Briracetam sustained-release pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention provides a briracetam sustained-release pharmaceutical composition as well as a preparation method and application thereof. The pharmaceutical composition comprises a pharmaceutical active ingredient and a pharmaceutical excipient, wherein the pharmaceutical excipient is selected from one or more of a framework material, a disintegrating agent, a swelling agent, an adhesive, a filler and a lubricant. The briracetam sustained-release pharmaceutical composition disclosed by the invention is good in sustained-release effect, stable in release speed and small in side effect, the medicine taking frequency is reduced, and the compliance of a patient is improved; the retention time of the medicine in the stomach is prolonged, so that the medicine is continuously released in the stomach and is absorbed at the upper end of the small intestine, the effect of continuously taking effect for 24 hours is achieved, the plasma concentration is stable, and the adverse reaction is small; a patient is prevented from randomly interrupting medication, and disease relapse and malignant complication development are prevented; the medicine is few in administration times, convenient to take and small in toxic and side effects.

Description

[0001] This application claims the priority of the following two prior applications: the patent application No. 202311691841.7, entitled "A Brivaracetam Sustained-Release Pharmaceutical Composition, Its Preparation Method and Application", filed with the State Intellectual Property Office of China on December 10, 2023, and the patent application No. 202411783409.5, entitled "A Brivaracetam Sustained-Release Pharmaceutical Composition, Its Preparation Method and Application", filed with the State Intellectual Property Office of China on December 5, 2024. The entire text of the prior application is 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, its preparation method and application. Background Art

[0003] Epilepsy is a chronic brain disease, which is a temporary brain dysfunction caused by highly synchronous discharges of neurons in the brain, commonly known as "epilepsy" or "hysterical fits". At present, epilepsy has become the second most common neurological disease in China. According to the latest epidemiological data in China, there are approximately 9 million epilepsy patients in China, among which 5 to 6 million are active epilepsy patients, and about 400,000 new epilepsy patients are added every year (https: / / www.caae.org.cn / news / show / id / 294). Epileptic seizures can affect patients' daily work and life, mainly manifested as mental disorders such as movement, sensation, autonomic nerve, and consciousness, cognitive function disorders such as memory impairment, reduced attention, and intellectual decline, as well as emotional disorders such as anxiety and depression. Long-term and frequent seizures have a serious impact on patients' physical and mental health and can also cause accidental injuries to patients. Since the first anti-epileptic drug, phenobarbital, appeared in 1912, the development of anti-epileptic drugs has been relatively rapid. Currently, anti-epileptic drugs can be divided into three generations: ① traditional anti-epileptic drugs, including phenytoin sodium, carbamazepine, and sodium valproate, etc.; ② modern anti-epileptic drugs, including oxcarbazepine, levetiracetam, and gabapentin, etc.; ③ new anti-epileptic drugs, including brivaracetam, carabostene, retigabine, and perampanel, etc. Clinically commonly used treatment drugs include phenytoin sodium, phenobarbital, primidone, carbamazepine, sodium valproate, etc.

[0004] Brivaracetam is an antiepileptic drug developed by UCB, which is 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 N 2 O 2 , and its structural formula is:

[0005]

[0006] Brivaracetam shows 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 the exocytosis of neurotransmitters. Binding to SV2A should be the main mechanism of the anticonvulsant activity of brivaracetam. The marketing of brivaracetam is a new addition to the adjunctive treatment of partial-onset epilepsy, especially for patients whose seizures cannot be adequately controlled with one or more other adjunctive treatments.

[0007] The currently marketed dosage forms of brivaracetam are ordinary oral tablets, oral solutions, and injections. The oral dosage forms require frequent administration, have large fluctuations in blood drug concentration, and have relatively large adverse reactions; the injection dosage form is cumbersome to use and has poor compliance.

[0008] Therefore, there is an urgent need to develop a sustained-release tablet to achieve the purposes of reducing the drug release rate, controlling the effective dose of the drug in the body, and reducing the daily dosing frequency. Summary of the Invention

[0009] The technical problem solved by the present invention is to provide a brivaracetam sustained-release pharmaceutical composition, its preparation method and application, which are different from the prior art, have good sustained-release effect, stable blood drug concentration, good curative effect, small side effects, and good compliance.

[0010] To improve the above technical problems, the present invention provides a brivaracetam sustained-release pharmaceutical composition, which slowly releases the drug for 24 hours, and its dissolution simultaneously satisfies the following four characteristics (determined according to the dissolution and release determination method, the seventh method in General Chapter 0931 of the Chinese Pharmacopoeia 2020 Edition, dissolution conditions: the dissolution medium is pH 1.2 hydrochloric acid solution and / or pH 4.5 acetate buffer solution, the immersion speed is 20 DPM, the sieve is made of 20-mesh polypropylene, and the dripping time is 15 seconds):

[0011] A) The drug active ingredient with a dissolution of no more than 40% within 1 hour;

[0012] B) The drug active ingredient with a dissolution of 20% - 70% within 4 hours;

[0013] C) The drug active ingredient with a dissolution of 60% - 90% within 12 hours;

[0014] D) The drug active ingredient with a dissolution of not less than 70% within 24 hours;

[0015] The drug active ingredient can be selected from one, two 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.

[0016] According to some embodiments of the present invention, the brivaracetam sustained - release pharmaceutical composition is a drug with a 24 - hour slow release, and its dissolution simultaneously satisfies the following four characteristics:

[0017] A) The drug active ingredient with a dissolution of no more than 35% within 1 hour;

[0018] B) The drug active ingredient with a dissolution of 30% - 70% within 4 hours;

[0019] C) The drug active ingredient with a dissolution of 60% - 85% within 12 hours;

[0020] D) The drug active ingredient with a dissolution of not less than 75% within 24 hours.

[0021] According to some embodiments of the present invention, the brivaracetam sustained - release pharmaceutical composition is a drug with a 24 - hour slow release, and its dissolution simultaneously satisfies the following four characteristics:

[0022] A) The drug active ingredient with a dissolution of no more than 30% within 1 hour; preferably, the brivaracetam or its pharmaceutically acceptable salt with a dissolution of no more than 30% within 1 hour;

[0023] B) The drug active ingredient with a dissolution of 35% - 60% within 4 hours; preferably, the brivaracetam or its pharmaceutically acceptable salt with a dissolution of 35% - 60% within 4 hours;

[0024] C) The drug active ingredient with a dissolution of 65% - 85% within 12 hours; preferably, the brivaracetam or its pharmaceutically acceptable salt with a dissolution of 65% - 85% within 12 hours;

[0025] D) The drug active ingredient is dissolved by no less than 80% within 24 hours; preferably, the brivaracetam or its pharmaceutically acceptable salt is dissolved by no less than 80% within 24 hours.

[0026] Wherein, the "dissolution" refers to the cumulative dissolution degree of the drug active ingredient (such as brivaracetam or its pharmaceutically acceptable salt); further, the cumulative dissolution degree is measured in a pH 1.2 hydrochloric acid solution or a pH 4.5 acetic acid buffer solution. Those skilled in the art can understand that as time increases, the dissolution degree of the brivaracetam or its pharmaceutically acceptable salt gradually increases.

[0027] The present invention provides a brivaracetam sustained-release pharmaceutical composition, which comprises a drug active ingredient and a drug excipient, and the drug excipient is selected from one or more of a matrix material, a disintegrant, a swelling agent, a binder, a filler and a lubricant; the drug 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;

[0028] Preferably, the brivaracetam sustained-release pharmaceutical composition has the dissolution characteristics as shown above.

[0029] According to an embodiment of the present invention, the brivaracetam sustained-release pharmaceutical composition comprises microcrystalline cellulose and / or hypromellose;

[0030] In some embodiments, the weight percentage of the microcrystalline cellulose is 1.00% to 60.00%, such as 2.00% to 40.00%, and also such as 5.00% to 15.00%, and exemplarily 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 in the total weight of the brivaracetam sustained-release pharmaceutical composition;

[0031] In some embodiments, the weight percentage of the hydroxypropyl methylcellulose is 1.00% to 40.00%, such as 2.00% to 20.00%, and exemplary are 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 hydroxypropyl methylcellulose in the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0032] According to an embodiment of the present invention, the pharmaceutically active ingredient is preferably brivaracetam.

[0033] 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%, such as 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 in the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0034] According to an embodiment of the present invention, the matrix material refers to a substance that can provide structural integrity and help control or extend the drug release rate, and is selected from one or more of polyvinyl acetate polyvinylpyrrolidone mixture ( hereinafter referred to as KSR), sodium alginate, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, poloxamer, polycarbophil, acrylic resin and polyvinyl alcohol; preferably KSR. Among them, the KSR can be produced by BASF and the trade name is KOLLIDON @ SR, containing an 80 / 20 (w / w) mixture of PVAc and PVP.

[0035] According to an embodiment of the present invention, the weight percentage of the skeleton material is preferably 5.00% to 60.00%, more preferably 20.00% to 40.00%, such as 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 skeleton material in the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0036] According to an embodiment of the present invention, the disintegrant refers to an excipient that promotes the rapid disintegration of a drug into small particles in the gastrointestinal tract, and is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, corn starch, and cross-linked sodium carboxymethyl cellulose; preferably sodium carboxymethyl starch.

[0037] 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%, such as 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 in the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0038] According to an embodiment of the present invention, the swelling agent refers to a substance that can absorb water from gastric juice to cause the size of a solid preparation to expand, and can affect the drug release rate by generating channels or by forming a hydrophilic colloid. The swelling agent may be soluble or insoluble in water, and is selected from one or more of polyethylene oxide (PEO), cross-linked polyvinylpyrrolidone, carbomer, sodium carboxymethyl cellulose, and calcium carboxymethyl cellulose; preferably one or more of polyethylene oxide, cross-linked polyvinylpyrrolidone, and carbomer; more preferably polyethylene oxide and / or cross-linked polyvinylpyrrolidone. The polyethylene oxide may be a conventional commercially available polyethylene oxide product, such as polyethylene oxide N60K and / or polyethylene oxide 1105.

[0039] 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%, such as 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 in the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0040] According to an embodiment of the present invention, the binder refers to an additive that can increase the viscosity of the dispersion medium to reduce the sedimentation rate of the fine particles or increase the hydrophilicity of the fine particles, which is conventional in the art, and is selected from one or more of hypromellose, pregelatinized starch, copovidone, hydroxyethyl cellulose, and dextrin; preferably hypromellose and / or pregelatinized starch.

[0041] 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 in the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0042] According to an embodiment of the present invention, the filler refers to a solid substance that can be added to the material to improve the material properties, or can increase the volume, weight, and reduce the cost of the material, and is selected from one or more of microcrystalline cellulose, siliconized microcrystalline cellulose, lactose (such as lactose hydrate or anhydrous lactose, and the lactose hydrate such as lactose monohydrate), mannitol, and sorbitol; preferably microcrystalline cellulose and / or lactose.

[0043] 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 in the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0044] According to an embodiment of the present invention, the lubricant refers to a substance that helps in processing steps such as component mixing and tableting, and is selected from one or more of magnesium stearate, calcium stearate, and sodium stearyl fumarate; preferably magnesium stearate.

[0045] 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 in the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0046] According to some embodiments of the present invention, the brivaracetam sustained-release pharmaceutical composition preferably consists of a pharmaceutically active ingredient, a matrix material, a disintegrant, a swelling agent, a binder, a filler, and a lubricant;

[0047] Preferably, the pharmaceutically active ingredient is brivaracetam or a pharmaceutically acceptable salt thereof;

[0048] and / or, the matrix material is a polyvinyl acetate-povidone mixture;

[0049] and / or, the disintegrant is sodium carboxymethyl starch;

[0050] and / or, the swelling agent is selected from one or more of polyethylene oxide, crosslinked povidone, and carbomer;

[0051] and / or, the binder is selected from hypromellose and / or pregelatinized starch;

[0052] and / or, the filler is selected from microcrystalline cellulose and / or lactose;

[0053] and / or, the lubricant is selected from magnesium stearate.

[0054] In some embodiments, the brivaracetam sustained-release pharmaceutical composition consists of the following components in weight percentages: 2.00% to 50.00% brivaracetam, 5.00% to 60.00% matrix 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, and the weight percentages refer to the weight of a single component accounting for the total weight of the brivaracetam sustained-release tablet.

[0055] In some embodiments, the brivaracetam sustained-release pharmaceutical composition consists of the following components in weight percentages: 3.00% to 20.00% brivaracetam, 20.00% to 40.00% matrix 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, and the weight percentages refer to the weight of a single component accounting for the total weight of the brivaracetam sustained-release tablet.

[0056] According to the embodiments of the present invention, the brivaracetam pharmaceutical sustained-release composition preferably consists of the following components:

[0057] Component 1: brivaracetam, KSR, crosslinked povidone, carbomer, lactose, hypromellose, and magnesium stearate;

[0058] Component 2: brivaracetam, KSR, crospovidone, carbomer, lactose, hypromellose, microcrystalline cellulose, and magnesium stearate;

[0059] Component 3: brivaracetam, KSR, crospovidone, polyoxyethylene, microcrystalline cellulose, hypromellose, and magnesium stearate;

[0060] Component 4: brivaracetam, KSR, sodium carboxymethyl starch, crospovidone, polyoxyethylene, microcrystalline cellulose, pregelatinized starch, hypromellose, and magnesium stearate;

[0061] Component 5: brivaracetam, KSR, sodium carboxymethyl starch, crospovidone, polyoxyethylene (such as polyoxyethylene N60K and / or polyoxyethylene 1105), microcrystalline cellulose, pregelatinized starch, hypromellose, and magnesium stearate.

[0062] According to an embodiment of the present invention, the brivaracetam sustained-release pharmaceutical composition may be selected from any of the following prescriptions:

[0063] 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;

[0064] 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;

[0065] 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;

[0066] Prescription 4: 10.00% brivaracetam, 32.00% polyvinyl acetate povidone mixture, 5.00% sodium carboxymethyl starch, 12.00% crospovidone, 15.00% polyoxyethylene N60K, 7.00% hypromellose, 8.00% pregelatinized starch, 10.00% microcrystalline cellulose, and 1.00% magnesium stearate;

[0067] 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;

[0068] 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;

[0069] Prescription 7: 9.09% brivaracetam, 30.27% polyvinyl acetate povidone mixture, 6.10% sodium carboxymethyl starch, 15.18% crospovidone, 15.18% polyoxyethylene N60K, 5.09% hypromellose, 10.00% pregelatinized starch, 8.09% microcrystalline cellulose, and 1.00% magnesium stearate;

[0070] Prescription 8: 4.55% brivaracetam, 31.37% polyvinyl acetate povidone mixture, 5.18% sodium carboxymethyl starch, 14.36% crospovidone, 16.36% polyoxyethylene N60K, 9.09% hypromellose, 10.00% pregelatinized starch, 8.09% microcrystalline cellulose, and 1.00% magnesium stearate;

[0071] Prescription 9: 13.64% brivaracetam, 29.10% polyvinyl acetate povidone mixture, 6.36% sodium carboxymethyl starch, 15.45% crospovidone, 12.73% polyoxyethylene N60K, 3.45% hypromellose, 8.18% pregelatinized starch, 10.09% microcrystalline cellulose, and 1.00% magnesium stearate;

[0072] Prescription 10: 18.18% brivaracetam, 29.10% polyvinyl acetate povidone mixture, 6.36% sodium carboxymethyl starch, 15.45% crospovidone, 12.73% polyoxyethylene N60K, 3.45% hypromellose, 8.18% pregelatinized starch, 5.55% microcrystalline cellulose, and 1.00% magnesium stearate;

[0073] The percentages mentioned refer to the percentages of the weights of the respective components in the total weight of the brivaracetam sustained-release pharmaceutical composition.

[0074] The present invention also provides a brivaracetam sustained-release tablet, which comprises the above-mentioned brivaracetam sustained-release pharmaceutical composition.

[0075] Preferably, the brivaracetam sustained-release tablets are composed of a tablet core and a coating agent, and the tablet core contains the above-mentioned brivaracetam sustained-release pharmaceutical composition.

[0076] 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% and 4.00%. The content refers to the percentage of the weight of the coating agent to the total weight of the tablet core.

[0077] 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% matrix 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 tablets.

[0078] 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% matrix 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 tablets.

[0079] Preferably, the brivaracetam sustained-release pharmaceutical composition has the dissolution characteristics as shown above.

[0080] The present invention also provides a preparation method of the brivaracetam sustained-release pharmaceutical composition or the brivaracetam sustained-release tablets. The preparation method can be direct powder compression, dry granulation, wet granulation, or fluidized granulation.

[0081] For example, the preparation method of the brivaracetam sustained-release pharmaceutical composition or the brivaracetam sustained-release tablets: Mix and screen the components (such as the drug active ingredient, matrix former, and swelling agent) in the sustained-release pharmaceutical composition except for the lubricant, then mix with the lubricant, press into tablets to obtain the tablets, that is, the brivaracetam sustained-release composition;

[0082] The tablets can be further coated to obtain coated tablets, that is, the brivaracetam sustained-release tablets.

[0083] The brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablets according to the present invention contain 25 mg to 200 mg of brivaracetam, preferably 25 mg, 50 mg, 100 mg, 150 mg or 200 mg.

[0084] The present invention also provides the use of the brivaracetam sustained-release pharmaceutical composition in the preparation of a medicament. Further, the medicament is used for treating and / or preventing the following disorders or diseases: epilepsy (such as partial seizures), Parkinson's disease, movement disorders, migraine, tremors, essential tremor, bipolar disorder, chronic diseases, neuropathic pain, bronchial asthma or allergic bronchial asthma and other diseases. In some embodiments, the medicament is the brivaracetam sustained-release tablets.

[0085] The brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablets according to the present invention are particularly suitable for treating partial seizures in patients over 16 years old.

[0086] The present invention also provides the use of the brivaracetam sustained-release pharmaceutical composition in the preparation of a pharmaceutical preparation. The pharmaceutical preparation may be an ordinary oral preparation, and the dosage form of the ordinary oral preparation includes oral tablets. In some embodiments, the pharmaceutical preparation is the brivaracetam sustained-release tablets.

[0087] The present invention also provides a method for treating the conditions of patients responsive to brivaracetam, the method comprising orally administering to the patient once daily the above brivaracetam drug sustained-release composition or brivaracetam sustained-release tablets.

[0088] The present invention also provides a method for preventing and / or treating a disorder or disease, comprising administering to a patient a therapeutically effective amount of the above brivaracetam drug sustained-release composition or brivaracetam sustained-release tablets; for example, orally administering to the patient once daily the above brivaracetam drug sustained-release composition or brivaracetam sustained-release tablets;

[0089] Preferably, the disorder or disease has the definition as shown above.

[0090] The brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablets according to the present invention are stable in nature and suitable for once-daily oral administration. When administered in a solid dosage form, the sustained-release pharmaceutical composition has a longer residence time in the stomach than an immediate-release preparation. When the sustained-release pharmaceutical composition remains in the stomach, brivaracetam can be continuously released. When the brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablets are taken as a whole and enter the patient's stomach, they can quickly float and slowly expand or swell in gastric juice. When the preparation expands to a certain size, it can prevent it from leaving the stomach via the pylorus. The diameter of the adult pylorus is about 12 mm, so the size of the expanded preparation is not less than, preferably greater than 12 mm. The brivaracetam sustained-release tablets can have any shape, such as round, oval, irregular shape, polygon, etc.

[0091] The minimum size of the brivaracetam sustained-release tablets described in the present invention after swelling is not less than 12 mm, and even swells to more than 13 mm, will not be discharged from the pylorus of the stomach, and continuously releases in the stomach to achieve the therapeutic effect.

[0092] The brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablets described in the present invention can swell to any diameter from 12 mm to 35 mm, preferably from 13 mm to 32 mm, and more preferably from 13 mm to 29 mm.

[0093] For example, the size of the brivaracetam sustained-release pharmaceutical composition or brivaracetam sustained-release tablets after swelling is 28.4×15×11.6 mm 3 、31.6×16.4×12.1 mm 3 、28×14×12 mm 3 、28.0×14.1×12.2 mm 3 、30.5×15.5×14.4 mm 3 、29.2×15.2×14.5 mm 3 、29.5×15.1×13.7 mm 3 or 29.4×15.0×13.7 mm 3 。

[0094] Term Definition and Explanation

[0095] In the present invention, the term "pharmaceutically acceptable" refers to salts, complexes, solvates, hydrates of a drug (such as brivaracetam), which are applicable to contact with the tissues of patients within the scope of normal medical judgment without undue toxicity, irritation, allergic reaction, etc., have a reasonable benefit-risk ratio, and can be effectively used for their intended uses.

[0096] The term "solvate" refers to a molecular complex containing a drug (such as brivaracetam) and one or more pharmaceutically acceptable solvent molecules (such as ethanol) in stoichiometric or non-stoichiometric amounts. When the solvent is tightly bound to the drug, the formed complex has a definite stoichiometry and is independent of humidity. However, when the solvent has weak binding (such as in channel solvates and hygroscopic compounds), the solvent content depends on humidity and drying conditions; in this case, the complex usually has non-stoichiometry.

[0097] The term "hydrate" represents a solvate containing a drug (such as brivaracetam) and water in stoichiometric or non-stoichiometric amounts.

[0098] In the present invention, the polyvinyl acetate (PVAc) described is a homopolymer of vinyl acetate, and the molecular weight M w is usually about 1×10 5 to about 1×10 6 。

[0099] KSR can be produced for BSAF, and its trade name is An 80 / 20 (w / w) mixture labeled as PVAc and PVP.

[0100] In the present invention, the poly(ethylene oxide) ((PEO), also known as polyoxirane and polyoxyethylene. Poly(ethylene oxide) is a homopolymer of ethylene oxide, and its molecular weight M w is usually about 1×10 5 to about 1×10 7 or about 1×10 6 to about 1×10 7 . Poly(ethylene oxide) has various grades according to the molecular weight, and can be produced by Union Carbide, and its trade name is

[0101] The term "plurality" means more than two, such as two, three or four.

[0102] The term "more species" means more than three, such as three, four or five.

[0103] The term "therapeutically effective amount" refers to the amount of the active pharmaceutical 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, etc., which can be easily determined by those of ordinary skill in the art. The specific dose will vary depending on the following factors: the particular active ingredient selected, the dosing regimen followed, whether administered in combination with other compounds, the timing of administration, the tissue to which it is administered and the physical delivery system employed.

[0104] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans.

[0105] The term "matrix former" includes a skeleton material, a disintegrant and a binder.

[0106] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0107] Advantages of the present invention

[0108] The brivaracetam sustained-release pharmaceutical composition of the present invention has good sustained-release effect, stable release rate and small side effects. Administering the drug once a day can improve patient compliance, and by reducing the maximum content of the drug in the blood, prolong the time of the drug in the body, control the effective dose of the drug in the body, reduce the drug toxicity and side effects, and achieve an effective therapeutic effect.

[0109] Compared with ordinary immediate-release preparations, the advantages of the brivaracetam sustained-release pharmaceutical composition are as follows: (1) The number of drug administrations is reduced, and good therapeutic effects can be achieved through the sustained-release effect, improving patient compliance; (2) The residence time of the drug in the stomach can be prolonged, enabling the drug to be continuously released in the stomach and absorbed in the upper part of the small intestine, achieving the effect of continuous efficacy for 24 hours, with stable blood drug concentration and few adverse reactions; (3) Prevent patients from interrupting drug use at will, and prevent the recurrence of diseases and the progression of malignant complications; (4) Once a day, select a suitable specification according to the clinical manifestations, with fewer drug administrations, convenient medication, and relatively small toxic and side effects. Description of the Drawings

[0110] Figure 1 Dissolution curves of the brivaracetam sustained-release pharmaceutical compositions prepared in Examples 1 to 7 in pH 4.5 acetate buffer solution;

[0111] Figure 2 Dissolution curves of the brivaracetam sustained-release pharmaceutical compositions prepared in Examples 7 to 10 in pH 4.5 acetate buffer solution;

[0112] Figure 3 Dissolution curves of the brivaracetam sustained-release pharmaceutical compositions prepared in Examples 7 to 10 in the reciprocating cylinder dissolution method;

[0113] Figure 4 Average concentration-time curve of brivaracetam after administering the test article (brivaracetam sustained-release tablets prepared in Example 6) / reference listed drug to Beagle dogs; wherein, represents the curve of the reference listed drug control group, represents the curve of the test article group;

[0114] Figure 5 Average plasma concentration-time curve of brivaracetam in the reference listed drug control group and the test article group (brivaracetam sustained-release tablets prepared in Example 7) in healthy subjects; wherein, represents the curve of the reference listed drug control group, represents the curve of the test article group. Detailed Description of the Invention

[0115] The technical solution of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only for exemplarily illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0116] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products, or can be prepared by known methods.

[0117] Sources of raw and auxiliary materials in the examples:

[0118] Brivaracetam: Purchased from Guangdong Yangguang Pharmaceutical Co., Ltd., purity: 98% - 102%.

[0119] Crosslinked polyvinylpyrrolidone: Chongqing Sterck Rohm & Haas Materials Technology Co., Ltd., its trade name is

[0120] Polyethylene oxide: Produced by DUPONT, its trade name is POLYOX TM 。

[0121] KSR: Produced by BSAF, its trade name is A nominally 80 / 20 (w / w) mixture of PVAc and PVP.

[0122] Examples 1 - 4

[0123] The prescriptions of Examples 1 - 4 are shown in Table 1.

[0124] Table 1

[0125]

[0126] Examples 5 - 7

[0127] The prescriptions of Examples 5 - 7 are shown in Table 2.

[0128] Table 2

[0129] Preparation process of brivaracetam sustained-release tablets:

[0130] Pass the brivaracetam in the above prescription through a 40-mesh sieve and set aside.

[0131] Mix the brivaracetam (passed through a 40-mesh sieve) in the above prescription and other excipients except magnesium stearate in a hopper mixer, set the mixing speed at 18 rpm, and mix for 20 min; sieve the mixed materials using a granulator, with the sieve aperture being 0.8 mm and the rotation speed being 7 - 12 Hz; then place the sieved materials in the hopper mixer, set the mixing speed at 18 rpm, and mix for 20 min; finally, add magnesium stearate, set the mixing speed at 18 rpm, and mix for 5 min to obtain the brivaracetam total mixed powder.

[0132] Press the above brivaracetam total mixed powder using a 22.0 mm × 10.9 mm melon seed-shaped punch die, adjust parameters such as the pressing speed, pre-pressing pressure, and main pressure to make the hardness reach 140 N - 240 N for pressing to obtain brivaracetam sustained-release tablets, and then coat them with an aqueous solution of film coating powder to obtain brivaracetam sustained-release tablets.

[0133] Test Example 1

[0134] Detect the dissolution curves and the swelling sizes after 24 hours of the brivaracetam sustained-release tablets obtained in Examples 1 - 7, and the comparative research results are as follows:

[0135] Dissolution detection method: 900 mL of pH 4.5 acetate buffer solution, according to the second method of 0931 in Chinese Pharmacopoeia (2020 Edition), 50 rpm, 37 ± 0.5 °C; the dissolution results are shown in Table 3 and Figure 1 as follows.

[0136] Table 3

[0137]

[0138] Detect the swelling sizes after 24 hours of the brivaracetam sustained-release tablets obtained in Examples 1 - 7, and the comparative research results are shown in Table 4.

[0139] Table 4

[0140]

[0141] The above data indicate 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 diameter, width diameter, and thickness of the tablet can all reach the size of the pyloric sphincter of the human stomach.

[0142] Examples 8 - 10

[0143] The prescriptions of Examples 8 - 10 are shown in Table 5.

[0144] Table 5

[0145]

[0146] Test Example 2

[0147] (1) The dissolution curves and the swelling dimensions after 24 hours of the brivaracetam sustained-release tablets obtained in Examples 7 to 10 were detected, and the comparative research results are as follows:

[0148] Dissolution detection method: 900 mL of pH 4.5 acetate buffer solution. According to the second method of 0931 in the Chinese Pharmacopoeia (2020 Edition), 50 rpm, 37 ± 0.5 °C; the dissolution results are shown in Table 6 and Figure 2 as follows.

[0149] Table 6

[0150]

[0151] The swelling dimensions after 24 hours of the brivaracetam sustained-release tablets obtained in Examples 7 to 10 were detected, and the comparative research results are shown in Table 7:

[0152] Table 7

[0153] The 50 mg to 200 mg specification brivaracetam sustained-release tablets prepared in Examples 7 to 10 all had good sustained-release effects. After the gastric retention tablets swelled for 24 hours, the length diameter, width diameter, and thickness of the tablets could all reach the size of the pyloric sphincter of the human stomach, proving that the 50 mg, 100 mg, 150 mg, and 200 mg specification brivaracetam sustained-release tablets obtained in the present invention had good gastric retention effects and good sustained-release effects; and the dissolution behaviors of the brivaracetam sustained-release tablets with different specifications in the present invention were basically the same, and the sustained-release speed was stable.

[0154] (2) According to the dissolution and release determination method, the seventh method in General Principles 0931 of the Chinese Pharmacopoeia 2020 Edition was used for determination. The dissolution conditions were as follows: the dissolution medium was pH 1.2 hydrochloric acid solution and pH 4.5 acetate buffer solution, the immersion speed was 20 DPM, the sieve was made of 20-mesh polypropylene, and the dripping time was 15 seconds. To further evaluate the release of the brivaracetam sustained-release tablets in the stomach in the present invention, the reciprocating cylinder dissolution method was used for evaluation. This dissolution method could simulate the release speed of the tablets under the conditions of gastric contents or gastric peristalsis in the stomach. The dissolution method using the reciprocating cylinder method is shown in Table 8:

[0155] Table 8

[0156]

[0157] The release speeds of the brivaracetam sustained-release tablets under different specifications are shown in Table 9 and Figure 3 as follows:

[0158] Table 9

[0159]

[0160] The research results of simulating in vivo gastric peristalsis and food factors show that the brivaracetam sustained-release tablets described in the present invention can achieve a good sustained-release effect in the stomach, maintain a stable blood drug concentration, continuously take effect, and play a role in treating diseases.

[0161] PK Study in Beagle Dogs in Test Example 3

[0162] Three Beagle dogs were selected in this experiment, including 2 males and 1 female. The test article group used the tablets in Example 6, with a dose of 100 mg / animal / day. The dosing dose of the reference control group (i.e., brivaracetam tablets) was 100 mg / animal / day. The test article group was administered once, and the reference control group was administered 1 tablet every 8 h for a total of 2 times. Blood samples were collected from the test article animals at the time points of before drug administration (collected one day before dosing), 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h after the end of dosing; blood samples were collected from the reference control group animals at the time points of before drug administration (collected one day before dosing), 0.25 h, 0.5 h, 0.75 h, 1 h, 1.25 h, 1.5 h, 2 h, 3 h, 5 h, 8 h (after collection, the second dose was administered), 8.25 h, 8.5 h, 8.75 h, 9 h, 9.25 h, 9.5 h, 10 h, 11 h, 13 h, and 16 h. The blood drug concentration results are shown in Table 10:

[0163] Table 10

[0164] The results show that the half-life of the test article group (brivaracetam sustained-release tablets of Example 6) was prolonged, and the maximum blood drug concentration was lower than that of the reference control group (brivaracetam tablets), showing a good sustained-release effect. The blood drug concentration curves of the reference control group and the test article group are as Figure 4 shown. PK Study in Healthy Subjects in Test Example 4

[0165] A PK study of the brivaracetam sustained-release tablets of Example 7 of the present invention was carried out in healthy subjects. The reference product (50 mg brivaracetam tablets) and the test article (100 mg brivaracetam sustained-release tablets) were selected as the study drugs. The test article group used the tablets in Example 7, with a dose of 100 mg / day. The dosing dose of the reference control group (i.e., brivaracetam tablets) was 100 mg / day. The test article group was administered once, and the reference control group was administered 1 tablet every 12 h for a total of 2 times. The reference control group and the test article group were respectively subjected to staged blood sampling to detect the blood drug concentration. The blood drug concentration results are shown in Table 11:

[0166] Table 11

[0167]

[0168] The results show that: the C of the test article group (brivaracetam sustained-release tablets) maxThe geometric mean ratios with AUC were all within the range of 80% to 125%. The therapeutic effects of 1 brexpiprazole sustained-release tablet were comparable to those of 2 brexpiprazole tablets. The brexpiprazole sustained-release tablet had a slower drug release rate, a more stable blood drug concentration, reduced the occurrence of adverse reactions while achieving the therapeutic effect, and brought better therapeutic effects, compliance, and safety to patients. The blood drug concentration curves of the original research control group and the test article group are as shown in Figure 5 shown.

[0169] Test Example 5 Stability test of Example 7

[0170] The tablet product obtained in Example 7 was placed under accelerated conditions (40°C ± 2°C, 75% ± 5% RH) for a 6-month stability test, and the related substances, isomers, content, and dissolution (dissolution was tested by the reciprocating cylinder method in Test Example 2) were detected. The results are shown in Table 12:

[0171] Table 12

[0172] The above stability test results indicate that during the stability period of the brexpiprazole sustained-release tablet described in the present invention, there were no obvious changes in the related substances, isomers, content, and dissolution, and the product had excellent stability.

[0173] Test Example 6 Comparison between Example 7 and Tablets A and E in the prior art CN113908153A

[0174] Example 7, Tablets A and E in CN113908153A were placed at 60°C, and samples were taken on the 10th and 30th days to detect the content of related substances. The results are shown in Table 13.

[0175] Table 13 Comparison data of related substances

[0176]

[0177] The dissolution curves and the swelling sizes after 24 hours of Example 7, Tablet A, and Tablet E were detected, and the comparative research results are shown in Tables 14 and 15.

[0178] Dissolution detection method: 900 mL of pH 4.5 acetate buffer solution, according to the second method of 0931 in the Chinese Pharmacopoeia (2020 Edition), 50 rpm, 37 ± 0.5°C.

[0179] Table 14 Comparison data of tablet swelling sizes

[0180] Table 15 Comparison data of dissolution rates

[0181]

[0182] Through the above comparison, the tablets obtained in Example 7 of the present invention have low impurity content and good stability, while the impurity content of Tablet A and Tablet E in CN113908153A is relatively high and the stability is poor; the expansion size of the tablets in Example 7 of the present invention meets the requirements, while the size of Tablet E in CN113908153A is small, which is not conducive to the retention of the tablets in the stomach; the dissolution rate of the tablets in Example 7 of the present invention is slow and the sustained-release effect is better. Through comprehensive evaluation, Example 7 of the present invention has comprehensive advantages in terms of product stability, tablet expansion size and sustained-release effect.

[0183] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope 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 binder is selected from one or more of hydroxypropyl methylcellulose, pregelatinized starch, copovidone, 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.

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