] (2) Preparation steps: a. Place 20g bricetan, 70g lactose, 6g croscarmellose sodium, and 4g povidone K30 in a mixer and mix for 15 minutes.

[0041] b. Add 2g of magnesium stearate and continue mixing for 5 minutes to obtain the immediate-release outer layer powder.

[0042] 3. Compress into tablets: Use the ZP-19 tablet press with a 12mm round shallow concave punch.

[0043] First, fill about 51g of the immediate-release outer layer powder (1 / 2 of the total amount) into the mold hole, place the sustained-release core prepared in step 1g in the center, and then fill in the remaining 51g of the immediate-release outer layer powder.

[0044] By controlling the pressure, bricetam extended-release tablets were obtained.

[0045] Comparative Example 1 Comparative Example 1 served as the control group for Example 1. Compared to Example 1, in the formulation of the sustained-release core, 45g of HPMCK100M and 15g of HPMC K15M were replaced with an equal amount of a single high-viscosity HPMC, namely 60g of HPMC K100M. All other raw materials, dosages, and preparation processes were exactly the same as in Example 1, ultimately yielding bricetam sustained-release tablets.

[0046] Comparative Example 2 Comparative Example 2 served as the control group for Example 1. Compared to Example 1, the sustained-release core formulation contained 25g of micronized ethyl cellulose (Ethocel). TM Replace 10 FP Premium with an equal amount of 25g standard granular ethyl cellulose (Ethocel). TM (10 Premium). All other raw materials, dosages, and preparation processes were exactly the same as in Example 1, ultimately yielding bricetrast extended-release tablets.

[0047] Comparative Example 3 Comparative Example 3 served as the control group for Example 1. Compared to Example 1, the sustained-release core formulation was modified by replacing "45g HPMCK100M + 15g HPMC K15M" with "60g HPMC K100M" and "25g micronized EC" with "25g standard particle-grade EC". All other raw materials, dosages, and preparation processes were identical to those in Example 1, ultimately yielding bricetam sustained-release tablets.

[0048] Comparative Example 4 Comparative Example 4 served as the control group for Example 1. Compared to Example 1, 25g of micronized ethyl cellulose was removed from the sustained-release core formulation and replaced with an equal amount of filler (25g of microcrystalline cellulose) to maintain a substantially unchanged core weight. Specifically, the sustained-release core formulation was adjusted to: 80g bricetam, 45g HPMC K100M, 15g HPMC K15M, 60g microcrystalline cellulose (35g + 25g), and 2g magnesium stearate. All other preparation processes remained identical to those in Example 1, ultimately yielding bricetam sustained-release tablets.

[0049] Test Example 1 The bricetam sustained-release tablets prepared in Example 1 and Comparative Examples 1 to 4 were subjected to particle properties (angle of repose and compressibility index). The test procedure is as follows, and the test results are shown in Table 1: (1) Angle of repose determination: The fixed funnel method was used. An appropriate amount of bricetam sustained-release tablets was taken and allowed to fall freely from the funnel, forming a conical accumulation on a horizontal plate. The height (h) and the radius (r) of the base of the accumulation were measured, and the angle of repose α was calculated using the formula tan(α) = h / r. The measurement was repeated 3 times, and the average value was taken.

[0050] (2) Compression index determination: Take a certain amount (m) of bricetam sustained-release tablets and gently place them into a 100mL graduated cylinder. Record the volume (V0) at its loose density. Then, vibrate the graduated cylinder on a tapped density meter at a specified frequency and amplitude until the volume no longer changes. Record the volume (V0) at the tapped density. f Compression index (%) is calculated using the formula: Compression Index (%) = [(V0 - V)] f Calculate using [(V0)]×100%. Repeat the measurement 3 times and take the average value.

[0051] Table 1. Results of particle property tests

[0052] Analysis of the data in Table 1: (1) Superiority of Example 1: The angle of repose (29.5°) and compressibility index (12.6%) of Example 1 were the lowest among all groups, indicating that its particles have excellent flowability and compressibility. This is entirely attributed to its unique technical solution: the synergistic effect of composite hydrophilic gel framework material (high viscosity HPMC K100M + medium viscosity HPMC K15M) and micronized hydrophobic inert framework material (micronized EC).

[0053] (2) Comparative Analysis with Comparative Example 1: Comparative Example 1 simply replaced the composite HPMC in Example 1 with a single high-viscosity HPMC K100M. The results showed that its angle of repose (35.2°) and compressibility index (18.1%) were significantly worse than those of Example 1. This directly proves that the introduction of medium-viscosity HPMC K15M is not a simple material replacement, but a key improvement to the particle processing performance. According to the description in the Summary of the Invention, HPMC K15M acts as a "plasticizer" and "binder" here, thereby significantly improving the flowability and compressibility of the particles.

[0054] (3) Comparative Analysis with Comparative Example 2: Comparative Example 2 simply replaced the micronized EC in Example 1 with standard particle-grade EC. The results showed that its angle of repose (37.8°) and compressibility index (20.5%) were worse than those of Comparative Example 1. This strongly demonstrates that the "micronization" of the hydrophobic framework material is another key factor in achieving excellent processing performance. Micronized EC can be more uniformly dispersed and filled in the voids between HPMC framework particles, reducing friction and porosity, thereby improving the overall flowability and compressibility of the powder, while standard particle-grade EC cannot effectively achieve this effect.

[0055] (4) Comparative Analysis with Comparative Example 3: Comparative Example 3 used both high-viscosity HPMC and standard particle-grade EC, representing a superposition of problems. Its angle of repose (41.3°) and compressibility index (25.4%) were the worst among all groups, indicating that its flowability and compressibility were very unsatisfactory. This result perfectly matches the technical problem of "poor powder flowability and poor compressibility" described in the background art, thus proving that the technical solution of Example 1 (composite HPMC + micronized EC) is an effective solution to this problem.

[0056] (5) Comparative Analysis with Comparative Example 4: Comparative Example 4, based on the composite HPMC of Example 1, removed the micronized EC. Its angle of repose (31.8°) and compressibility index (15.5%) were superior to Comparative Examples 1, 2, and 3, but still inferior to Example 1. This reveals two important pieces of information: A. The composite HPMC system itself can significantly improve particle properties.

[0057] B. The addition of micronized EC further enhances the performance of the composite HPMC system, achieving optimal results. This demonstrates the synergistic effect between composite HPMC and micronized EC.

[0058] Test Example 2 The brisaectatine sustained-release tablets prepared in Example 1 and Comparative Examples 1 to 4 were tested for their tablet physical properties (hardness and friability). The test process is as follows, and the test results are shown in Table 2: (1) Hardness test: Randomly select 10 finished tablets and use a tablet hardness tester to measure the radial crushing pressure (N). Record the value of each tablet and calculate the average value.

[0059] (2) Friability determination: Accurately weigh a certain weight (W0, about 6.5g) of tablets and place them in a friability tester, rotating it 100 times at a speed of 25 rpm. After removing it, use a soft brush to remove the floating powder and weigh it accurately again (W). Calculate the friability using the formula: Friability (%) = [(W0-W) / W0] × 100%.

[0060] Table 2. Results of physical properties of tablets

[0061] Analysis of the data in Table 2: (1) Advantages of Example 1: The tablets of Example 1 have the highest hardness (115N) and the lowest brittleness (0.15%), and their physical properties are excellent, fully meeting the requirements of commercial production and distribution.

[0062] (2) Correlation with Table 1 data: The results in Table 2 show a completely positive correlation with the results in Table 1. The better the compressibility of the granules (the lower the compressibility index), the higher the hardness and the lower the brittleness of the compressed tablets.

[0063] A. The hardness of Comparative Examples 1, 2, and 3 decreased sequentially (90N→80N→75N), while their brittleness increased sequentially (0.42%→0.64%→0.90%), which corresponds perfectly to their gradually deteriorating particle properties in Table 1.

[0064] B. In particular, Comparative Example 3 showed a friability of 0.90%, which is close to the upper limit of 1.0% in the conventional pharmacopoeia, indicating a clear quality risk.

[0065] C. The physical properties of Comparative Example 4 (hardness 105N, brittleness 0.28%) are also better than those of Comparative Examples 1, 2 and 3, but not as good as those of Example 1, which once again confirms the necessity of the combination of composite HPMC and micronized EC for obtaining the best formability.

[0066] Test Example 3 The in vitro dissolution tests were performed on the brisaectam sustained-release tablets prepared in Example 1 and Comparative Examples 1 to 4. The test procedures are as follows, and the test results are shown in Table 3: (1) Test items: In vitro cumulative release under simulated fasting and postprandial conditions.

[0067] (2) Testing process: a. Apparatus: Paddle plate method (Chinese Pharmacopoeia / USP Dissolution Determination Method II).

[0068] b. Dissolution medium: Fasted conditions: First, rotate in 900 mL of hydrochloric acid solution at pH 1.2 for 2 hours, then replace the medium with 900 mL of phosphate buffer at pH 6.8 at the end of the second hour, and continue dissolution for 24 hours; Fed conditions: Dissolve directly in 900 mL of phosphate buffer (pH 5.0, containing an appropriate amount of surfactant such as sodium dodecyl sulfate to simulate bile salts) simulating a postprandial state for 24 hours.

[0069] c. Parameters: Rotation speed 50 rpm, temperature 37±0.5℃.

[0070] d. Sampling: Samples were taken at 1h, 2h, 4h, 8h, 12h, and 24h, and an equal volume of dissolution medium at the same temperature was added. After filtration through a 0.45μm filter membrane, the concentration of bricetam was determined by high-performance liquid chromatography (HPLC), and the cumulative release rate was calculated. Six tablets were measured in each group, and the average value was calculated.

[0071] Table 3. Results of in vitro dissolution test (cumulative release rate %)

[0072] Analysis of the data in Table 3: (1) Example 1: Successfully achieving stable sustained release and overcoming food effects: A. Stable release: According to the data from Example 1 (fasting), the drug was released stably within 24 hours, with 27.8% released in 1 hour (rapid onset of action in the immediate-release layer), and the rate gradually slowed down thereafter, reaching about 81.4% by 12 hours and complete release in 24 hours, showing an ideal sustained-release curve.

[0073] B. Overcoming the food effect: Comparing the "fasting" and "postprandial" curves of Example 1, the cumulative release rates at each time point are almost identical (e.g., 45.2% vs 46.8% at 4h; 65.8% vs 68.1% at 8h). This strongly demonstrates that the "dual-phase regulated microporous composite framework system" constructed in this invention has extremely high structural stability, effectively resists interference from the simulated postprandial environment, fundamentally avoids the risk of "dose dumping," and achieves a technological breakthrough.

[0074] (2) Comparative analysis with Comparative Example 1: The release rate of Comparative Example 1 (single high-viscosity HPMC) was significantly faster than that of Example 1 (e.g., 82.3% released after 8 hours, compared to 65.8% in Example 1). This indicates that the composite HPMC framework in Example 1 forms a stronger and more uniform gel layer than the single HPMC framework, resulting in stronger and more sustained control over drug release. The addition of medium-viscosity HPMCK15M optimized the structural integrity of the gel layer.

[0075] (3) Comparative Analysis with Comparative Examples 2 and 3: The results of Comparative Examples 2 and 3 revealed the critical issue of "large batch-to-batch variation." This indicates that standard particle-grade EC cannot form a uniform and stable composite framework with HPMC. During granulation and tableting, EC and HPMC may separate or be unevenly distributed, resulting in inconsistent internal structures in each tablet or even each batch of product, making drug release behavior unpredictable and uncontrollable. This is precisely the drawback of simple physical mixing as pointed out in the background art. Example 1, by using micronized EC, ensured a highly uniform dispersion of the hydrophobic framework in the hydrophilic gel network, thereby guaranteeing high reproducibility of release behavior and uniformity of product quality.

[0076] (4) Comparative Analysis with Comparative Example 4: Comparative Example 4 (containing only compound HPMC, without EC) was tested under simulated postprandial (Fed) conditions, and the results were decisive. This tablet released over 52.3% within 1 hour and over 91.5% within 4 hours, exhibiting a typical "dose dumping" phenomenon. This result contrasts sharply with the stable release observed in Example 1 under the same postprandial conditions, irrefutably demonstrating that the hydrophobic, inert microporous framework constructed by micronized EC is indispensable for resisting changes in the postprandial gastrointestinal environment and preventing drug burst release, and is key to solving the food effect problem.

[0077] It should be noted that, in this document, terms such as “comprising,” “including,” or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0078] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A sustained release tablet of brivaracetam, characterized in that, The brivaracetam sustained-release tablet is a tablet-in-tablet structure, comprising a sustained-release core and a rapid-release outer layer coated outside the sustained-release core; The sustained-release core is made from the following raw materials by weight: Brivaracetam: 40-100 parts; Composite hydrophilic gel matrix material: 30-80 parts; Micro-powdered hydrophobic inert matrix material: 10-50 parts; Filling agent: 20-60 parts; Lubricant: 0.5-2 parts; The composite hydrophilic gel matrix material is a mixture of high-viscosity hypromellose and medium-viscosity hypromellose at a mass ratio of (3-5):1; The micro-powdered hydrophobic inert matrix material is ethyl cellulose with an average particle size of less than 20 μm; The rapid-release outer layer is made from the following raw materials by weight: Brivaracetam: 10-25 parts; Filling agent: 30-90 parts; Disintegrant: 2-10 parts; Binder: 1-5 parts; Lubricant: 0.5-2 parts.

2. The brivaracetam sustained release tablet according to claim 1, wherein The high-viscosity hypromellose has a viscosity of 80000-120000 mPa·s; and the medium-viscosity hypromellose has a viscosity of 10000-20000 mPa·s.

3. The brucetam sustained-release tablet according to claim 1, characterized in that, The filling agent in the sustained-release core and the rapid-release outer layer is selected from one or more of microcrystalline cellulose, lactose, and calcium hydrogen phosphate.

4. The brucetam sustained-release tablet according to claim 1, characterized in that, The disintegrant in the rapid-release outer layer is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, and low-substitution hydroxypropyl cellulose.

5. A brucetam sustained-release tablet according to claim 1, characterized in that, The binder in the rapid-release outer layer is selected from one of povidone K30 and hydroxypropyl cellulose.

6. The brivaracetam sustained release tablet according to claim 1, wherein The lubricant in the sustained-release core and the rapid-release outer layer is selected from one or both of magnesium stearate and silicon dioxide.

7. The method of claim 1 to 6, wherein the method is characterized in that, The method comprises the following steps: (1) Preparation of the sustained-release core: uniformly premix the prescription amount of high-viscosity hypromellose and medium-viscosity hypromellose to obtain a composite hydrophilic gel matrix material, then mix the prescription amount of brivaracetam, the composite hydrophilic gel matrix material, the micro-powdered hydrophobic inert matrix material, and the filling agent to obtain a dry mixture, then add a 75% volume fraction ethanol aqueous solution to the dry mixture for granulation, pass the wet granules through a 20-mesh sieve, then fluidized bed dry the wet granules at 50-60°C, control the weight loss of the granules to be less than 2.0%, then pass the dried granules through an 18-24-mesh sieve for sizing, add the prescription amount of lubricant, and total mix in a three-dimensional mixer for 5-10 minutes to obtain sustained-release core granules, and then use a tablet press to pre-press the sustained-release core granules into a sustained-release core; (2) Preparation of the rapid-release outer layer powder: mix the prescription amount of brivaracetam, the filling agent, the disintegrant, and the binder, then add the lubricant and mix to obtain the rapid-release outer layer powder; (3) Compression into tablets: place the sustained-release core in the center of half of the total amount of the rapid-release outer layer powder, then fill in the remaining rapid-release outer layer powder, and then compress to obtain the brivaracetam sustained-release tablet.

8. The method of claim 7, wherein the brivaracetam sustained release tablet is prepared by the steps of, The amount of the 75% volume fraction ethanol aqueous solution is 35%-45% of the total weight of the dry mixture.

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