Brivaracetam controlled release tablets and preparation method thereof

Abstract

The present application provides a controlled release tablet of Brivaracetam and a preparation method thereof, which comprises: a bilayer tablet core containing Brivaracetam, which is composed of a drug-containing layer and a push layer; and a semi-permeable membrane coating with a drug release hole arranged outside the bilayer tablet core, wherein the drug-containing layer contains an effective dose of Brivaracetam, a sustained-release material I, a sustained-release material II, a binder I and other pharmaceutical excipients; the sustained-release material I is carbomer, the sustained-release material II is selected from any one of hydroxypropyl methyl cellulose, polyethylene oxide and polyvinyl pyrrolidone, and the weight ratio of the sustained-release material II to the sustained-release material I is 1:1-5:1; and the push layer contains a hydrophilic polymer, an osmotic pressure regulator, a binder II and other pharmaceutical excipients. The controlled release tablet of Brivaracetam of the present application has a significant zero-order drug release feature, a stable blood drug concentration, a long-lasting drug effect, and a good medication compliance with once-a-day administration.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to brucetam controlled-release tablets, an antiepileptic drug, and its preparation method. Background Technology

[0002] Brivaceratam, a levetiracetam derivative developed by UCB, Inc., is a next-generation antiepileptic drug used as adjunctive therapy for partial-onset seizures. Brivaceratam's mechanism of action is similar to levetiracetam, binding to SV2A (synaptic vesicle protein 2A) in the brain, regulating neurotransmitter release, and inhibiting abnormal brain discharges. However, brivaceratam's binding affinity to SV2A is 10 times stronger than that of levetiracetam, and its pharmacokinetic parameters, pharmacological properties, and safety profile are also significantly better.

[0003] Bricilant was approved by the EMA on January 14, 2016, and by the FDA on February 18, 2016 (trade name: It is available in three dosage forms: tablets (strengths: 10, 25, 50, 75, 100 mg), oral solution (strength: 10 mg / mL), and injection (strength: 50 mg / 5 mL). The recommended starting dose for the marketed tablet dosage form is 50 mg twice daily (100 mg / day). Subsequently, based on individual patient tolerance and treatment response, the dose may be adjusted downwards to 25 mg twice daily (50 mg / day) or upwards to 100 mg twice daily (200 mg / day).

[0004] Chinese patent application CN102292071B discloses a pharmaceutical composition of a 2-oxo-1-pyrrolidine derivative (briceracetam), its preparation method, and its therapeutic application. The composition is in solid tablet form and is an immediate-release composition, exhibiting at least 75% in vitro dissolution release (USP 711 instrument n°2) within 45 minutes in a suitable buffered aqueous medium. This immediate-release composition comprises particles, the particles containing, relative to their total weight,: 1) briceracetam as the active ingredient; 2) 0.1-60% by weight of at least one cyclodextrin reagent; 3) 0.5-25% by weight of a disintegrant; and 4) 5-95% by weight of a diluent. Currently, commercially available briceracetam tablets are prepared using the formulation described in this patent, with excipients including: lactose monohydrate, anhydrous lactose, β-cyclodextrin, croscarmellose sodium, and magnesium stearate, prepared using a dry granulation process. According to the guidelines for immediate-release oral dosage forms, the test standard is met: 85% dissolves in 900 mL of 0.1 NHCl within 15 minutes. Therefore, the commercially available formulation is an immediate-release preparation, administered twice daily, which is inconvenient.

[0005] Chinese patent application CN111407738A discloses a briceracetam controlled-release formulation and its preparation method. The briceracetam controlled-release tablet is characterized by comprising a tablet core, a membrane-controlled coating system, and a drug release pore. The tablet core includes briceracetam, a hydrophilic matrix, excipients, a flow aid, and a lubricant, wherein briceracetam accounts for 20-80% of the total weight of the tablet core, preferably 30-60%. This controlled-release formulation is a single-layer osmotic pump controlled-release tablet.

[0006] For single-layer osmotic pump controlled-release tablets, drug release relies solely on osmotic pressure. This requires the tablet core to continuously provide sufficient osmotic pressure to maintain a adequate osmotic pressure difference across the membrane, ensuring "zero-order release." However, for highly water-soluble drugs, the osmotic pressure difference across the membrane gradually decreases and approaches equilibrium in the later stages of release. The zero-order release rate becomes difficult to maintain for extended periods, and the actual drug release tends towards first-order release, severely impacting the controlled-release effect. Furthermore, briracetam, a BCS Class I drug (easily soluble and permeable), is prone to dose dumping. Developing it as a sustained-release formulation could lead to rapid drug release within a short time, endangering patient safety. Summary of the Invention

[0007] In view of the problems existing in the prior art, the present invention provides a brucetam controlled-release tablet with a cumulative drug release rate of not less than 95% and a uniform drug release rate within 20 hours, so that patients can obtain a more stable blood drug concentration level after taking it, realize once-daily dosing, and improve patients' medication compliance.

[0008] To achieve the above-mentioned objective, the present invention provides a bricetram controlled-release tablet, comprising: a bilayer tablet core consisting of a drug-containing layer and a driving layer, and a semi-permeable membrane coating disposed outside the bilayer tablet core; the semi-permeable membrane coating having a drug release pore on the drug-containing layer side; the drug-containing layer comprising bricetram or a pharmaceutically acceptable salt thereof, sustained-release material I and sustained-release material II, binder I and lubricant I; the driving layer comprising a hydrophilic polymer, an osmotic pressure regulator, binder II and lubricant II; wherein, the sustained-release material I is carbomer, the sustained-release material II is selected from any one of hydroxypropyl methylcellulose, polyoxyethylene and polyvinylpyrrolidone, and the weight ratio of sustained-release material II to sustained-release material I is 1:1 to 5:1.

[0009] In some preferred embodiments, the weight ratio of the sustained-release material II to the sustained-release material I is 1:1 to 3:1, 1:1 to 5:2, 3:2 to 5:1, 3:2 to 5:2, more preferably 1:1 to 5:1, more preferably 3:2 to 5:2, and most preferably 2.2:1.

[0010] In some preferred embodiments, the carbomer is carbomer homopolymer type A 71G, carbomer 974P, or carbomer 971P, with carbomer homopolymer type A 71G being the most preferred.

[0011] In some preferred embodiments, the hydroxypropyl methylcellulose is HPMC K15MCR, HPMC K4M, or HPMCK1100M, with HPMC K15MCR being the most preferred.

[0012] In some preferred embodiments, the polyoxyethylene is polyoxyethylene WSR-N-60K, polyoxyethylene WSRN80, polyoxyethylene WSR205, or polyoxyethylene WSR303, with polyoxyethylene WSR-N-60K being the most preferred.

[0013] In some preferred embodiments, the polyvinylpyrrolidone is polyvinylpyrrolidone VA64, polyvinylpyrrolidone K17, polyvinylpyrrolidone K30, or polyvinylpyrrolidone VA55, with polyvinylpyrrolidone VA64 being the most preferred.

[0014] In some preferred embodiments, the weight ratio of the drug-containing layer to the propellant layer is 1:2 to 3:1, 1:2 to 2:1, 1:2 to 3:2, 1:1 to 3:1, 1:1 to 2:1, or 1:1 to 3:2, preferably 1:1 to 3:2, and more preferably 1.4:1.

[0015] In some preferred embodiments, the controlled-release tablet, by weight, comprises: 80-200 parts by weight of briracetam, 20-65 parts by weight of sustained-release material I, 45-160 parts by weight of sustained-release material II, and 10-80 parts by weight of binder I; the propellant layer comprises: 15-250 parts by weight of hydrophilic polymer, 70-250 parts by weight of osmotic pressure regulator, and 2-10 parts by weight of binder II.

[0016] In some preferred embodiments, the controlled-release tablet, by weight, comprises: 80-160 parts by weight of bricetan, 30-55 parts by weight of sustained-release material I, 55-150 parts by weight of sustained-release material II, and 10-65 parts by weight of binder I; and the propellant layer comprises: 80-250 parts by weight of hydrophilic polymer, 70-110 parts by weight of osmotic pressure regulator, and 4-10 parts by weight of binder II.

[0017] In some preferred embodiments, the controlled-release tablet, by weight, comprises: 100-140 parts by weight of bricetan, 40-50 parts by weight of sustained-release material I, 90-110 parts by weight of sustained-release material II, and 45-50 parts by weight of binder I; and the propellant layer comprises: 80-135 parts by weight of hydrophilic polymer, 70-90 parts by weight of osmotic pressure regulator, and 5-7 parts by weight of binder II.

[0018] In some preferred embodiments, based on the total weight of the drug-containing layer, the brucetam content ranges from 30% to 51%, 30% to 48%, 30% to 45%, 30% to 42%, 34% to 51%, 34% to 48%, 34% to 45%, 34% to 42%, and preferably 30% to 45%.

[0019] In some preferred embodiments, the content of the sustained-release material I ranges from 7% to 21%, 7% to 13%, 13% to 15%, and 15% to 21% based on the total weight of the drug-containing layer, preferably 15% to 21%.

[0020] In some preferred embodiments, the content of the sustained-release material II ranges from 20% to 40%, 20% to 28%, 28% to 32%, 32% to 36%, and 36% to 40% based on the total weight of the drug-containing layer.

[0021] In some preferred embodiments, the content of adhesive I, based on the total weight of the medicated layer, ranges from 3% to 30%, 13% to 30%, 13% to 20%, 13% to 15%, 15% to 30%, and 20% to 30%, preferably 13% to 20%.

[0022] In some preferred embodiments, the adhesive I is selected from one or more of sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, starch paste, hydroxypropyl cellulose, sucrose, sodium alginate, and dextrin, with hydroxypropyl cellulose being preferred.

[0023] In some preferred embodiments, the hydrophilic polymer is selected from one or more of polyethylene oxide, croscarmellose sodium, polyvinyl alcohol, or croscarmellose, preferably polyethylene oxide. In some more preferred embodiments, the hydrophilic polymer content ranges from 43% to 76%, 43% to 58%, 49% to 58%, and preferably 49% to 58%, based on the total weight of the driving layer.

[0024] In some preferred embodiments, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, lactose, sorbitol, or sodium phosphate, preferably sodium chloride. In some more preferred embodiments, based on the total weight of the driving layer, the osmotic pressure regulator ranges from 21% to 84%, 21% to 53%, 21% to 49%, 38% to 84%, 38% to 53%, 38% to 49%, preferably 38% to 49%.

[0025] In some preferred embodiments, the adhesive II is selected from one or more of polyvinylpyrrolidone, polyvinyl alcohol, monolaurate, and maltitol, preferably polyvinylpyrrolidone. In some more preferred embodiments, the content of the adhesive II ranges from 0.3% to 8%, 0.3% to 3%, and 0.3% to 1% based on the total weight of the pusher layer, preferably 0.3% to 3%.

[0026] In some embodiments, lubricant I and lubricant II may be the same or different, and are selected from one or more of magnesium stearate, talc, stearic acid, glyceryl monostearate, sodium stearate fumarate, talc and micronized silica, preferably magnesium stearate.

[0027] In some embodiments, the drug-containing layer, the propellant layer, or both the drug-containing layer and the propellant layer further comprise a colorant selected from one or more of lemon yellow lead lake, sunset yellow lead lake, iron oxide red, iron oxide yellow, iron oxide violet, and iron oxide black.

[0028] In some preferred embodiments, the semi-permeable membrane coating uses a cellulose acetate-based osmotic pump coating premix.

[0029] The drug release hole is made by laser drilling, which can be used for single-hole drilling with a hole diameter of 0.1 to 0.3 mm.

[0030] The controlled-release tablets contain bricetam, which is released primarily by the osmotic pressure in the osmotic pump, and continuously released for 20 hours in a controlled or sustained-release manner.

[0031] The bricetrastetan controlled-release tablets of the present invention can be designed as cylinders, preferably with a size of 8.0mm × 8.0mm × 8.0mm, which makes them easier to swallow and improves patient compliance.

[0032] This invention also discloses a preparation process for briracetam controlled-release tablets, comprising the following steps:

[0033] 1) Preparation of the drug-containing layer: Bricetan raw material is ground and then mixed evenly with sustained-release material I, sustained-release material II, binder I, lubricant and optionally colorant, and then compressed into tablets;

[0034] 2) Preparation of the driving layer: The osmotic pressure regulator is mixed with the hydrophilic polymer, optionally binder II, lubricant and / or colorant to obtain the driving layer powder;

[0035] 3) Compression of double-layer tablet core: Fill the drug-containing tablet core with the pushing layer powder and compress it into a double-layer tablet;

[0036] 4) Coating with a semi-permeable film: Coating the pressed double-layer sheet using a fluidized bed;

[0037] 5) Drilling release holes: After the coating has aged, drill holes with a diameter of 0.1 to 0.3 mm on one side of the drug-containing layer to obtain bricetram controlled-release tablets.

[0038] The bricetam controlled-release tablet of the present invention has a semi-permeable membrane thickness of about 0.17 mm and a tablet diameter of about 8 mm.

[0039] The briceceran controlled-release tablets of the present invention have the following beneficial effects:

[0040] The brisaectatine controlled-release tablets provided by this invention exhibit significant zero-order release characteristics, avoiding the problem of changes in release rate characteristics in the later stages of drug release in monolayer osmotic pump controlled-release tablets. This ensures that the drug is basically completely released under the premise of zero-order release, with a cumulative release rate of not less than 95%. It can continuously and stably release the drug for 20 hours, achieving a sustained controlled-release effect, enabling once-daily dosing, effectively reducing the number of times patients need to take medication, and improving patient medication adherence.

[0041] The brisaectam controlled-release tablet provided by the present invention comprises a double-layer tablet core consisting of a drug-containing layer and a propellant layer. The drug-containing layer of the tablet core can be activated by absorbing water in the gastrointestinal tract. The polymer material of the propellant layer, which serves as the drug release driving force, expands continuously after absorbing water, slowly and at a constant rate pushing the hydrated drug-containing suspension out of the drug release orifice. By adjusting the weight ratio of the drug-containing layer and the propellant layer, the drug can be released in a zero-order manner.

[0042] The bricetam controlled-release tablets of this invention utilize a sustained-release material to form the drug-carrying framework in the drug-containing layer. The drug release rate is controlled by slow water absorption and swelling, resulting in stable blood drug concentrations with minimal peak-to-trough fluctuations. In the driving layer, this invention employs a hydrophilic polymer. This polymer both absorbs water and swells to promote drug release and maintains osmotic pressure through self-dissolution. This reduces the loss of osmotic pressure regulators due to changes in osmotic pressure, stabilizing the environment within the driving layer. This helps the driving layer continuously generate driving force, maintaining a sufficient osmotic pressure difference across the membrane for a longer period, and promoting sustained controlled release of the drug.

[0043] The brucetam controlled-release tablets provided by this invention exhibit zero-order release characteristics during in vitro release from 0 to 20 hours, with correlation coefficients r greater than 0.98.

[0044] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application can be realized and obtained by means of the solutions described in the description and the accompanying drawings. Attached Figure Description

[0045] The accompanying drawings are used to provide an understanding of the technical solutions of this application and constitute a part of the specification. They are used together with the embodiments of this application to explain the technical solutions of this application and do not constitute a limitation on the technical solutions of this application.

[0046] Figure 1 This is a schematic diagram of the structure of the bricetam double-layer osmotic pump controlled-release tablet of the present invention, wherein 1 is the drug-containing layer, 2 is the driving layer, 3 is the semi-permeable membrane, and 4 is the drug release pore.

[0047] Figures 2-1 to 2-8 The in vitro cumulative release curves of the bricetan bilayer osmotic pump controlled-release tablets prepared in Examples 1-8 are shown.

[0048] Figures 3-1 to 3-3 The in vitro cumulative release curves of the bricetratan controlled-release tablets prepared in Comparative Examples 1-3 are shown.

[0049] Figure 4-1 The release curves are a comparison of the briceceran bilayer osmotic pump controlled-release tablets prepared in Example 3 and the briceceran monolayer controlled-release tablets prepared in Comparative Example 1. Figure 4-2 The graph shows the release curves of the bricetram bilayer osmotic pump controlled-release tablets prepared in Example 3 and those prepared in Comparative Examples 2 and 3.

[0050] Figure 5 The blood drug concentration-time curves are shown for the briceceran bilayer osmotic pump controlled-release tablets prepared in Example 3 and the briceceran controlled-release tablets prepared in Comparative Examples 1-3. Detailed Implementation

[0051] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of the present invention will be described in detail below. These embodiments all have the following characteristics: Figure 1 The double-layer osmotic pump controlled-release structure is shown.

[0052] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined arbitrarily with each other.

[0053] In a first aspect of the invention, a briracetam controlled-release tablet is provided, comprising: a bilayer tablet core consisting of a drug-containing layer and a driving layer, and a semi-permeable membrane coating disposed outside the bilayer tablet core; the semi-permeable membrane coating having a drug release pore on the drug-containing layer side; the drug-containing layer comprising briracetam or a pharmaceutically acceptable salt thereof, a sustained-release material I, a sustained-release material II, a lubricant I, and a binder I; the driving layer comprising a hydrophilic polymer, an osmotic pressure regulator, a lubricant II, and a binder II; wherein the sustained-release material I is carbomer, the sustained-release material II is selected from any one of hydroxypropyl methylcellulose, polyoxyethylene, and polyvinylpyrrolidone, and the weight ratio of the sustained-release material II to the sustained-release material I is 1:1 to 5:1.

[0054] In some preferred embodiments, the weight ratio of the sustained-release material II to the sustained-release material I is 1:1 to 3:1, 1:1 to 5:2, 3:2 to 5:1, 3:2 to 5:2, more preferably 1:1 to 5:1, more preferably 3:2 to 5:2, and most preferably 2.2:1.

[0055] In some preferred embodiments, the weight ratio of the drug-containing layer to the propellant layer is 1:2 to 3:1, 1:2 to 2:1, 1:2 to 3:2, 1:1 to 3:1, 1:1 to 2:1, or 1:1 to 3:2, preferably 1:1 to 3:2, and more preferably 1.4:1.

[0056] In some preferred embodiments, the controlled-release tablet, by weight, comprises: 80-200 parts by weight of briracetam, 20-65 parts by weight of sustained-release material I, 45-160 parts by weight of sustained-release material II, and optionally 10-80 parts by weight of binder I; the propellant layer comprises: 15-250 parts by weight of hydrophilic polymer, 70-250 parts by weight of osmotic pressure regulator, and optionally 2-10 parts by weight of binder II.

[0057] In some preferred embodiments, the controlled-release tablet, by weight, comprises: 80-160 parts by weight of briracetam, 30-55 parts by weight of sustained-release material I, 55-150 parts by weight of sustained-release material II, and optionally 10-65 parts by weight of binder I; the propellant layer comprises: 80-250 parts by weight of hydrophilic polymer, 70-110 parts by weight of osmotic pressure regulator, and optionally 4-10 parts by weight of binder II.

[0058] In some preferred embodiments, the controlled-release tablet, by weight, comprises: 100-140 parts by weight of briracetam, 40-50 parts by weight of sustained-release material I, 90-110 parts by weight of sustained-release material II, and optionally 45-50 parts by weight of binder I; the propellant layer comprises: 80-135 parts by weight of hydrophilic polymer, 70-90 parts by weight of osmotic pressure regulator, and optionally 5-7 parts by weight of binder II.

[0059] In some preferred embodiments, the brucetan content ranges from 30% to 51%, 30% to 48%, 30% to 45%, 30% to 42%, 34% to 51%, 34% to 48%, 34% to 45%, 34% to 42%, and preferably 30% to 45%, based on the total weight of the drug-containing layer.

[0060] In some preferred embodiments, the content of the sustained-release material I ranges from 7% to 21%, 7% to 13%, 13% to 15%, and 15% to 21% based on the total weight of the drug-containing layer, preferably 15% to 21%.

[0061] In some preferred embodiments, the content of the sustained-release material II ranges from 20% to 40%, 20% to 28%, 28% to 32%, 32% to 36%, and 36% to 40% based on the total weight of the drug-containing layer.

[0062] In some preferred embodiments, the hydrophilic polymer is selected from one or more of polyethylene oxide, croscarmellose sodium, polyvinyl alcohol, or croscarmellose, preferably polyethylene oxide. Preferably, based on the total weight of the driving layer, the content of the hydrophilic polymer ranges from 43% to 76%, 43% to 58%, 49% to 58%, and most preferably 49% to 58%.

[0063] In some preferred embodiments, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, lactose, sorbitol, or sodium phosphate, preferably sodium chloride. Preferably, based on the total weight of the driving layer, the osmotic pressure regulator ranges from 21% to 84%, 21% to 53%, 21% to 49%, 38% to 84%, 38% to 53%, 38% to 49%, and most preferably 38% to 49%.

[0064] In some preferred embodiments, the binder I is selected from one or more of sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, starch paste, hydroxypropyl cellulose, sucrose, sodium alginate, and dextrin, with hydroxypropyl cellulose being preferred. Preferably, based on the total weight of the drug-containing layer, the content of the binder I ranges from 3% to 30%, 13% to 30%, 13% to 20%, 13% to 15%, 15% to 30%, and 20% to 30%, with 13% to 20% being the most preferred.

[0065] In some preferred embodiments, the adhesive II is selected from one or more of polyvinylpyrrolidone, polyvinyl alcohol, monolaurate, and maltitol, preferably polyvinylpyrrolidone. Preferably, based on the total weight of the pusher layer, the content of the adhesive II ranges from 0.3% to 8%, 0.3% to 3%, and 0.3% to 1%, preferably 0.3% to 3%.

[0066] In some preferred embodiments, lubricant I and lubricant II are each independently selected from one or more of magnesium stearate, talc, stearic acid, glyceryl monostearate, sodium stearate fumarate, talc, and micronized silica gel, preferably magnesium stearate.

[0067] In some preferred embodiments, the drug-containing layer, the propellant layer, or both the drug-containing layer and the propellant layer further comprise a lubricant and / or a colorant; the colorant is selected from one or more of lemon yellow lead lake, sunset yellow lead lake, iron oxide red, iron oxide yellow, iron oxide violet, and iron oxide black.

[0068] In some preferred embodiments, the double-layer sheet coating material is selected from cellulose acetate fully formulated osmotic pump coating premix. The novel, improved semi-permeable membrane coating material exhibits a more stable and gradual controlled-release effect compared to semi-permeable membrane coated tablets formulated using traditional methods.

[0069] In some implementations, the drug release hole is made by laser drilling, which can be used to drill a single hole with a diameter of 0.1 to 0.3 mm.

[0070] In some preferred embodiments, the tablets of the present invention are cylindrical, preferably with a size of 8.0 mm × 8.0 mm × 8.0 mm, which makes them easier to swallow and improves compliance.

[0071] In some preferred embodiments, the tablets of the present invention comprise a drug-containing layer and a propellant layer. The drug-containing layer comprises briracetam, carbomer, HPMC, hydroxypropyl cellulose, and magnesium stearate. The propellant layer comprises polyoxyethylene, sodium chloride, polyvinylpyrrolidone, magnesium stearate, and a colorant. More preferably, by weight, the drug-containing layer comprises 80 parts of briracetam, 55 parts of carbomer, 55 parts of HPMC, 80 parts of hydroxypropyl cellulose, and 1 part of magnesium stearate. The propellant layer comprises 250 parts of polyoxyethylene, 250 parts of sodium chloride, 2 parts of polyvinylpyrrolidone, 5 parts of magnesium stearate, and 0.005 parts of a colorant.

[0072] In some preferred embodiments, the tablets of the present invention comprise a drug-containing layer and a propellant layer. The drug-containing layer comprises briracetam, carbomer, HPMC, hydroxypropyl cellulose, magnesium stearate, and a colorant. The propellant layer comprises polyoxyethylene, sodium chloride, polyvinylpyrrolidone, and magnesium stearate. More preferably, by weight, the drug-containing layer comprises 140 parts of briracetam, 50 parts of carbomer, 75 parts of HPMC, 65 parts of hydroxypropyl cellulose, 2 parts of magnesium stearate, and 0.003 parts of colorant. The propellant layer comprises 250 parts of polyoxyethylene, 70 parts of sodium chloride, 4 parts of polyvinylpyrrolidone, and 5 parts of magnesium stearate.

[0073] In some preferred embodiments, the tablets of the present invention comprise a drug-containing layer and a propellant layer. The drug-containing layer comprises briracetam, carbomer, HPMC, hydroxypropyl cellulose, and magnesium stearate. The propellant layer comprises polyoxyethylene, sodium chloride, polyvinylpyrrolidone, magnesium stearate, and a colorant. More preferably, by weight, the drug-containing layer comprises 100 parts briracetam, 45 parts carbomer, 100 parts HPMC, 45 parts hydroxypropyl cellulose, and 1 part magnesium stearate. The propellant layer comprises 120 parts polyoxyethylene, 80 parts sodium chloride, 6 parts polyvinylpyrrolidone, 1 part magnesium stearate, and 0.002 parts colorant.

[0074] In some preferred embodiments, the tablets of the present invention comprise a drug-containing layer and a propellant layer. The drug-containing layer comprises briracetam, carbomer, HPMC, hydroxypropyl cellulose, magnesium stearate, and a colorant. The propellant layer comprises polyoxyethylene, sodium chloride, polyvinylpyrrolidone, and magnesium stearate. More preferably, by weight, the drug-containing layer comprises 160 parts of briracetam, 40 parts of carbomer, 100 parts of HPMC, 50 parts of hydroxypropyl cellulose, 3 parts of magnesium stearate, and 0.002 parts of colorant. The propellant layer comprises 134 parts of polyoxyethylene, 90 parts of sodium chloride, 7 parts of polyvinylpyrrolidone, and 4 parts of magnesium stearate.

[0075] In some preferred embodiments, the tablets of the present invention comprise a drug-containing layer and a propellant layer. The drug-containing layer comprises briracetam, carbomer, HPMC, hydroxypropyl cellulose, magnesium stearate, and a colorant. The propellant layer comprises polyoxyethylene, sodium chloride, polyvinylpyrrolidone, and magnesium stearate. More preferably, by weight, the drug-containing layer comprises 180 parts of briracetam, 35 parts of carbomer, 105 parts of HPMC, 50 parts of hydroxypropyl cellulose, 4 parts of magnesium stearate, and 0.002 parts of colorant. The propellant layer comprises 80 parts of polyoxyethylene, 100 parts of sodium chloride, 5 parts of polyvinylpyrrolidone, and 2 parts of magnesium stearate.

[0076] In some preferred embodiments, the tablets of the present invention comprise a drug-containing layer and a propellant layer. The drug-containing layer comprises briracetam, carbomer, HPMC, hydroxypropyl cellulose, magnesium stearate, and a colorant. The propellant layer comprises polyoxyethylene, sodium chloride, polyvinylpyrrolidone, and magnesium stearate. More preferably, by weight, the drug-containing layer comprises 200 parts of briracetam, 30 parts of carbomer, 150 parts of HPMC, 10 parts of hydroxypropyl cellulose, 5 parts of magnesium stearate, and 0.004 parts of colorant. The propellant layer comprises 10.5 parts of polyoxyethylene, 110 parts of sodium chloride, 10 parts of polyvinylpyrrolidone, and 1 part of magnesium stearate.

[0077] In some preferred embodiments, the tablets of the present invention comprise a drug-containing layer and a propellant layer. The drug-containing layer comprises bricetram, carbomer, polyvinylpyrrolidone, hydroxypropyl cellulose, and magnesium stearate. The propellant layer comprises polyoxyethylene, sodium chloride, polyvinyl alcohol, magnesium stearate, and a colorant. More preferably, by weight, the drug-containing layer comprises 100 parts of bricetram, 45 parts of carbomer, 100 parts of polyvinylpyrrolidone, 45 parts of hydroxypropyl cellulose, and 1 part of magnesium stearate. The propellant layer comprises 120 parts of polyoxyethylene, 80 parts of sodium chloride, 6 parts of polyvinyl alcohol, 1 part of magnesium stearate, and 0.002 parts of colorant.

[0078] In some preferred embodiments, the tablets of the present invention comprise a drug-containing layer and a propellant layer. The drug-containing layer comprises briracetam, carbomer, polyoxyethylene, hydroxypropyl cellulose, and magnesium stearate. The propellant layer comprises polyvinyl alcohol, sodium chloride, polyvinylpyrrolidone, magnesium stearate, and a colorant. More preferably, by weight, the drug-containing layer comprises 100 parts of briracetam, 45 parts of carbomer, 100 parts of polyoxyethylene, 45 parts of hydroxypropyl cellulose, and 1 part of magnesium stearate. The propellant layer comprises 120 parts of polyvinyl alcohol, 80 parts of sodium chloride, 6 parts of polyvinylpyrrolidone, 1 part of magnesium stearate, and 0.002 parts of colorant.

[0079] This invention also provides a process for preparing briceceran controlled-release tablets, comprising the following steps:

[0080] 1) Preparation of drug-containing layer: After grinding the briracetam raw material, it is mixed with sustained-release material I, sustained-release material II, and binder I through a 20-mesh sieve three times. After being mixed evenly according to the prescription amount, it is then mixed evenly with lubricant I that has been passed through a 30-mesh sieve according to the prescription amount, and then compressed into tablets.

[0081] 2) Preparation of the driving layer: After the osmotic pressure regulator is passed through a 30-mesh sieve, it is mixed with the hydrophilic polymer and adhesive II and passed through a 20-mesh sieve three times. After being mixed evenly according to the prescription amount, it is then mixed evenly with the lubricant II after being passed through a 30-mesh sieve according to the prescription amount to obtain the driving layer powder.

[0082] 3) Compression of double-layer tablet core: Fill the drug-containing tablet core with the pushing layer powder and compress it into a double-layer tablet.

[0083] 4) Coating with a semi-permeable membrane: The pressed double-layer sheet is coated with a fluidized bed. The semi-permeable membrane is 0.17 mm thick and the sheet diameter is 8 mm.

[0084] 5) Drilling release holes: After coating, place the tablets in a 50°C oven for 60 minutes. Then, drill holes with a diameter of 0.1-0.3 mm on one side of the drug-containing layer of the coated tablets using a laser drilling machine to obtain bricetam controlled-release tablets.

[0085] The excipients used in the embodiments of this invention are as follows: Carbomer is carbomer homopolymer type A 71G, purchased from Lubrizol Advanced Materials Inc. (USA); hydroxypropyl methylcellulose is HPMC K15MCR, purchased from Dow Chemical Pacific Ltd.; polyoxyethylene is polyoxyethylene WSR-N-60K, purchased from Dow Chemical Pacific Ltd.; polyvinylpyrrolidone is polyvinylpyrrolidone VA64, purchased from BASF; hydroxypropyl cellulose is HPC-L, purchased from Shin-Etsu Chemical Industries, Ltd.; polyvinyl alcohol is polyvinyl alcohol 18-88, purchased from Merck Chemical Technology Shanghai Co., Ltd.; and semi-permeable membrane coating is cellulose acetate full-formulation osmotic pump coating premix - Opadry 500F190007-CN CLEAR, purchased from Shanghai Calcare Coating Technology Co., Ltd.

[0086] Example 1

[0087]

[0088] The preparation method includes the following steps:

[0089] 1) Preparation of drug-containing layer: Bricetan raw material is ground and then passed through a 20-mesh sieve three times with HPMC, carbomer and hydroxypropyl cellulose. It is mixed evenly according to the prescription amount, granulated through a 20-mesh sieve, and dried completely by forced air at 50℃. After the granules are completely dried, they are granulated through a 20-mesh sieve and then mixed with the prescription amount of magnesium stearate that has passed through a 30-mesh sieve for 5 minutes. The mixture is then compressed into tablets with a hardness controlled at 80-120N to obtain drug-containing granules.

[0090] 2) Preparation of the driving layer: Sodium chloride is passed through a 30-mesh sieve and then passed through a 20-mesh sieve three times together with polyoxyethylene, polyvinylpyrrolidone, and sunset yellow lead lake. The mixture is then mixed evenly according to the prescription amount, granulated through a 20-mesh sieve, and dried completely in a forced-air drying process at 50°C. After the granules are completely dried, they are granulated through a 20-mesh sieve and then mixed with the prescription amount of magnesium stearate that has passed through a 30-mesh sieve for 5 minutes. The mixture is then compressed into tablets to obtain the driving layer granules.

[0091] 3) Compression of double-layer tablet core: First, the drug-containing granules are placed into the groove of the tablet press according to the prescription amount and pre-compressed with a small pressure. Then, the pusher granules are filled into the tablet press according to the prescription amount and pressed into a double-layer tablet, finally obtaining a double-layer tablet core.

[0092] 4) Coating with a semi-permeable membrane: Coat the pressed double-layer sheet with a fluidized bed (semi-permeable membrane thickness 0.17mm, sheet diameter 8mm);

[0093] 5) Drilling release holes: After coating, place the tablet in a 50℃ oven for 60 minutes, and then drill a hole with a diameter of 0.1 mm on one side of the coated tablet containing the drug layer using a laser drilling machine to obtain bricetan double-layer pump-controlled release tablets.

[0094] Example 2

[0095]

[0096] The preparation method includes the following steps:

[0097] 1) Preparation of drug-containing layer: Bricetan raw material is ground and then passed through a 20-mesh sieve three times with HPMC, carbomer, hydroxypropyl cellulose and tartrazine lead lake. The mixture is then mixed evenly according to the prescription amount, granulated through a 20-mesh sieve, and dried completely in a forced-air drying at 50℃. After the granules are completely dried, they are granulated through a 20-mesh sieve and then mixed with the prescription amount of magnesium stearate that has passed through a 30-mesh sieve for 5 minutes. The mixture is then compressed into tablets with a hardness controlled at 80-120N to obtain drug-containing granules.

[0098] 2) Preparation of the driving layer: Sodium chloride is passed through a 30-mesh sieve and then passed through a 20-mesh sieve three times together with polyoxyethylene and polyvinylpyrrolidone. The mixture is then mixed evenly according to the prescription amount, granulated through a 20-mesh sieve, and dried completely by forced air at 50°C. After the granules are completely dried, they are granulated through a 20-mesh sieve and then mixed with the prescription amount of magnesium stearate that has passed through a 30-mesh sieve for 5 minutes. The mixture is then compressed into tablets to obtain the driving layer granules.

[0099] 3) Compression of double-layer tablet core: First, the drug-containing granules are placed into the groove of the tablet press according to the prescription amount and pre-compressed with a small pressure. Then, the pusher granules are filled into the tablet press according to the prescription amount and pressed into a double-layer tablet, finally obtaining a double-layer tablet core.

[0100] 4) Coating with a semi-permeable membrane: Coat the pressed double-layer sheet with a fluidized bed (semi-permeable membrane thickness 0.17mm, sheet diameter 8mm);

[0101] 5) Drilling release holes: After coating, place the tablet in a 50℃ oven for 60 minutes, and then drill a hole with a diameter of 0.18 mm on one side of the coated tablet containing the drug layer using a laser drilling machine to obtain bricetam double-layer pump-controlled release tablets.

[0102] Example 3

[0103]

[0104] The preparation method includes the following steps:

[0105] 1) Preparation of drug-containing layer: Bricetan raw material is ground and then passed through a 20-mesh sieve three times with HPMC, carbomer and hydroxypropyl cellulose. It is mixed evenly according to the prescription amount, granulated through a 20-mesh sieve, and dried completely by forced air at 50℃. After the granules are completely dried, they are granulated through a 20-mesh sieve and then mixed with the prescription amount of magnesium stearate that has passed through a 30-mesh sieve for 5 minutes. The mixture is then compressed into tablets with a hardness controlled at 80-120N to obtain drug-containing granules.

[0106] 2) Preparation of the driving layer: Sodium chloride is passed through a 30-mesh sieve and then passed through a 20-mesh sieve three times together with polyoxyethylene, polyvinylpyrrolidone, and sunset yellow lead lake. The mixture is then mixed evenly according to the prescription amount, granulated through a 20-mesh sieve, and dried completely in a forced-air drying process at 50°C. After the granules are completely dried, they are granulated through a 20-mesh sieve and then mixed with the prescription amount of magnesium stearate that has passed through a 30-mesh sieve for 5 minutes. The mixture is then compressed into tablets to obtain the driving layer granules.

[0107] 3) Compression of double-layer tablet core: First, the drug-containing granules are placed into the groove of the tablet press according to the prescription amount and pre-compressed with a small pressure. Then, the pusher granules are filled into the tablet press according to the prescription amount and pressed into a double-layer tablet, finally obtaining a double-layer tablet core.

[0108] 4) Coating with a semi-permeable membrane: Coat the pressed double-layer sheet with a fluidized bed (semi-permeable membrane thickness 0.17mm, sheet diameter 8mm);

[0109] 5) Drilling release holes: After coating, place the tablet in a 50℃ oven for 60 minutes. Then, drill a hole with a diameter of 0.26 mm on one side of the coated tablet containing the drug layer using a laser drilling machine to obtain bricetam double-layer pump-controlled release tablets.

[0110] Example 4

[0111]

[0112] The preparation method is the same as in Example 2.

[0113] Example 5

[0114]

[0115] The preparation method is the same as in Example 2.

[0116] Example 6

[0117]

[0118] The preparation method is the same as in Example 2.

[0119] Example 7

[0120]

[0121] The preparation method is the same as in Example 3.

[0122] Example 8

[0123]

[0124] The preparation method is the same as in Example 3.

[0125] Comparative Example 1: Prepared according to the method of Example 2 in Chinese Patent Application CN111407738A

[0126]

[0127]

[0128] Process:

[0129] 1) HPMC is used as a hydrophilic matrix and premixed with sorbitol and microcrystalline cellulose for 5 min. Then, the active pharmaceutical ingredient of crystal form A is added and mixed for 5 min. Then, colloidal silica and magnesium stearate are added in sequence and mixed for 2 min and 1 min respectively. The tablets are then compressed to obtain the tablet core.

[0130] 2) Pour talc and triethyl citrate into water and homogenize using a high-shear homogenizer. Just before use, pour the homogenate into Eudragit RL30D / RS30D aqueous dispersion and filter through a 40-mesh sieve. Stir continuously during the coating process to obtain the semi-permeable membrane coating solution.

[0131] 3) Place the tablet core in a high-efficiency coating machine for semi-permeable membrane coating. The spray pressure is 0.1 MPa, the main machine speed is 10 rpm, the inlet air temperature is 35-40℃, the material temperature is 28-32℃, and the spray rate is 4-6 g / min. When the coating weight gain reaches 5%, remove the coated tablet and place it in a 40℃ oven for static aging for 24 hours. Then, punch a hole with a diameter of 0.6 mm in the center of the front of the coated irregularly shaped tablet (12.6*5.4 mm).

[0132] Comparative Example 2: Preparation of a bilayer osmotic pump controlled-release tablet in which sustained-release material I is not carbomer

[0133]

[0134]

[0135] The preparation method is the same as in Example 3.

[0136] Comparative Example 3: Preparation of a bilayer osmotic pump controlled-release tablet with carbomer as the only sustained-release material.

[0137]

[0138] The preparation method is the same as in Example 3.

[0139] Example 9 In vitro release experiment

[0140] This experiment used an in vitro release rate test, according to USP. <711> According to the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 0931, "Determination of Dissolution and Release Rate", the second method, the paddle method, was used. The rotation speed was 50 rpm, the water medium was 900 ml, and samples were taken at 1, 2, 4, 6, 8, 10, 12, 16, and 20 hours to investigate the in vitro release characteristics of samples from Examples 1-8 and Comparative Examples 1-3 within 20 hours.

[0141] Table 1. Release rates of Examples 1-8 and Comparative Examples 1-3 in aqueous medium at 37°C for 0-20 hours.

[0142]

[0143] Table 1 shows the in vitro release rates of samples from Examples 1-8 and Comparative Examples 1-3. The release rates of samples from Examples 1-8 within 20 hours were all not less than 95%, with the release rate of Sample 3 reaching as high as 99%. In general, samples from Examples 1-8 and Comparative Examples 1-3 all meet the general requirements of the Chinese Pharmacopoeia for sustained-release and controlled-release preparations.

[0144] Table 2. Correlation coefficients r of release curves of Examples 1-8 and Comparative Examples 1-3 in aqueous medium at 37°C for 0-20 h.

[0145]

[0146]

[0147] Table 2 shows the correlation coefficients r of the release curves of samples from Examples 1 to 8 and Comparative Examples 1 to 3 from 0 to 20 h. Figures 2-1 to 2-8 This shows the cumulative release rate-time curves of samples from Examples 1-8 accumulated in vitro over 20 hours. Figures 3-1 to 3-3 This represents the cumulative release rate-time curves of comparative samples 1-3 over 20 hours in vitro. Figure 4-1 and Figure 4-2 The cumulative release rate-time curves of the sample of Example 3 and the samples of Comparative Examples 1, 2 and 3 accumulated in vitro for 20 hours are shown.

[0148] The results showed that the correlation coefficient r of Comparative Example 1 (single-layer osmotic pump controlled-release tablet) was 0.9557, which was significantly different from zero-order release. The correlation coefficients r of Comparative Example 2 (carbomer-free double-layer osmotic pump controlled-release tablet) and Comparative Example 3 (carbomer-only double-layer osmotic pump controlled-release tablet) were 0.9659 and 0.9643, respectively, with slightly better release performance than Comparative Example 1, but significantly different from Examples 1-8. Compared with the single-layer osmotic pump controlled-release tablet of Comparative Example 1, the carbomer-free double-layer osmotic pump controlled-release tablet of Comparative Example 2, and the carbomer-only double-layer osmotic pump controlled-release tablet of Comparative Example 3, the bricetam double-layer osmotic pump controlled-release tablets of Examples 1-8 of this invention showed stable in vitro release from 0 to 20 hours, with minimal change in drug release rate over time, and correlation coefficients r greater than 0.9800, which is consistent with the characteristics of zero-order release and the results are consistent with the design of this invention.

[0149] Example 9 Pharmacokinetics

[0150] Sixteen Beagle dogs, half male and half female, were randomly divided into four groups. In the first cycle, Group 1 dogs received a single oral dose of brisecaltan bilayer osmotic pump controlled-release tablets (Group A, Example 3 of the Invention); Group 2 dogs received a single oral dose of brisecaltan bilayer osmotic pump controlled-release tablets (Comparative Example 1, Group B); Group 3 dogs received a single oral dose of brisecaltan bilayer osmotic pump controlled-release tablets (Comparative Example 2, Group C); and Group 4 dogs received a single oral dose of brisecaltan bilayer osmotic pump controlled-release tablets (Comparative Example 3, Group D). All four groups of animals received one tablet (equivalent to 100 mg of the active ingredient) orally. Plasma samples were collected before administration (0 h) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 h after administration. Approximately 0.4 mL of whole blood was collected intravenously. After blood sample collection, the sample was placed in an anticoagulant tube containing heparin sodium (1000 IU / mL, approximately 10 μL), centrifuged at 4000 rpm for 5 min at 4°C, and the plasma was separated. The concentration of the active pharmaceutical ingredient in the plasma was determined by LC-MS / MS. The main metabolic kinetic parameters, including Cmax, Tmax, T1 / 2, and AUC0-20, were calculated using WinNonlin (V6.2).

[0151] The results showed that there were no significant sex differences in systemic exposure (AUC0-20 and Cmax) among groups A, B, C, and D at an oral dose of 100 mg / animal. Therefore, the pharmacokinetic parameters were evaluated using average values ​​for both males and females. The experimental results are shown in Table 3 below:

[0152] Table 3. Pharmacokinetic parameters in animals of groups A, B, C, and D.

[0153]

[0154] Table 3 shows that the AUC0-20 (ng h / mL) of groups A, B, C, and D were basically consistent, indicating bioequivalence among the groups. Compared with group B, group A showed a decrease in Cmax and a prolongation in Tmax, indicating that the bricetram bilayer osmotic pump controlled-release tablets prepared according to Example 3 had a better sustained-release effect than the monolayer controlled-release tablets of Comparative Example 1. Compared with groups C and D, the Cmax of group A was decreased, and the Tmax of group A was prolonged compared with group D, but there was no difference compared with group C. However, overall, the sustained-release effect of the bricetram bilayer osmotic pump controlled-release tablets prepared in Example 3 was better than that of the bilayer osmotic pump controlled-release tablets prepared in Comparative Examples 2 and 3.

[0155] The blood drug concentration-time curves for groups A, B, C, and D, plotted based on the pharmacokinetic study results, are shown below. Figure 5 .

[0156] Figure 5The results showed that, compared with the tablets prepared in Comparative Examples 1, 2, and 3 (Groups B, C, and D), the bricetram bilayer osmotic pump controlled-release tablets prepared according to Example 3 (Group A) had smaller fluctuations in blood drug concentration peaks and troughs, and more stable blood drug concentrations. The effective blood drug concentration range (therapeutic window) maintained within 4–20 hours was narrower than that of Comparative Examples 1, 2, and 3, avoiding excessively high or low blood drug concentrations and better ensuring the safety and efficacy of bricetram administration.

[0157] This invention enables long-acting controlled release, that is, uniform release of the drug over a longer period of time, with the drug being almost completely released. This uniform release of the drug provides special pharmacological characteristics for the delivery of active substances. Once-daily administration can meet the patient's medication needs, resulting in good compliance. It also reduces the maximum blood drug concentration after the patient takes the drug, reduces adverse drug reactions caused by excessively high blood drug concentrations, and effectively reduces the abuse of brucetam-class controlled drugs.

[0158] This application describes several embodiments, but these descriptions are exemplary and not restrictive, and it will be apparent to those skilled in the art that many more embodiments and implementations are possible within the scope of the embodiments described herein. Although many possible combinations of features are shown in the drawings and discussed in the detailed description, many other combinations of the disclosed features are also possible. Unless specifically limited, any feature or element of any embodiment may be used in combination with or in lieu of any other feature or element in any other embodiment.

Claims

1. A briceracetam controlled-release tablet, comprising a bilayer tablet core consisting of a drug-containing layer and a propellant layer, and a semi-permeable membrane coating disposed outside the bilayer tablet core; the semi-permeable membrane coating having a drug release pore on the drug-containing layer side; the drug-containing layer comprising briceracetam or a pharmaceutically acceptable salt thereof, sustained-release material I and sustained-release material II, binder I, lubricant I, and optionally a colorant; the propellant layer comprising a hydrophilic polymer, an osmotic pressure regulator, binder II, lubricant II, and optionally a colorant; characterized in that, The sustained-release material I is carbomer, and the sustained-release material II is selected from any one of hydroxypropyl methylcellulose, polyoxyethylene, and polyvinylpyrrolidone. The weight ratio of sustained-release material II to sustained-release material I is 1:1 to 5:

1. The hydrophilic polymer is polyoxyethylene or polyvinyl alcohol. The drug-containing layer comprises, by weight, 80-200 parts of briracetam, 20-65 parts of sustained-release material I, 45-160 parts of sustained-release material II, and 10-80 parts of binder I. The propellant layer comprises 15-250 parts of hydrophilic polymer, 70-250 parts of osmotic pressure regulator, and 2-10 parts of binder II.

2. The controlled release tablet according to claim 1, wherein, The weight ratio of the sustained-release material II to the sustained-release material I is 1:1 to 3:

1.

3. The controlled release tablet according to claim 1, wherein, The weight ratio of the sustained-release material II to the sustained-release material I is 1:1 to 5:

2.

4. The controlled release tablet according to claim 1, wherein, The weight ratio of the sustained-release material II to the sustained-release material I is 3:2 to 5:

1.

5. The controlled release tablet according to claim 1, wherein, The weight ratio of sustained-release material II to sustained-release material I is 3:2 to 5:

2.

6. The controlled release tablet according to claim 1, wherein, The weight ratio of sustained-release material II to sustained-release material I is 2.2:

1.

7. The controlled release tablet according to claim 1, wherein, The weight ratio of the drug-containing layer to the driving layer is 1:2 to 3:

1.

8. The controlled-release tablet according to claim 1, wherein, The weight ratio of the drug-containing layer to the driving layer is 1:2 to 2:

1.

9. The controlled release tablet according to claim 1, wherein, The weight ratio of the drug-containing layer to the driving layer is 1:2 to 3:

2.

10. The controlled release tablet according to claim 1, wherein, The weight ratio of the drug-containing layer to the driving layer is 1:1 to 3:

1.

11. The controlled release tablet according to claim 1, wherein, The weight ratio of the drug-containing layer to the driving layer is 1:1 to 2:

1.

12. The controlled release tablet according to claim 1, wherein, The weight ratio of the drug-containing layer to the driving layer is 1:1 to 3:

2.

13. The controlled release tablet according to claim 1, wherein, The weight ratio of the drug-containing layer to the driving layer is 1.4:

1.

14. The controlled release tablet according to claim 1, wherein, By weight, the drug-containing layer comprises: 80-160 parts by weight of briracetam, 30-55 parts by weight of sustained-release material I, 55-150 parts by weight of sustained-release material II, and 10-65 parts by weight of binder I; the propellant layer comprises: 80-250 parts by weight of hydrophilic polymer, 70-110 parts by weight of osmotic pressure regulator, and 4-10 parts by weight of binder II.

15. The controlled release tablet according to claim 1, wherein, By weight, the drug-containing layer comprises: 100-140 parts by weight of briracetam, 40-50 parts by weight of sustained-release material I, 90-110 parts by weight of sustained-release material II, and 45-50 parts by weight of binder I; the propellant layer comprises: 80-135 parts by weight of hydrophilic polymer, 70-90 parts by weight of osmotic pressure regulator, and 5-7 parts by weight of binder II.

16. The controlled release tablet according to claim 1, wherein, Based on the total weight of the drug-containing layer, the briracetam content ranges from 30% to 51%; Based on the total weight of the drug-containing layer, the content of the sustained-release material I ranges from 7% to 21%. Based on the total weight of the drug-containing layer, the content of the sustained-release material II ranges from 20% to 40%; Based on the total weight of the drug-containing layer, the content of adhesive I ranges from 3% to 30%.

17. The controlled-release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the brucetam content ranges from 30% to 48% or from 34% to 51%.

18. The controlled-release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the brucetam content ranges from 30% to 42% or from 34% to 48%.

19. The controlled release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the brucetam content ranges from 30% to 45%.

20. The controlled release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the brucetam content ranges from 34% to 45%.

21. The controlled release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the brucetam content ranges from 34% to 42%.

22. The controlled release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the content of the sustained-release material I ranges from 7% to 13%, 13% to 15%, or 15% to 21%.

23. The controlled release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the content of the sustained-release material I ranges from 15% to 21%.

24. The controlled release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the content of the sustained-release material II ranges from 20% to 28%, 28% to 32%, 32% to 36%, or 36% to 40%.

25. The controlled-release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the content of adhesive I ranges from 13% to 30%.

26. The controlled release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the content of adhesive I ranges from 13% to 20% or from 15% to 30%.

27. The controlled release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the content of adhesive I ranges from 13% to 15% or from 20% to 30%.

28. The controlled release tablet according to claim 16, wherein, Based on the total weight of the drug-containing layer, the content of adhesive I ranges from 13% to 20%.

29. The controlled release tablet according to claim 1, wherein, The adhesive I is selected from one or more of sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, starch paste, hydroxypropyl cellulose, sucrose, sodium alginate, and dextrin; Based on the total weight of the propulsion layer, the content of the hydrophilic polymer ranges from 43% to 76%. The osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, lactose, sorbitol, or sodium phosphate; The adhesive II is selected from one or more of polyvinylpyrrolidone, polyvinyl alcohol, monolaurate, and maltitol.

30. The controlled release tablet according to claim 29, wherein, The adhesive I is hydroxypropyl cellulose.

31. The controlled release tablet according to claim 29, wherein, Based on the total weight of the propulsion layer, the content of the hydrophilic polymer ranges from 43% to 58%.

32. The controlled release tablet according to claim 29, wherein, Based on the total weight of the propulsion layer, the content of the hydrophilic polymer ranges from 49% to 58%.

33. The controlled release tablet according to claim 29, wherein, The osmotic pressure regulator is sodium chloride.

34. The controlled release tablet according to claim 29, wherein, Based on the total weight of the driving layer, the osmotic pressure regulator ranges from 21% to 84%.

35. The controlled release tablet according to claim 29, wherein, Based on the total weight of the driving layer, the osmotic pressure regulator ranges from 21% to 53% or from 38% to 84%.

36. The controlled release tablet according to claim 29, wherein, Based on the total weight of the driving layer, the osmotic pressure regulator ranges from 21% to 49% or from 38% to 53%.

37. The controlled release tablet according to claim 29, wherein, Based on the total weight of the driving layer, the osmotic pressure regulator ranges from 38% to 49%.

38. The controlled release tablet according to claim 29, wherein, The adhesive II is polyvinylpyrrolidone.

39. The controlled release tablet according to claim 29, wherein, Based on the total weight of the push layer, the content of adhesive II ranges from 0.3% to 8%.

40. The controlled release tablet according to claim 29, wherein, Based on the total weight of the push layer, the content of adhesive II ranges from 0.3% to 3%.

41. The controlled release tablet according to claim 29, wherein, Based on the total weight of the push layer, the content of adhesive II ranges from 0.3% to 1%.

42. The controlled release tablet according to claim 1, wherein, Lubricant I and Lubricant II are each independently selected from one or more of magnesium stearate, talc, stearic acid, glyceryl monostearate, sodium stearate fumarate, talc, and micronized silica.

43. The controlled release tablet according to claim 1, wherein, Lubricant I and lubricant II are each independently magnesium stearate.

44. The controlled release tablet according to claim 1, wherein, The drug-containing layer, the propellant layer, or both the drug-containing layer and the propellant layer further contain a colorant selected from one or more of lemon yellow lead lake, sunset yellow lead lake, iron oxide red, iron oxide yellow, iron oxide violet, and iron oxide black.

45. The controlled-release tablet according to claim 1, wherein the pore size of the drug release pore is 0.1 to 0.3 mm.

46. ​​A process for preparing briceceran controlled-release tablets as described in any one of claims 1-45, comprising the following steps: 1) Preparation of the drug-containing layer: The briracetam raw material is ground and then mixed evenly with sustained-release material I, sustained-release material II, binder I, lubricant I and optional colorant, and then compressed into tablets; 2) Preparation of the driving layer: The osmotic pressure regulator is mixed evenly with the hydrophilic polymer, binder II, lubricant II and optional colorant to obtain the driving layer powder; 3) Compression of double-layer tablet cores: Fill the drug-containing tablet core with the pushing layer powder and compress it into a double-layer tablet core; 4) Coating with a semi-permeable film: The pressed double-layer core is coated using a fluidized bed; 5) Drilling release holes: After the coating has aged, drill holes with a diameter of 0.1 to 0.3 mm on one side of the drug-containing layer to obtain bricetam controlled-release tablets.

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