Brivaracetam sustained-release pharmaceutical composition, preparation method therefor, and use thereof

Abstract

A brivaracetam sustained-release pharmaceutical composition, a preparation method therefor, and use thereof. The brivaracetam sustained-release pharmaceutical composition comprises an active pharmaceutical ingredient and a pharmaceutical excipient. The pharmaceutical excipient is selected from one or more of a matrix material, a disintegrating agent, a swelling agent, a binder, a filler, and a lubricant.

Description

A brivaracetam sustained-release pharmaceutical composition, preparation method and application thereof

[0001] This application claims priority to two prior applications: Patent application No. 202311691841.7, filed with the State Intellectual Property Office of China on December 10, 2023, entitled “A sustained-release pharmaceutical composition of brivaracetam, its preparation method and use thereof”; and Patent application No. 202411783409.5, filed with the State Intellectual Property Office of China on December 5, 2024, entitled “A sustained-release pharmaceutical composition of brivaracetam, its preparation method and use thereof”. The entire contents of the prior applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compositions and relates to a brivaracetam sustained-release pharmaceutical composition, a preparation method and an application thereof. Background Art

[0003] Epilepsy is a chronic brain disease characterized by transient brain dysfunction caused by highly synchronized neuronal discharges, commonly known as "epilepsy" or "seizures." Epilepsy has become the second most common neurological disorder in China. According to the latest epidemiological data from China, there are approximately 9 million epilepsy patients in my country, of which 5-6 million have active epilepsy, and approximately 400,000 new cases are diagnosed each year (https: / / www.caae.org.cn / news / show / id / 294). Epileptic seizures can disrupt patients' daily lives and manifest primarily as motor, sensory, autonomic, and cognitive impairments, including memory loss, decreased attention span, and intellectual decline, as well as mood disorders such as anxiety and depression. Long-term, frequent seizures can severely impact patients' physical and mental well-being and can also lead to accidental injury. Since the development of phenobarbital, the first drug for treating epilepsy, in 1912, anti-epileptic drugs have developed rapidly. Currently, anti-epileptic drugs can be divided into three generations: ① Traditional anti-epileptic drugs, including phenytoin, carbamazepine, and sodium valproate; ② Modern anti-epileptic drugs, including oxcarbazepine, levetiracetam, and gabapentin; and ③ New anti-epileptic drugs, including brivaracetam, carabosalt, retigabine, and perampanel. Commonly used clinical treatments include phenytoin, phenobarbital, primidone, carbamazepine, and sodium valproate.

[0004] Brivaracetam is an anti-epileptic drug developed by UCB, suitable for the treatment of partial-onset epilepsy. The chemical name of brivaracetam (also known as brivaracetam) is (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide, and its molecular formula is C 11 H 20 N2O2, its structural formula is:

[0005] Brivaracetam exhibits selectivity and high affinity for synaptic vesicle protein 2A (SV2A) in the brain. SV2A is a transmembrane glycoprotein found at the presynaptic level in neurons and endocrine cells. Although the exact role of this protein remains to be elucidated, it has been shown to regulate neurotransmitter exocytosis. Binding to SV2A is believed to be the primary mechanism of brivaracetam's anticonvulsant activity. The launch of brivaracetam represents a new addition to the adjunctive treatment of partial-onset epilepsy, particularly for patients whose seizures have not been adequately controlled with one or more other adjunctive therapies.

[0006] The currently available brivaracetam dosage forms are ordinary oral tablets, oral solutions, and injections. The oral dosage form requires frequent administration, with large fluctuations in blood drug concentrations and greater adverse reactions; the injection dosage form is cumbersome to use and has poor compliance.

[0007] Therefore, there is an urgent need to develop a sustained-release tablet to achieve the purpose of reducing the drug release rate, controlling the effective dose of the drug in the body, and reducing the number of daily administrations. Summary of the Invention

[0008] The technical problem solved by the present invention is to provide a brivaracetam sustained-release pharmaceutical composition which is different from the prior art and has good sustained-release effect, stable blood drug concentration, good efficacy, few side effects and good compliance, as well as a preparation method and application thereof.

[0009] To improve the above technical problems, the present invention provides a sustained-release pharmaceutical composition of brivaracetam, which slowly releases the drug over 24 hours, and its dissolution simultaneously meets the following four characteristics (determined according to the dissolution and release rate determination method, Method 7 of the General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia, dissolution conditions: the dissolution medium is a pH 1.2 hydrochloric acid solution and / or a pH 4.5 acetate buffer solution, the immersion speed is 20 DPM, the screen is made of 20 mesh polypropylene material, and the instillation time is 15 seconds):

[0010] A) no more than 40% of the active pharmaceutical ingredient dissolves within 1 hour;

[0011] B) dissolve 20% to 70% of the active pharmaceutical ingredient within 4 hours;

[0012] C) dissolve 60% to 90% of the active pharmaceutical ingredient within 12 hours;

[0013] D) dissolve not less than 70% of the active pharmaceutical ingredient within 24 hours;

[0014] The pharmaceutically active ingredient may be one, two or more selected from the group consisting of brivaracetam, a pharmaceutically acceptable complex of brivaracetam, a pharmaceutically acceptable salt of brivaracetam, a pharmaceutically acceptable solvate of brivaracetam and a pharmaceutically acceptable hydrate of brivaracetam.

[0015] According to some embodiments of the present invention, the brivaracetam sustained-release pharmaceutical composition is a 24-hour slow-release drug, and its dissolution simultaneously satisfies the following four characteristics:

[0016] A) no more than 35% of the active pharmaceutical ingredient dissolves within 1 hour;

[0017] B) dissolve 30% to 70% of the active pharmaceutical ingredient within 4 hours;

[0018] C) dissolve 60% to 85% of the active pharmaceutical ingredient within 12 hours;

[0019] D) No less than 75% of the active pharmaceutical ingredient is dissolved within 24 hours.

[0020] According to some embodiments of the present invention, the brivaracetam sustained-release pharmaceutical composition is a 24-hour slow-release drug, and its dissolution simultaneously satisfies the following four characteristics:

[0021] A) dissolving no more than 30% of the pharmaceutically active ingredient within 1 hour; preferably, dissolving no more than 30% of the brivaracetam or a pharmaceutically acceptable salt thereof within 1 hour;

[0022] B) dissolving 35% to 60% of the active pharmaceutical ingredient within 4 hours; preferably, dissolving 35% to 60% of brivaracetam or a pharmaceutically acceptable salt thereof within 4 hours;

[0023] C) dissolving 65% to 85% of the active pharmaceutical ingredient within 12 hours; preferably, dissolving 65% to 85% of brivaracetam or a pharmaceutically acceptable salt thereof within 12 hours;

[0024] D) dissolving not less than 80% of the pharmaceutical active ingredient within 24 hours; preferably, dissolving not less than 80% of the brivaracetam or a pharmaceutically acceptable salt thereof within 24 hours.

[0025] Here, the term "dissolution" refers to the cumulative dissolution rate of the active pharmaceutical ingredient (e.g., brivaracetam or a pharmaceutically acceptable salt thereof); further, the cumulative dissolution rate is measured in a pH 1.2 hydrochloric acid solution or a pH 4.5 acetate buffer. Those skilled in the art will appreciate that the dissolution rate of brivaracetam or a pharmaceutically acceptable salt thereof gradually increases over time.

[0026] The present invention provides a brivaracetam sustained-release pharmaceutical composition, comprising a pharmaceutically active ingredient and a pharmaceutical excipient, wherein the pharmaceutical excipient is selected from one or more of a skeleton material, a disintegrant, a swelling agent, a binder, a filler, and a lubricant; and the pharmaceutically active ingredient is selected from one or more of the following substances: brivaracetam, a pharmaceutically acceptable complex of brivaracetam, a pharmaceutically acceptable salt of brivaracetam, a pharmaceutically acceptable solvate of brivaracetam, and a pharmaceutically acceptable hydrate of brivaracetam.

[0027] Preferably, the brivaracetam sustained-release pharmaceutical composition has the dissolution characteristics as described above.

[0028] According to an embodiment of the present invention, the brivaracetam sustained-release pharmaceutical composition comprises microcrystalline cellulose and / or hypromellose;

[0029] In some embodiments, the weight percentage of the microcrystalline cellulose is 1.00% to 60.00%, for example, 2.00% to 40.00%, and further such as 5.00% to 15.00%, exemplified by 2.00%, 3.00%, 4.00%, 5.00%, 5.55%, 6.00%, 7.00%, 8.00%, 8.09%, 9.00%, 10.00%, 10.09%, 11.00%, 12.00%, 13.00%, 14.00%, 15.00%, 20.00%, 25.00%, 30.00%, 35.00%, 40.00%, 50.00% or 60.00%; the weight percentage refers to the percentage of the weight of the microcrystalline cellulose to the total weight of the brivaracetam sustained-release pharmaceutical composition;

[0030] In some embodiments, the weight percentage of the hypromellose is 1.00% to 40.00%, for example 2.00% to 20.00%, exemplified by 2.00%, 3.00%, 3.45%, 4.00%, 5.00%, 5.09%, 6.00%, 7.00%, 8.00%, 8.09%, 9.00%, 9.09%, 10.00%, 11.00%, 12.00%, 13.00%, 14.00%, 15.00%, 20.00%, 25.00%, 30.00%, 35.00% or 40.00%; the weight percentage refers to the percentage of the weight of the hypromellose to the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0031] According to an embodiment of the present invention, the pharmaceutically active ingredient is preferably brivaracetam.

[0032] According to an embodiment of the present invention, the weight percentage of the pharmaceutically active ingredient is preferably 2.00% to 50.00%, more preferably 3.00% to 20.00%, for example, 4.00%, 4.55%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 9.09%, 10.00%, 11.00%, 12.00%, 13.00%, 13.64%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 18.18%, 19.00%, 20.00%, 25.00%, 30.00%, 35.00%, 40.00% or 50.00%; the weight percentage refers to the percentage of the weight of the pharmaceutically active ingredient to the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0033] According to an embodiment of the present invention, the skeleton material refers to a substance that can provide structural integrity and help control or prolong the drug release rate, selected from a polyvinyl acetate-povidone mixture ( One or more of sodium alginate, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, poloxamer, potassium polyacrylate, acrylic resin and polyvinyl alcohol; preferably KSR. The KSR may be produced by BASF under the trade name KOLLIDON @ SR, contains an 80 / 20 (w / w) mixture of PVAc and PVP.

[0034] According to an embodiment of the present invention, the weight percentage of the framework material is preferably 5.00% to 60.00%, more preferably 20.00% to 40.00%, for example, 20.00%, 25.00%, 29.10%, 30.00%, 30.27%, 31.37%, 32.00%, 33.00%, 34.00%, 35.00% or 40.00%; the weight percentage refers to the percentage of the weight of the framework material to the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0035] According to an embodiment of the present invention, the disintegrant refers to an excipient that promotes the rapid disintegration of the drug into small particles in the gastrointestinal tract, and is selected from one or more of sodium starch glycolate, low-substituted hydroxypropyl cellulose, corn starch and cross-linked sodium carboxymethyl cellulose; preferably sodium starch glycolate.

[0036] According to an embodiment of the present invention, the weight percentage of the disintegrant is preferably 1.00% to 10.00%, more preferably 2.00% to 8.00%, for example, 3.00%, 4.00%, 5.00%, 5.18%, 6.00%, 6.10%, 6.36% or 7.00%; the weight percentage refers to the percentage of the weight of the disintegrant to the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0037] According to an embodiment of the present invention, the swelling agent refers to a substance that can absorb water from gastric fluid to cause the size of the solid preparation to expand, and can affect the drug release rate by creating channels or forming hydrophilic colloids. The swelling agent is soluble or insoluble in water and is selected from one or more of polyoxyethylene (PEO), crospovidone, carbomer, sodium carboxymethylcellulose, and calcium carboxymethylcellulose; preferably one or more of polyoxyethylene, crospovidone, and carbomer; further preferably polyoxyethylene and / or crospovidone. The polyoxyethylene can be a conventional commercially available polyoxyethylene product, such as polyoxyethylene N60K and / or polyoxyethylene 1105.

[0038] According to an embodiment of the present invention, the weight percentage of the swelling agent is preferably 5.00% to 60.00%, more preferably 10.00% to 40.00%, for example, 10.00%, 15.00%, 17.00%, 19.00%, 20.00%, 23.00%, 25.00%, 27.00%, 28.18%, 30.00%, 30.36%, 30.72%, 33.00%, 35.00% or 40.00%; the weight percentage refers to the percentage of the weight of the swelling agent to the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0039] According to an embodiment of the present invention, the binder refers to an additive conventional in the art that can increase the viscosity of the dispersion medium to reduce the sedimentation rate of the microparticles or increase the hydrophilicity of the microparticles, and is selected from one or more of hydroxypropyl methylcellulose, pregelatinized starch, copovidone, hydroxyethyl cellulose and dextrin; preferably hydroxypropyl methylcellulose and / or pregelatinized starch.

[0040] According to an embodiment of the present invention, the weight percentage of the binder is preferably 1.00% to 40.00%, more preferably 5.00% to 20.00%, for example, 2.00%, 3.00%, 4.00%, 5.00%, 7.00%, 8.00%, 10.00%, 11.63%, 15.00%, 15.09%, 16.00%, 19.09%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00% or 30.00%; the weight percentage refers to the percentage of the weight of the binder to the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0041] According to an embodiment of the present invention, the filler refers to a solid substance that is added to the material to improve the material properties, or to increase the volume, increase the weight, and reduce the cost of the material, and is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, lactose (e.g., lactose hydrate or anhydrous lactose, the lactose hydrate is such as lactose monohydrate), mannitol and sorbitol; preferably, microcrystalline cellulose and / or lactose.

[0042] According to an embodiment of the present invention, the weight percentage of the filler is preferably 1.00% to 60.00%, more preferably 5.00% to 40.00%, for example, 2.00%, 3.00%, 4.00%, 5.00%, 5.55%, 6.00%, 7.00%, 8.00%, 8.09%, 9.00%, 10.00%, 10.09%, 15.00%, 19.00%, 20.00%, 25.00%, 28.91%, 30.00%, 32.91%, 35.00% or 40.00%; the weight percentage refers to the percentage of the weight of the filler to the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0043] According to an embodiment of the present invention, the lubricant refers to a substance that helps processing steps such as component mixing and tableting, and is selected from one or more of magnesium stearate, calcium stearate and sodium fumarate; preferably magnesium stearate.

[0044] According to an embodiment of the present invention, the weight percentage of the lubricant is preferably 1.00% to 5.00%, more preferably 1.00% to 2.00%, for example 1.00%; the weight percentage refers to the percentage of the weight of the lubricant to the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0045] According to some embodiments of the present invention, the brivaracetam sustained-release pharmaceutical composition is preferably composed of a pharmaceutically active ingredient, a skeleton material, a disintegrant, a swelling agent, a binder, a filler, and a lubricant;

[0046] Preferably, the pharmaceutically active ingredient is brivaracetam or a pharmaceutically acceptable salt thereof;

[0047] and / or, the skeleton material is a polyvinyl acetate-povidone mixture;

[0048] and / or, the disintegrant is sodium starch glycolate;

[0049] and / or, the swelling agent is selected from one or more of polyoxyethylene, cross-linked polyvinylpyrrolidone and carbomer;

[0050] and / or, the binder is selected from hypromellose and / or pregelatinized starch;

[0051] and / or, the filler is selected from microcrystalline cellulose and / or lactose;

[0052] And / or, the lubricant is selected from magnesium stearate.

[0053] In some embodiments, the brivaracetam sustained-release pharmaceutical composition is composed of the following components in percentage by weight: 2.00% to 50.00% brivaracetam, 5.00% to 60.00% skeleton material, 1.00% to 10.00% disintegrant, 5.00% to 60.00% swelling agent, 1.00% to 40.00% binder, 1.00% to 60.00% filler and 1.00% to 5.00% lubricant, wherein the percentage by weight refers to the percentage of the weight of a single component to the total weight of the brivaracetam sustained-release tablet.

[0054] In some embodiments, the brivaracetam sustained-release pharmaceutical composition is composed of the following components in percentage by weight: 3.00% to 20.00% brivaracetam, 20.00% to 40.00% skeleton material, 2.00% to 8.00% disintegrant, 10.00% to 40.00% swelling agent, 5.00% to 20.00% binder, 5.00% to 40.00% filler and 1.00% to 2.00% lubricant, wherein the percentage by weight refers to the percentage of the weight of a single component to the total weight of the brivaracetam sustained-release tablet.

[0055] According to an embodiment of the present invention, the brivaracetam sustained-release pharmaceutical composition is preferably composed of the following components:

[0056] Component 1: brivaracetam, KSR, crospovidone, carbomer, lactose, hypromellose, and magnesium stearate;

[0057] Component 2: brivaracetam, KSR, crospovidone, carbomer, lactose, hypromellose, microcrystalline cellulose, and magnesium stearate;

[0058] Component 3: brivaracetam, KSR, crospovidone, polyethylene oxide, microcrystalline cellulose, hypromellose, and magnesium stearate;

[0059] Component 4: brivaracetam, KSR, sodium starch glycolate, crospovidone, polyoxyethylene, microcrystalline cellulose, pregelatinized starch, hypromellose, and magnesium stearate;

[0060] Component 5: brivaracetam, KSR, sodium starch glycolate, crospovidone, polyoxyethylene (eg, polyoxyethylene N60K and / or polyoxyethylene 1105), microcrystalline cellulose, pregelatinized starch, hypromellose, and magnesium stearate.

[0061] According to an embodiment of the present invention, the brivaracetam sustained-release pharmaceutical composition can be selected from any of the following prescriptions:

[0062] Prescription 1: 9.09% brivaracetam, 30.00% polyvinyl acetate povidone mixture, 15.00% crospovidone, 4.00% carbomer, 8.00% hypromellose, 32.91% lactose monohydrate, and 1.00% magnesium stearate;

[0063] Prescription 2: 9.09% brivaracetam, 30.00% polyvinyl acetate povidone mixture, 15.00% crospovidone, 8.00% carbomer, 8.00% hypromellose, 20.91% lactose monohydrate, 8.00% microcrystalline cellulose, and 1.00% magnesium stearate;

[0064] Prescription 3: 10.00% brivaracetam, 30.00% polyvinyl acetate povidone mixture, 17.00% crospovidone, 16.00% polyoxyethylene 1105, 7.00% hypromellose, 19.00% microcrystalline cellulose, and 1.00% magnesium stearate;

[0065] Prescription 4: 10.00% brivaracetam, 32.00% polyvinyl acetate povidone mixture, 5.00% sodium starch glycolate, 12.00% crospovidone, 15.00% polyoxyethylene N60K, 7.00% hypromellose, 8.00% pregelatinized starch, 10.00% microcrystalline cellulose, and 1.00% magnesium stearate;

[0066] Prescription 5: 10.00% brivaracetam, 32.00% polyvinyl acetate povidone mixture, 5.00% sodium carboxymethyl starch, 12.00% crospovidone, 7.50% polyoxyethylene N60K, 7.50% polyoxyethylene 1105, 8.00% hypromellose, 8.00% pregelatinized starch, 9.00% microcrystalline cellulose, and 1.00% magnesium stearate;

[0067] Prescription 6: 10.00% brivaracetam, 30.00% polyvinyl acetate povidone mixture, 6.00% sodium starch glycolate, 15.00% crospovidone, 15.00% polyoxyethylene N60K, 5.00% hypromellose, 10.00% pregelatinized starch, 8.00% microcrystalline cellulose, and 1.00% magnesium stearate;

[0068] Prescription 7: 9.09% brivaracetam, 30.27% polyvinyl acetate povidone mixture, 6.10% sodium starch glycolate, 15.18% crospovidone, 15.18% polyoxyethylene N60K, 5.09% hypromellose, 10.00% pregelatinized starch, 8.09% microcrystalline cellulose, and 1.00% magnesium stearate;

[0069] Prescription 8: 4.55% brivaracetam, 31.37% polyvinyl acetate povidone mixture, 5.18% sodium starch glycolate, 14.36% crospovidone, 16.36% polyoxyethylene N60K, 9.09% hypromellose, 10.00% pregelatinized starch, 8.09% microcrystalline cellulose, and 1.00% magnesium stearate;

[0070] Prescription 9: 13.64% brivaracetam, 29.10% polyvinyl acetate povidone mixture, 6.36% sodium starch glycolate, 15.45% crospovidone, 12.73% polyoxyethylene N60K, 3.45% hypromellose, 8.18% pregelatinized starch, 10.09% microcrystalline cellulose, and 1.00% magnesium stearate;

[0071] Prescription 10: 18.18% brivaracetam, 29.10% polyvinyl acetate povidone mixture, 6.36% sodium starch glycolate, 15.45% crospovidone, 12.73% polyoxyethylene N60K, 3.45% hypromellose, 8.18% pregelatinized starch, 5.55% microcrystalline cellulose, and 1.00% magnesium stearate;

[0072] The percentages mentioned above refer to the percentage of the weight of each component to the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0073] The present invention also provides a brivaracetam sustained-release tablet comprising the brivaracetam sustained-release pharmaceutical composition.

[0074] Preferably, the brivaracetam sustained-release tablet consists of a tablet core and a coating agent, and the tablet core contains the above-mentioned brivaracetam sustained-release pharmaceutical composition.

[0075] According to an embodiment of the present invention, the coating agent is preferably a film coating powder. The content of the coating agent is preferably 0% to 10.0%, such as 3.00% or 4.00%, where the content refers to the percentage of the weight of the coating agent to the total weight of the tablet core.

[0076] According to an embodiment of the present invention, the tablet core is composed of the following components in weight percentage: 2.00% to 50.00% brivaracetam, 5.00% to 60.00% skeleton material, 1.00% to 10.00% disintegrant, 5.00% to 60.00% swelling agent, 1.00% to 40.00% binder, 1.00% to 60.00% filler and 1.00% to 5.00% lubricant. The weight percentage refers to the percentage of the weight of a single component to the total weight of the brivaracetam sustained-release tablet.

[0077] According to an embodiment of the present invention, the tablet core is composed of the following components in weight percentage: 3.00% to 20.00% brivaracetam, 20.00% to 40.00% skeleton material, 2.00% to 8.00% disintegrant, 10.00% to 40.00% swelling agent, 5.00% to 20.00% binder, 5.00% to 40.00% filler and 1.00% to 2.00% lubricant. The weight percentage refers to the percentage of the weight of a single component to the total weight of the brivaracetam sustained-release tablet.

[0078] Preferably, the brivaracetam sustained-release pharmaceutical composition has the dissolution characteristics as described above.

[0079] The present invention also provides a method for preparing the brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablets, which can be prepared by direct powder compression, dry granulation, wet granulation or fluidized granulation.

[0080] For example, the preparation method of the brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablet is as follows: each component of the sustained-release pharmaceutical composition except the lubricant (e.g., the active pharmaceutical ingredient, the matrix-forming agent, and the swelling agent) is mixed and sieved, and then mixed with the lubricant and tableted to obtain a tablet, i.e., the brivaracetam sustained-release composition;

[0081] The tablets can be further subjected to coating treatment to obtain coated tablets, namely the brivaracetam sustained-release tablets.

[0082] The brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablet of the present invention contains 25 mg to 200 mg of brivaracetam, preferably 25 mg, 50 mg, 100 mg, 150 mg or 200 mg.

[0083] The present invention also provides the use of the brivaracetam sustained-release pharmaceutical composition in the preparation of a medicament. Furthermore, the medicament is used to treat and / or prevent the following conditions or diseases: epilepsy (e.g., partial seizures), Parkinson's disease, movement disorders, migraine, tremor, essential tremor, bipolar disorder, chronic diseases, neuropathic pain, bronchial asthma, or allergic bronchial asthma. In some embodiments, the medicament is the brivaracetam sustained-release tablet.

[0084] The brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablet of the present invention is particularly suitable for treating partial epileptic seizures in patients over 16 years old.

[0085] The present invention also provides the use of the brivaracetam sustained-release pharmaceutical composition in the preparation of a pharmaceutical preparation. The pharmaceutical preparation can be a conventional oral preparation, the dosage form of which includes an oral tablet. In some embodiments, the pharmaceutical preparation is the brivaracetam sustained-release tablet.

[0086] The present invention also provides a method for treating a disease in a patient responsive to brivaracetam, comprising orally administering the above-mentioned brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablet to the patient once a day.

[0087] The present invention also provides a method for preventing and / or treating a condition or disease, comprising administering a therapeutically effective amount of the above-mentioned brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablet to a patient; for example, allowing the patient to orally administer the above-mentioned brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablet once a day;

[0088] Preferably, the disorder or disease is as defined above.

[0089] The brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablet described herein is stable and suitable for once-daily oral administration. When administered as a solid dosage form, the sustained-release pharmaceutical composition retains brivaracetam in the stomach longer than an immediate-release formulation. While retained in the stomach, the sustained-release pharmaceutical composition continuously releases brivaracetam. When the sustained-release pharmaceutical composition or brivaracetam sustained-release tablet is ingested as a whole and enters the patient's stomach, it rapidly floats in the gastric fluid and slowly expands or swells. The formulation expands to a certain size, preventing it from leaving the stomach through the pylorus. The diameter of the pylorus in adults is approximately 12 mm, so the size of the expanded formulation is no less than, and preferably greater than, 12 mm. The sustained-release brivaracetam tablet can have any shape, such as round, oval, irregular, polygonal, etc.

[0090] The brivaracetam sustained-release tablet of the present invention has a minimum size of not less than 12 mm after expansion, and can even expand to more than 13 mm. It will not be discharged from the pylorus of the stomach and is continuously released in the stomach to achieve a therapeutic effect.

[0091] The brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablet of the present invention can be expanded to any diameter of 12 mm to 35 mm, preferably 13 mm to 32 mm, and more preferably 13 mm to 29 mm.

[0092] For example, the size of the brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablet after expansion is 28.4×15×11.6 mm. 3 、31.6×16.4×12.1mm 3 , 28×14×12mm 3 、28.0×14.1×12.2mm 3 、30.5×15.5×14.4mm 3 、29.2×15.2×14.5mm 3 、29.5×15.1×13.7mm 3 or 29.4×15.0×13.7mm 3 .

[0093] Definitions and Explanations of Terms

[0094] In the present invention, the term "pharmaceutically acceptable" means that the salts, complexes, solvates and hydrates of the drug (e.g., brivaracetam) are suitable for contact with the patient's tissues without undue toxicity, irritation, allergic reaction, etc. within the scope of normal medical judgment, have a reasonable benefit-risk ratio, and can be effectively used for its intended use.

[0095] The term "solvate" refers to a molecular complex comprising a drug (e.g., brivaracetam) and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is tightly bound to the drug, the resulting complex has a well-defined stoichiometry that is independent of humidity. However, when the solvent is weakly bound (as in channel solvates and hygroscopic compounds), the solvent content depends on humidity and drying conditions; in this case, the complex is generally non-stoichiometric.

[0096] The term "hydrate" refers to a solvate comprising a drug (eg, brivaracetam) and stoichiometric or non-stoichiometric amounts of water.

[0097] In the present invention, the polyvinyl acetate (PVAc) is a homopolymer of vinyl acetate with a molecular weight of M w Typically about 1×10 5 to about 1×10 6 .

[0098] KSR can be produced by BSAF, and its trade name is Nominally an 80 / 20 (w / w) mixture of PVAc and PVP.

[0099] In the present invention, the polyethylene oxide (PEO) is also called polyethylene oxide (polyoxirane) and polyethylene oxide (polyoxyethylene). Polyethylene oxide is a homopolymer of ethylene oxide, and its molecular weight M w Typically about 1×10 5 to about 1×10 7 or about 1×10 6 to about 1×10 7 Polyethylene oxide is available in various grades depending on molecular weight and is manufactured by UnionCarbide under the trade name

[0100] The term "plurality" refers to two or more, for example, two, three or four.

[0101] The term "more than one kind" refers to three or more kinds, for example, three, four or five kinds.

[0102] The term "therapeutically effective amount" refers to an amount of the active ingredient of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific active ingredient selected, the dosage regimen relied upon, whether to be administered in combination with other compounds, the time schedule for administration, the tissue to be administered, and the physical delivery system carried.

[0103] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0104] The term "matrix forming agent" includes matrix materials, disintegrants and binders.

[0105] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0106] Beneficial effects of the present invention

[0107] The brivaracetam sustained-release pharmaceutical composition of the present invention has a good sustained-release effect, a steady release rate, and minimal side effects. Once-daily administration improves patient compliance and can achieve effective therapeutic effects by reducing the maximum drug level in the blood, prolonging the drug's time in the body, controlling the drug's effective dose in the body, and reducing drug toxicity and side effects.

[0108] Compared with ordinary rapid-release preparations, the advantages of brivaracetam sustained-release pharmaceutical composition are: (1) it reduces the number of times the drug is taken, and can achieve good therapeutic effects through sustained-release effect, thereby improving patient compliance; (2) it can prolong the residence time of the drug in the stomach, so that the drug is continuously released in the stomach and absorbed in the upper end of the small intestine, achieving a 24-hour continuous effect, stable blood drug concentration, and few adverse reactions; (3) it prevents patients from arbitrarily interrupting medication, preventing disease recurrence and progression of malignant complications; (4) once a day, the appropriate specifications are selected according to clinical manifestations, the number of doses is small, the medication is convenient, and the toxic and side effects are small. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] Figure 1 is a dissolution curve of the brivaracetam sustained-release pharmaceutical composition prepared in Examples 1 to 7 in acetate buffer at pH 4.5;

[0110] FIG2 is a dissolution curve of the brivaracetam sustained-release pharmaceutical composition prepared in Examples 7 to 10 in acetate buffer at pH 4.5;

[0111] FIG3 is a dissolution curve of the brivaracetam sustained-release pharmaceutical composition prepared in Examples 7 to 10 in a reciprocating cylinder dissolution method;

[0112] Figure 4 shows the average concentration-time curve of brivaracetam after administration of the test sample (brivaracetam sustained-release tablets prepared in Example 6) / the original reference product to Beagle dogs; wherein, represents the original research control group curve, represents the test product group curve;

[0113] Figure 5 shows the average concentration-time curves of brivaracetam in the original control group and the test sample group (brivaracetam sustained-release tablets prepared in Example 7) in healthy subjects; wherein, represents the original research control group curve, Represents the test product group curve. DETAILED DESCRIPTION

[0114] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0115] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0116] Sources of raw materials in the examples:

[0117] Brivaracetam: purchased from Ruyuan Dongyangguang Pharmaceutical Co., Ltd., purity: 98%~102%.

[0118] Cross-linked polyvinyl pyrrolidone: Chongqing Steckreidenmeier Material Technology Co., Ltd., its trade name is

[0119] Polyethylene oxide: produced by DUPONT, its trade name is POLYOX TM .

[0120] KSR: BSAF product, its trade name is Nominally an 80 / 20 (w / w) mixture of PVAc and PVP.

[0121] Example 1 to Example 4

[0122] The prescriptions of Examples 1 to 4 are shown in Table 1.

[0123] Table 1

[0124] Example 5 to Example 7

[0125] The prescriptions of Examples 5 to 7 are shown in Table 2.

[0126] Table 2

[0127] Preparation process of brivaracetam sustained-release tablets:

[0128] Pass the brivaracetam in the above prescription through a 40-mesh sieve for later use.

[0129] The brivaracetam (passed through a 40-mesh sieve) in the above formulation and the other excipients except magnesium stearate were placed in a hopper mixer, the mixing speed was set to 18 rpm, and the mixture was mixed for 20 minutes; the mixed material was sieved using a granulator with a sieve aperture of 0.8 mm and a rotation speed of 7-12 Hz; the sieved material was then placed in a hopper mixer, the mixing speed was set to 18 rpm, and the mixture was mixed for 20 minutes; finally, magnesium stearate was added, the mixing speed was set to 18 rpm, and the mixture was mixed for 5 minutes to obtain the brivaracetam total mixed powder.

[0130] The brivaracetam total mixed powder was tableted using a 22.0 mm × 10.9 mm melon seed-shaped die. The tableting speed, pre-compression pressure, main pressure and other parameters were adjusted to make the hardness reach 140N to 240N for compression to obtain brivaracetam sustained-release tablets, which were then coated with an aqueous solution of film coating powder to obtain brivaracetam sustained-release tablets.

[0131] Test Example 1

[0132] The dissolution curves and swelling sizes of the brivaracetam sustained-release tablets obtained in Examples 1 to 7 were tested, and the comparative study results are as follows:

[0133] Dissolution test method: 900 mL of pH 4.5 acetate buffer, according to the second method of 0931 of the Chinese Pharmacopoeia (2020 edition), 50 rpm, 37±0.5°C; the dissolution results are shown in Table 3 and Figure 1.

[0134] Table 3

[0135] The swelled sizes of the brivaracetam sustained-release tablets obtained in Examples 1 to 7 were tested after 24 hours, and the comparative study results are shown in Table 4.

[0136] Table 4

[0137] The above data show that the brivaracetam sustained-release tablets prepared by the present invention have a good sustained-release effect. After the gastric retention tablets swell for 24 hours, the length, width and thickness of the tablets can reach the size of the pyloric sphincter of the human stomach.

[0138] Example 8 to Example 10

[0139] The prescriptions of Examples 8 to 10 are shown in Table 5.

[0140] Table 5

[0141] Test Example 2

[0142] (1) The dissolution curves and swelling sizes of the brivaracetam sustained-release tablets obtained in Examples 7 to 10 were tested, and the comparative study results were as follows:

[0143] Dissolution test method: 900 mL of pH 4.5 acetate buffer, according to the second method of 0931 of the Chinese Pharmacopoeia (2020 edition), 50 rpm, 37±0.5°C; the dissolution results are shown in Table 6 and Figure 2.

[0144] Table 6

[0145] The swelled sizes of the brivaracetam sustained-release tablets obtained in Examples 7 to 10 were measured after 24 hours, and the comparative study results are shown in Table 7:

[0146] Table 7

[0147] The 50 mg to 200 mg brivaracetam sustained-release tablets prepared in Examples 7 to 10 all had good sustained-release effects. After the gastric retention tablets expanded for 24 hours, the length, width, and thickness of the tablets all reached the size of the pyloric sphincter of the human stomach, demonstrating that the 50 mg, 100 mg, 150 mg, and 200 mg brivaracetam sustained-release tablets obtained in the present invention had good gastric retention effects and good sustained-release effects. In addition, the dissolution behavior of the brivaracetam sustained-release tablets of different specifications of the present invention was basically consistent, and the sustained-release rate was steady.

[0148] (II) According to the dissolution and release rate determination method, the Chinese Pharmacopoeia 2020 General Chapter 0931 Method 7 was determined, and the dissolution conditions were: the dissolution medium was pH 1.2 hydrochloric acid solution and pH 4.5 acetate buffer, the immersion speed was 20 DPM, the screen was 20 mesh polypropylene material, and the instillation time was 15 seconds. The release of the brivaracetam sustained-release tablets in the stomach of the present invention was further evaluated by the reciprocating cylinder dissolution method. This dissolution method can simulate the release rate of the tablets in the stomach under the conditions of gastric food or gastric peristalsis. The dissolution method using the reciprocating cylinder method is shown in Table 8:

[0149] Table 8

[0150] The release rates of brivaracetam sustained-release tablets under different specifications are shown in Table 9 and Figure 3:

[0151] Table 9

[0152] The results of studies simulating gastric motility and food factors in vivo show that the brivaracetam sustained-release tablets of the present invention can achieve a good sustained-release effect in the stomach, maintain stable blood drug concentration, and achieve a sustained effect, thereby achieving the effect of treating diseases.

[0153] Test Example 3: In vivo PK study in Beagle dogs

[0154] Three Beagle dogs (two male and one female) were used in this study. The test group received the tablets described in Example 6 at a dose of 100 mg / dog / day. The original control group (i.e., brivaracetam tablets) received a dose of 100 mg / dog / day. The test group received a single dose, while the original control group received one tablet every 8 hours for a total of two doses. Blood samples were collected from the test animals before administration (one day before administration), and at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 16h, and 24h after administration; blood samples were collected from the original control group before administration (one day before administration), and at 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 5h, 8h (second administration after collection), 8.25h, 8.5h, 8.75h, 9h, 9.25h, 9.5h, 10h, 11h, 13h, and 16h after the first administration. The blood drug concentration results are shown in Table 10:

[0155] Table 10

[0156] The results showed that the half-life of the test sample group (brivaracetam sustained-release tablets of Example 6) was prolonged, and the maximum blood concentration was lower than that of the original control group (brivaracetam tablets), indicating a good sustained-release effect. The blood concentration curves of the original control group and the test sample group are shown in Figure 4.

[0157] Test Example 4 In vivo PK study in healthy subjects

[0158] A PK study was conducted in healthy subjects on the brivaracetam sustained-release tablets of Example 7 of the present invention. The original product (50 mg brivaracetam tablets) and the test product (100 mg brivaracetam sustained-release tablets) were selected as the study drugs. The test product group selected the tablets in Example 7 at a dose of 100 mg / day, and the original control group (i.e., brivaracetam tablets) was administered at a dose of 100 mg / day. The test product group was administered a single dose, and the original control group was administered one tablet every 12 hours for a total of two doses. Periodic blood sampling was performed for the original control group and the test product group to detect blood drug concentrations. The blood drug concentration results are shown in Table 11:

[0159] Table 11

[0160] The results showed that the C max The geometric mean ratios of AUC and AUC were both within the range of 80% to 125%, indicating that the therapeutic efficacy of one brivaracetam extended-release tablet was equivalent to that of two brivaracetam tablets. The slower release rate of brivaracetam extended-release tablets results in more consistent blood concentrations, achieving therapeutic efficacy while reducing adverse reactions, resulting in better patient efficacy, compliance, and safety. The blood concentration curves for the control and test groups are shown in Figure 5.

[0161] Test Example 5 Stability Test of Example 7

[0162] The tablet product obtained in Example 7 was placed under accelerated conditions (40°C ± 2°C, 75% ± 5% RH) for a stability test of up to 6 months. The relevant substances, isomers, content and dissolution rate were tested (dissolution test using the reciprocating cylinder method in Test Example 2). The results are shown in Table 12:

[0163] Table 12

[0164] The above stability test results show that the brivaracetam sustained-release tablets of the present invention did not show significant changes in related substances, isomers, content and dissolution during the stability period, and the product stability is excellent.

[0165] Comparison of Test Example 6 Example 7 with Tablets A and E in the Prior Art CN113908153A

[0166] Tablets A and E in Example 7 and CN113908153A were stored at 60°C. Samples were taken on the 10th and 30th days to test the contents of related substances. The results are shown in Table 13.

[0167] Table 13 Comparative data of relevant substances

[0168] Example 7: Tablets A and E were tested for dissolution curves and swelling size after 24 hours. The comparative study results are shown in Tables 14 and 15.

[0169] Dissolution test method: 900 mL of pH 4.5 acetate buffer, according to the second method of Chinese Pharmacopoeia (2020 edition) 0931, 50 rpm, 37±0.5℃.

[0170] Table 14 Comparative data of tablet expansion size

[0171] Table 15 Dissolution rate comparison data

[0172] Through the above comparison, the tablets obtained in Example 7 of the present invention have low impurity content and good stability, while Tablets A and E of CN113908153A have high impurity content and poor stability. The tablets of Example 7 of the present invention have an expanded size that meets the requirements, while Tablet E of CN113908153A is smaller in size, which is not conducive to the retention of the tablets in the stomach. The tablets of Example 7 of the present invention have a slow dissolution rate and a better sustained-release effect. Overall evaluation shows that Example 7 of the present invention has comprehensive advantages in product stability, tablet expansion size, and sustained-release effect.

[0173] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A brivaracetam sustained-release pharmaceutical composition, characterized in that: The brivaracetam sustained-release pharmaceutical composition is a 24-hour slow-release drug, and its dissolution simultaneously satisfies the following four characteristics: A) no more than 40% of the active pharmaceutical ingredient is dissolved within 1 hour; B) 20% to 70% of the active pharmaceutical ingredient is dissolved within 4 hours; C) dissolve 60% to 90% of the active pharmaceutical ingredient within 12 hours; D) dissolve no less than 70% of the active pharmaceutical ingredient within 24 hours; The pharmaceutically active ingredient is selected from one or more of brivaracetam, a pharmaceutically acceptable complex of brivaracetam, a pharmaceutically acceptable salt of brivaracetam, a pharmaceutically acceptable solvate of brivaracetam and a pharmaceutically acceptable hydrate of brivaracetam; Preferably, the brivaracetam pharmaceutical composition is a 24-hour slow-release drug, and its dissolution satisfies the following four characteristics simultaneously: A) no more than 35% of the active pharmaceutical ingredient dissolves within 1 hour; B) 30% to 70% of the active pharmaceutical ingredient is dissolved within 4 hours; C) 60% to 85% of the active pharmaceutical ingredient is dissolved within 12 hours; D) dissolve no less than 75% of the active pharmaceutical ingredient within 24 hours; Preferably, the brivaracetam pharmaceutical composition is a 24-hour slow-release drug, and its dissolution satisfies the following four characteristics simultaneously: A) dissolving no more than 30% of the active pharmaceutical ingredient within 1 hour; preferably, dissolving no more than 30% of the brivaracetam or a pharmaceutically acceptable salt thereof within 1 hour; B) dissolving 35% to 60% of the active pharmaceutical ingredient within 4 hours; preferably, dissolving 35% to 60% of brivaracetam or a pharmaceutically acceptable salt thereof within 4 hours; C) dissolving 65% to 85% of the active pharmaceutical ingredient within 12 hours; preferably, dissolving 65% to 85% of brivaracetam or a pharmaceutically acceptable salt thereof within 12 hours; D) dissolving not less than 80% of the active pharmaceutical ingredient within 24 hours; preferably, dissolving not less than 80% of the brivaracetam or a pharmaceutically acceptable salt thereof within 24 hours.

2. A brivaracetam sustained-release pharmaceutical composition, characterized in that: The brivaracetam sustained-release pharmaceutical composition comprises a pharmaceutically active ingredient and a pharmaceutical excipient, wherein the pharmaceutical excipient is selected from one or more of a skeleton material, a disintegrant, a swelling agent, a binder, a filler and a lubricant; the pharmaceutically active ingredient is selected from one or more of the following substances: brivaracetam, a pharmaceutically acceptable complex of brivaracetam, a pharmaceutically acceptable salt of brivaracetam, a pharmaceutically acceptable solvate of brivaracetam and a pharmaceutically acceptable hydrate of brivaracetam; Preferably, the brivaracetam sustained-release pharmaceutical composition has a dissolution characteristic as shown in claim 1.

3. The brivaracetam sustained-release pharmaceutical composition according to claim 2, characterized in that: The active ingredient of the medicine is brivaracetam; and / or, The weight percentage of the active pharmaceutical ingredient is 2.00% to 50.00%, preferably 3.00% to 20.00%, for example, 4.00%, 4.55%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 9.09%, 10.00%, 11.00%, 12.00%, 13.00%, 13.64%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 18.18%, 19.00%, 20.00%, 25.00%, 30.00%, 35.00%, 40.00% or 50.00%; the weight percentage refers to the weight of the active pharmaceutical ingredient as a percentage of the total weight of the brivaracetam sustained-release pharmaceutical composition; and / or, The brivaracetam sustained-release pharmaceutical composition comprises microcrystalline cellulose and / or hypromellose; Preferably, the weight percentage of the microcrystalline cellulose is 1.00% to 60.00%, for example, 2.00% to 40.00% or 5.00% to 15.00%; the weight percentage refers to the weight of the microcrystalline cellulose as a percentage of the total weight of the brivaracetam sustained-release pharmaceutical composition; Preferably, the weight percentage of the hypromellose is 1.00% to 40.00%, for example 2.00% to 20.00%; the weight percentage refers to the weight of the hypromellose as a percentage of the total weight of the brivaracetam sustained-release pharmaceutical composition; and / or, The brivaracetam sustained-release pharmaceutical composition comprises 25 mg to 200 mg of brivaracetam, preferably 25 mg, 50 mg, 100 mg, 150 mg or 200 mg.

4. The brivaracetam sustained-release pharmaceutical composition according to claim 2, characterized in that: The skeleton material is selected from one or more of polyvinyl acetate-povidone mixture, sodium alginate, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, poloxamer, polyvinyl chloride potassium, acrylic resin and polyvinyl alcohol; preferably polyvinyl acetate-povidone mixture; and / or, The disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, corn starch and cross-linked sodium carboxymethyl cellulose; sodium carboxymethyl starch is preferred; and / or, The swelling agent is selected from one or more of polyoxyethylene, cross-linked polyvinylpyrrolidone, carbomer, sodium carboxymethylcellulose and calcium carboxymethylcellulose; preferably one or more of polyoxyethylene, cross-linked polyvinylpyrrolidone and carbomer; further preferably polyoxyethylene and / or cross-linked polyvinylpyrrolidone; and / or, The adhesive is selected from one or more of hydroxypropyl methylcellulose, pregelatinized starch, copolyvidone, hydroxyethyl cellulose and dextrin; preferably hydroxypropyl methylcellulose and / or pregelatinized starch; and / or, The filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol and sorbitol; preferably microcrystalline cellulose and / or lactose; and / or, The lubricant is selected from one or more of magnesium stearate, calcium stearate and sodium fumarate; magnesium stearate is preferred.

5. The brivaracetam sustained-release pharmaceutical composition according to claim 2 or 4, characterized in that: The weight percentage of the skeleton material is 5.00% to 60.00%, preferably 20.00% to 40.00%, for example, 20.00%, 25.00%, 29.10%, 30.00%, 30.27%, 31.37%, 32.00%, 33.00%, 34.00%, 35.00% or 40.00%; the weight percentage refers to the weight of the skeleton material as a percentage of the total weight of the brivaracetam sustained-release pharmaceutical composition; and / or, The weight percentage of the disintegrant is 1.00% to 10.00%, preferably 2.00% to 8.00%, for example 3.00%, 4.00%, 5.00%, 5.18%, 6.00%, 6.10%, 6.36% or 7.00%; the weight percentage refers to the weight of the disintegrant as a percentage of the total weight of the brivaracetam sustained-release pharmaceutical composition; and / or, The weight percentage of the swelling agent is 5.00% to 60.00%, preferably 10.00% to 40.00%, for example, 10.00%, 15.00%, 17.00%, 19.00%, 20.00%, 23.00%, 25.00%, 27.00%, 28.18%, 30.00%, 30.36%, 30.72%, 33.00%, 35.00% or 40.00%; the weight percentage refers to the weight of the swelling agent as a percentage of the total weight of the brivaracetam sustained-release pharmaceutical composition; and / or, The weight percentage of the binder is 1.00% to 40.00%, preferably 5.00% to 20.00%, for example, 2.00%, 3.00%, 4.00%, 5.00%, 7.00%, 8.00%, 10.00%, 11.63%, 15.00%, 15.09%, 16.00%, 19.09%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00% or 30.00%; the weight percentage refers to the weight of the binder as a percentage of the total weight of the brivaracetam sustained-release pharmaceutical composition; and / or, The weight percentage of the filler is 1.00% to 60.00%, preferably 5.00% to 40.00%, for example, 2.00%, 3.00%, 4.00%, 5.00%, 5.55%, 6.00%, 7.00%, 8.00%, 8.09%, 9.00%, 10.00%, 10.09%, 15.00%, 19.00%, 20.00%, 25.00%, 28.91%, 30.00%, 32.91%, 35.00% or 40.00%; the weight percentage refers to the weight of the filler as a percentage of the total weight of the brivaracetam sustained-release pharmaceutical composition; and / or, The weight percentage of the lubricant is 1.00% to 5.00%, preferably 1.00% to 2.00%, for example 1.00%; the weight percentage refers to the percentage of the weight of the lubricant to the total weight of the brivaracetam sustained-release pharmaceutical composition.

6. The brivaracetam sustained-release pharmaceutical composition according to any one of claims 2 to 5, characterized in that: The brivaracetam sustained-release pharmaceutical composition is composed of pharmaceutical active ingredients, skeleton materials, disintegrants, swelling agents, adhesives, fillers and lubricants; Preferably, the pharmaceutically active ingredient is brivaracetam or a pharmaceutically acceptable salt thereof; and / or, the skeleton material is a polyvinyl acetate-povidone mixture; And / or, the disintegrant is sodium starch glycolate; And / or, the swelling agent is selected from one or more of polyoxyethylene, cross-linked polyvinylpyrrolidone and carbomer; And / or, the binder is selected from hydroxypropyl methylcellulose and / or pregelatinized starch; and / or, the filler is selected from microcrystalline cellulose and / or lactose; and / or, the lubricant is selected from magnesium stearate; Preferably, the brivaracetam sustained-release pharmaceutical composition is composed of the following components in percentage by weight: 2.00% to 50.00% brivaracetam, 5.00% to 60.00% skeleton material, 1.00% to 10.00% disintegrant, 5.00% to 60.00% swelling agent, 1.00% to 40.00% binder, 1.00% to 60.00% filler and 1.00% to 5.00% lubricant, wherein the percentage by weight refers to the percentage of the weight of a single component to the total weight of the brivaracetam sustained-release tablet; Alternatively, the brivaracetam sustained-release pharmaceutical composition is composed of the following components in percentage by weight: 3.00% to 20.00% brivaracetam, 20.00% to 40.00% skeleton material, 2.00% to 8.00% disintegrant, 10.00% to 40.00% swelling agent, 5.00% to 20.00% binder, 5.00% to 40.00% filler and 1.00% to 2.00% lubricant, wherein the percentage by weight refers to the percentage of the weight of a single component to the total weight of the brivaracetam sustained-release tablet; Preferably, the brivaracetam sustained-release pharmaceutical composition consists of the following components: Component 1: brivaracetam, KSR, crospovidone, carbomer, lactose, hypromellose and magnesium stearate; Component 2: brivaracetam, KSR, crospovidone, carbomer, lactose, hypromellose, microcrystalline cellulose, and magnesium stearate; Component 3: brivaracetam, KSR, crospovidone, polyoxyethylene, microcrystalline cellulose, hypromellose, and magnesium stearate; Component 4: brivaracetam, KSR, sodium starch glycolate, crospovidone, polyoxyethylene, microcrystalline cellulose, pregelatinized starch, hypromellose, and magnesium stearate; Component 5: brivaracetam, KSR, sodium starch glycolate, crospovidone, polyoxyethylene (e.g., polyoxyethylene N60K and / or polyoxyethylene 1105), microcrystalline cellulose, pregelatinized starch, hypromellose, and magnesium stearate; Further preferably, the brivaracetam sustained-release pharmaceutical composition is selected from any one of the following prescriptions: Prescription 1: 9.09% brivaracetam, 30.00% polyvinyl acetate povidone mixture, 15.00% crospovidone, 4.00% carbomer, 8.00% hypromellose, 32.91% lactose monohydrate, and 1.00% magnesium stearate; Prescription 2: 9.09% brivaracetam, 30.00% polyvinyl acetate povidone mixture, 15.00% crospovidone, 8.00% carbomer, 8.00% hypromellose, 20.91% lactose monohydrate, 8.00% microcrystalline cellulose, and 1.00% magnesium stearate; Prescription 3: 10.00% brivaracetam, 30.00% polyvinyl acetate povidone mixture, 17.00% crospovidone, 16.00% polyoxyethylene 1105, 7.00% hypromellose, 19.00% microcrystalline cellulose, and 1.00% magnesium stearate; Prescription 4: 10.00% brivaracetam, 32.00% polyvinyl acetate povidone mixture, 5.00% sodium starch glycolate, 12.00% crospovidone, 15.00% polyoxyethylene N60K, 7.00% hypromellose, 8.00% pregelatinized starch, 10.00% microcrystalline cellulose, and 1.00% magnesium stearate; Prescription 5: 10.00% brivaracetam, 32.00% polyvinyl acetate povidone mixture, 5.00% sodium carboxymethyl starch, 12.00% crospovidone, 7.50% polyoxyethylene N60K, 7.50% polyoxyethylene 1105, 8.00% hypromellose, 8.00% pregelatinized starch, 9.00% microcrystalline cellulose, and 1.00% magnesium stearate; Prescription 6: 10.00% brivaracetam, 30.00% polyvinyl acetate povidone mixture, 6.00% sodium carboxymethyl starch, 15.00% crospovidone, 15.00% polyoxyethylene N60K, 5.00% hypromellose, 10.00% pregelatinized starch, 8.00% microcrystalline cellulose, and 1.00% magnesium stearate; Prescription 7: 9.09% brivaracetam, 30.27% polyvinyl acetate povidone mixture, 6.10% sodium starch glycolate, 15.18% crospovidone, 15.18% polyoxyethylene N60K, 5.09% hypromellose, 10.00% pregelatinized starch, 8.09% microcrystalline cellulose, and 1.00% magnesium stearate; Prescription 8: 4.55% brivaracetam, 31.37% polyvinyl acetate povidone mixture, 5.18% sodium starch glycolate, 14.36% crospovidone, 16.36% polyoxyethylene N60K, 9.09% hypromellose, 10.00% pregelatinized starch, 8.09% microcrystalline cellulose, and 1.00% magnesium stearate; Prescription 9: 13.64% brivaracetam, 29.10% polyvinyl acetate povidone mixture, 6.36% sodium starch glycolate, 15.45% crospovidone, 12.73% polyoxyethylene N60K, 3.45% hypromellose, 8.18% pregelatinized starch, 10.09% microcrystalline cellulose, and 1.00% magnesium stearate; Prescription 10: 18.18% brivaracetam, 29.10% polyvinyl acetate-povidone mixture, 6.36% sodium carboxymethyl starch, 15.45% cross-linked polyvidone, 12.73% polyoxyethylene N60K, 3.45% hydroxypropyl methylcellulose, 8.18% pregelatinized starch, 5.55% microcrystalline cellulose and 1.00% magnesium stearate; the percentages refer to the percentage of the weight of each component in the total weight of the brivaracetam sustained-release pharmaceutical composition.

7. A brivaracetam sustained-release tablet, characterized in that: The brivaracetam sustained-release tablet is composed of a tablet core and a coating agent, and the tablet core comprises the sustained-release pharmaceutical composition according to any one of claims 1 to 6; The coating agent is a film coating powder; and / or, The content of the coating agent is 0% to 10.0%, such as 4.00% or 3.00%, and the content refers to the percentage of the weight of the coating agent to the total weight of the tablet core.

8. A method for preparing the brivaracetam sustained-release pharmaceutical composition according to any one of claims 1 to 6 or the brivaracetam sustained-release tablet according to claim 7, characterized in that: The preparation method is a powder direct compression method, dry granulation, wet granulation or fluidized granulation method.

9. Use of the brivaracetam sustained-release pharmaceutical combination according to any one of claims 1 to 6 or the brivaracetam sustained-release tablet according to claim 7 in the preparation of a drug.

10. The use according to claim 9, characterized in that: The drug is used to treat and / or prevent the following diseases: epilepsy, Parkinson's disease, movement disorders, migraine, tremor, essential tremor, bipolar disorder, chronic disease, neuropathic pain, bronchial asthma or allergic bronchial asthma; Preferably, the medicament is used for treating and / or preventing partial epileptic seizures in patients over 16 years old.

11. A method for preventing and / or treating a condition or disease responsive to brivaracetam, characterized in that: The method comprises administering to a patient a therapeutically effective amount of the brivaracetam sustained-release pharmaceutical composition according to any one of claims 1 to 6 or the brivaracetam sustained-release tablet according to claim 7; Preferably, the disorder or disease is selected from epilepsy (eg partial seizures), Parkinson's, movement disorders, migraine, tremor, essential tremor, bipolar disorder, chronic disease, neuropathic pain, bronchial asthma or allergic bronchial asthma.

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