WO2024021050A1

WO2024021050A1 - Levetiracetam sustained-release formulation and preparation method therefor

Info

Publication number: WO2024021050A1
Application number: PCT/CN2022/109070
Authority: WO
Inventors: 雷继峰; 谭然然; 施陈君; 岳唯唯
Original assignee: 上海安必生制药技术有限公司
Priority date: 2022-07-29
Filing date: 2022-07-29
Publication date: 2024-02-01

Abstract

Disclosed are a levetiracetam sustained-release formulation and a preparation method therefor. The sustained-release formulation comprises a core, a sustained-release layer, and a modification layer sequentially from inside to outside, and has better stability and taste.

Description

Levetiracetam sustained-release preparation and preparation method thereof

Technical field

The present invention relates to the field of drugs for treating epilepsy, and in particular to levetiracetam sustained-release preparations and preparation methods thereof.

Background technique

Levetiracetam (LEV) is a second-generation acetylcholine agonist developed by the Belgian company UCB. It is a pyrrolidone derivative and is used to treat localized and secondary generalized epilepsy. The drug was approved by the US FDA in 1999. The drug has selective protective limitations and unique pharmacological effects on primary generalized epilepsy. It is well tolerated and is a new broad-spectrum anti-epileptic drug with low drug interactions. It has broad clinical application prospects. Levetiracetam tablets were first launched in the United States in 1999 by UCB under the trade name

Subsequently, the United States approved levetiracetam solution (trade name:

) was put on the market, and levetiracetam injection (trade name

) was launched on the market, and levetiracetam extended-release tablets (trade name

XR) is on the market.

In 2006, levetiracetam tablets developed by UCB were approved for marketing in China. The specifications are 0.25g, 0.5g, and 1.0g, and the trade name is Kaipulan.

In 2011, the oral solution of UCB was approved for marketing in China, with a specification of 10%. In 2017, UCB's levetiracetam injection concentrated solution was approved for marketing in China, with a specification of 5ml:500mg. Levetiracetam extended-release tablets (trade name) developed by UCB

XR, specifications 500mg, 750mg) have not applied for listing in China. At present, only the generic levetiracetam sustained-release tablets have been approved for marketing in China, and no sustained-release preparations composed of multi-unit units have been approved for marketing. Levetiracetam extended-release tablets are only suitable for children over 12 years old and adults. They are administered once a day, but they should be swallowed whole. Do not chew, destroy or crush the drug. Extended-release tablets The tablet weighs about 750mg and is not suitable for patients and children with swallowing difficulties. The only oral dosage forms suitable for children aged 4-11 years in China are oral liquid and ordinary tablets. Both are taken twice a day, and levetiracetam will taste bitter after oral administration.

Contents of the invention

In view of the current clinical application situation, this application provides a levetiracetam sustained-release preparation composed of multiple units. The unit diameter is less than 5 mm, which is conducive to dosage adjustment and is more convenient for children and elderly patients with dysphagia. Through advanced coating technology, a modified layer is wrapped outside the unit, which tastes good and is easy for patients to accept. It also reduces blood drug fluctuations and toxic side effects. It has good reproducibility of absorption in the body, small individual differences, and absorption is not affected by food. The effect characteristics can reduce the frequency of medication, achieve once-daily administration, and improve patient compliance. Moreover, compared with existing technologies, the preparation process is simple, the stability is good, the production cost is low, and it is suitable for industrial large-scale production.

One or more embodiments of the present application provide a levetiracetam sustained-release preparation, which is composed of multiple unit bodies, each unit body sequentially including a core, a sustained-release layer and a modification layer from the inside to the outside;

The core contains one or more of fillers, adhesives, lubricants, glidants, and levetiracetam;

The sustained-release layer contains at least one of a plasticizer, a porogen, and a sustained-release material;

The modification layer contains one or more of adhesives, flavoring agents, pH adjusters, anti-sticking agents, and flavors.

One or more embodiments of the present application provide a method for preparing a levetiracetam sustained-release formulation, which includes

(1) Preparation of core containing levetiracetam: Mix levetiracetam with one or more of fillers, binders, lubricants, and glidants in water to prepare wet granules. The wet granules are directly dried to prepare a granular core; optionally, levetiracetam is mixed with a filler, an aqueous solution of a binder is added to prepare wet granules, and the wet granules are directly dried to prepare a granular core. Granular cores are obtained, or pellet-type cores are obtained by extrusion, spheronization and drying; optionally, the dried particles are mixed with one or more of lubricants and glidants and then tableted to obtain micron cores. chip core;

(2) Prepare the sustained-release layer coating liquid: dissolve or disperse one or both of the sustained-release material, plasticizer, and porogen in an appropriate solvent to prepare a sustained-release coating liquid;

(3) Prepare the sustained-release unit: Place the core containing levetiracetam obtained in step (1) into a fluidized bed or other coating equipment. After turning on the fan, the core is placed in the fluidized bed or coating equipment. The coating equipment is in a moving state, and the sustained-release coating liquid obtained in step (2) is sprayed into the atomized spray gun to obtain a sustained-release unit;

(4) Prepare the coating liquid for the modified layer: dissolve or disperse one or more of adhesives, flavoring agents, pH regulators, anti-sticking agents, and flavors in an appropriate solvent to form a coating for the modified layer. liquid;

(5) Prepare the modified unit: Place the sustained-release unit obtained in step (3) in a fluidized bed or other coating equipment. After turning on the fan, the core is in the fluidized bed or coating equipment. In the moving state, spray the modification layer coating liquid obtained in step (4) through an atomizing spray gun to obtain a modified unit body;

(6) Preparation of sustained-release preparations: The unit obtained in step (5) is optionally mixed directly or with a small amount of excipients with antistatic effect, and then put into a capsule or pharmaceutical compound bag to prepare a left-release preparation. Etiracetam extended-release formulation.

One or more embodiments of the present application provide the use of the levetiracetam sustained-release formulation of the present application in the preparation of anti-epileptic drugs.

In one or more embodiments, the weight percentage of levetiracetam is 15% to 95% of the weight of the core, such as 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.

In one or more embodiments, the weight percentage of levetiracetam is 25% to 85% of the weight of the core.

In one or more embodiments, the weight percentage of levetiracetam is 35 to 75% of the weight of the core.

In one or more embodiments, the weight percentage of the filler is 10 to 80% of the core weight, such as 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%.

In one or more embodiments, the weight percentage of the filler is 15 to 75% by weight of the core.

In one or more embodiments, the weight percentage of the filler is 20 to 65% by weight of the core.

In one or more embodiments, the weight percentage of the binder is 0.5 to 10% of the weight of the core, such as 0.5%, 1%, 2%, 3%, 4%, 5%, 6% , 7%, 8%, 9%, or 10%.

In one or more embodiments, the weight percent of the binder is 0.5 to 7.5% by weight of the core.

In one or more embodiments, the weight percentage of the binder is 0.5 to 5% by weight of the core.

In one or more embodiments, the weight percentage of the lubricant is 0.2 to 5% by weight of the core, such as 0.2%, 0.5%, 1%, 2%, 3%, 4%, or 5% .

In one or more embodiments, the weight percentage of the lubricant is 0.2 to 4% by weight of the core, such as 0.2%, 0.5%, 1%, 2%, 3%, or 4%.

In one or more embodiments, the weight percentage of the lubricant is 0.2 to 3% of the weight of the core.

In one or more embodiments, the weight percentage of the glidant is 0.05 to 4% of the weight of the core, such as 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3% , or 4%.

In one or more embodiments, the weight percentage of the glidant is 0.05 to 3% by weight of the core.

In one or more embodiments, the weight percentage of the glidant is 0.05 to 2% by weight of the core.

In one or more embodiments, the weight percentage of the sustained release layer is 2 to 60% of the weight of the core, such as 2%, 3%, 4%, 5%, 6%, 7%, 8% , 9%, 10%, 20%, 30%, 40%, 50%, or 60%.

In one or more embodiments, the weight percentage of the sustained release layer is 4-50% of the weight of the core.

In one or more embodiments, the weight percentage of the sustained release layer is 6 to 40% of the weight of the core.

In one or more embodiments, the weight percentage of the sustained-release material is 45% to 98% by weight of the sustained-release layer, such as 45%, 50%, 60%, 70%, 80%, 90%, or 98%.

In one or more embodiments, the weight percentage of the sustained-release material is 50% to 97% of the weight of the sustained-release layer.

In one or more embodiments, the weight percentage of the sustained-release material is 55% to 96% by weight of the sustained-release layer.

In one or more embodiments, the weight percentage of the plasticizer is 2-40% by weight of the sustained-release layer, such as 2%, 3%, 4%, 5%, 6%, 7%, 8% %, 9%, 10%, 20%, 30%, or 40%.

In one or more embodiments, the weight percentage of the plasticizer is 2-35% by weight of the sustained-release layer.

In one or more embodiments, the weight percentage of the plasticizer is 2 to 30% by weight of the sustained release layer.

In one or more embodiments, the weight percentage of the porogen is 2-40% by weight of the sustained-release layer, such as 2%, 3%, 4%, 5%, 6%, 7%, 8% %, 9%, 10%, 20%, 30%, or 40%.

In one or more embodiments, the weight percentage of the porogen is 2-35% by weight of the sustained-release layer.

In one or more embodiments, the weight percentage of the porogen is 2-30% by weight of the sustained-release layer.

In one or more embodiments, the weight percentage of the modification layer is 2 to 30% of the weight of the core, such as 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, or 30%.

In one or more embodiments, the weight percentage of the modification layer is 2-20% of the weight of the core.

In one or more embodiments, the weight percentage of the modification layer is 2-10% of the weight of the core.

In one or more embodiments, the weight percentage of the adhesive is 10% to 95% by weight of the modified layer, such as 10%, 20%, 30%, 40%, 50%, 60%, 70% , 80%, 90%, or 95%.

In one or more embodiments, the weight percentage of the adhesive is 20% to 85% by weight of the modified layer, such as 20%, 30%, 40%, 50%, 60%, 70%, 80% , or 85%.

In one or more embodiments, the weight percentage of the adhesive is 30 to 75% of the weight of the modification layer.

In one or more embodiments, the weight percentage of the flavoring agent is 0.01 to 10% by weight of the modification layer, such as 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3% , 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

In one or more embodiments, the weight percentage of the flavoring agent is 0.02 to 8% by weight of the modification layer, such as 0.02%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3% , 4%, 5%, 6%, 7%, or 8%.

In one or more embodiments, the weight percentage of the flavoring agent is 0.03 to 5% by weight of the modification layer, such as 0.03%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3% , 4%, or 5%.

In one or more embodiments, the weight percentage of the pH adjuster is 0.5 to 25% by weight of the modification layer, such as 0.5%, 1%, 2%, 3%, 4%, 5%, 6% , 7%, 8%, 9%, 10%, 15%, 20%, or 25%.

In one or more embodiments, the weight percentage of the pH adjuster is 1 to 20% of the weight of the modification layer.

In one or more embodiments, the weight percentage of the pH adjuster is 2-15% by weight of the modified layer.

In one or more embodiments, the weight percentage of the anti-adhesive agent is 5% to 70% by weight of the modified layer, such as 5%, 6%, 7%, 8%, 9%, 10%, 20% , 30%, 40%, 50%, 60%, or 70%.

In one or more embodiments, the weight percentage of the anti-adhesive agent is 10% to 60% by weight of the modified layer.

In one or more embodiments, the weight percentage of the anti-adhesive agent is 15% to 50% by weight of the modified layer.

In one or more embodiments, the weight percentage of the fragrance is 0.01 to 10% of the weight of the modified layer, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4% , 5%, 6%, 7%, 8%, 9%, or 10%.

In one or more embodiments, the weight percentage of the fragrance is 0.02 to 8% of the weight of the modification layer.

In one or more embodiments, the weight percentage of the fragrance is 0.03 to 5% of the weight of the modification layer.

In one or more embodiments, the weight percentage of the fragrance is 2 to 4% of the weight of the modification layer.

In one or more embodiments, the filler is one or more of sucrose, lactose, glucose, starch, microcrystalline cellulose, mannitol, calcium dihydrogen phosphate, and sodium chloride.

In one or more embodiments, the filler is one or more of starch, microcrystalline cellulose, lactose, and mannitol;

In one or more embodiments, the binder is one or more of pregelatinized starch, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, acrylic resin, and carboxymethyl cellulose sodium. kind.

In one or more embodiments, the lubricant is one or more of magnesium stearate, talc, calcium stearate, zinc stearate, and glyceryl behenate.

In one or more embodiments, the glidant is one or more of colloidal silica and sodium lauryl sulfate.

In one or more embodiments, the plasticizer is glycerin, propylene glycol, polyethylene glycol, triethyl citrate, glyceryl acetate, diethyl phthalate, tributyl citrate, One or more types of dibutyl subebate.

In one or more embodiments, the porogen is polyethylene glycols, povidone, sucrose, lactose, salts, hypromellose, hydroxypropylcellulose, levetiracetam, talc One or more of powder, magnesium stearate, and titanium dioxide.

In one or more embodiments, the sustained-release material is acrylic resin, ethyl cellulose, cellulose acetate, hypromellose phthalate, polyvinyl acetate phthalate, succinic acid acetate One or more types of hypromellose.

In one or more embodiments, the flavoring agent is sucrose, aspartame, sucralose, stevia, sodium saccharin, glucose, fructose, lactose, mannitol, lactic acid, citric acid, malic acid, One or more of tartaric acid, succinic acid, and acetic acid.

In one or more embodiments, the pH adjuster is one or more of lactic acid, citric acid, malic acid, tartaric acid, succinic acid, and acetic acid.

In one or more embodiments, the anti-sticking agent is one or more of talc, titanium dioxide, magnesium stearate, calcium stearate, and zinc stearate.

In one or more embodiments, the flavor is one or more of apple flavor, orange flavor, lemon flavor, vanilla flavor, strawberry flavor, or other flavors available in the pharmaceutical or food fields.

In one or more embodiments, the pH of the modification layer after being dissolved in water is 1.0 to 8.0, such as 1, 2, 3, 4, 5, 6, 7, or 8.

In one or more embodiments, the pH of the modified layer after being dissolved in water is 1.5 to 7.0.

In one or more embodiments, the pH of the modification layer after being dissolved in water is 2.0-6.0.

In one or more embodiments, the levetiracetam sustained-release formulation of the present application is prepared as a capsule, granule or dry suspension.

In one or more embodiments, the levetiracetam sustained-release preparation obtained in step (6) is composed of multiple units, each unit including a core, a sustained-release layer and a Modification layer.

In one or more embodiments, the pH of the modified layer obtained in step (6) after being dissolved in water is 1.0 to 8.0, such as 1, 2, 3, 4, 5, 6, 7, or 8 .

In one or more embodiments, the pH of the modified layer obtained in step (6) after being dissolved in water is 2.0 to 7.0.

In one or more embodiments, the pH of the modification layer obtained in step (6) after being dissolved in water is 3.0 to 6.0.

In one or more embodiments, the levetiracetam sustained-release preparation obtained in step (6) is prepared into a capsule, granule or dry suspension.

In one or more embodiments, the levetiracetam sustained-release formulation of the present application has the following components by weight percentage:

In one or more embodiments, the preparation method of the etiracetam sustained-release preparation of the present application includes:

(1) Core containing levetiracetam: Mix the prescribed amount of levetiracetam with the filler, binder and glidant in a granulator, then add purified water to prepare wet granules. Add the above wet granules into the extrusion and spheronization machine, select a screen with mesh openings of 0.4~1.2mm, set the extrusion speed to 30±10rpm, and the spheronization speed to 500±100rpm. After spheronization, add the wet pellet core to the fluidized bed for drying. After drying, the pellet core is sieved, and pellets between 0.3 and 1.5 mm are selected as the core;

(2) Prepare the sustained-release layer coating liquid: Dissolve the prescribed amount of sustained-release materials, porogens, and plasticizers in the ethanol solution to prepare a sustained-release coating liquid;

(3) Prepare the sustained-release unit body: Place the core containing levetiracetam obtained in step (1) into the fluidized bed, and set the following parameters: the inlet air temperature is 40±5°C, and the material temperature is 30± 3℃, spray speed 12±3g/min, atomization pressure 1.5±0.2bar, air volume 70±20m ³ /h. Spray the coating liquid through an atomizing spray gun to obtain a sustained-release unit;

(4) Prepare the coating liquid for the modified layer: Add the prescribed amount of adhesive, flavoring agent, and pH regulator acid in the modified layer into purified water, stir until dissolved, add anti-sticking agent and disperse evenly to prepare the modified layer coating. liquid;

(5) Prepare the modified unit: Place the sustained-release unit obtained in step (3) into the fluidized bed and set the following parameters: the inlet air temperature is 50±5°C and the material temperature is 35± 3℃, spray speed 14±3g/min, atomization pressure 1.5±0.2bar, air volume 80±20m3/h. , that is, the modified unit body is obtained;

(6) Preparation of sustained-release preparation: Mix the unit obtained in step (5) with a small amount of talc powder and put it into a capsule or pharmaceutical composite bag to prepare a levetiracetam sustained-release preparation.

One or more embodiments of the present application provide the above sustained-release formulation of levetiracetam for use as a medicament.

One or more embodiments of the present application provide the above levetiracetam sustained-release formulation, which is used to treat or prevent epilepsy.

One or more embodiments of the present application provide a method for treating or preventing epilepsy, which includes administering the above-mentioned levetiracetam sustained-release formulation of the present application to a subject in need thereof.

In one or more embodiments, levetiracetam sustained-release formulations have better stability, thus solving the problem of quality changes during product stability.

In one or more embodiments, by wrapping a modified layer outside the sustained-release unit, while improving the patient's taste and convenience of taking medication, only 0.5 to 1 hour of coating can be achieved, which is superior to the existing technology. The aging effect makes the prepared levetiracetam sustained-release preparation have better stability.

In one or more embodiments, the levetiracetam sustained-release preparation can reduce the frequency of medication, reduce blood drug fluctuations, reduce toxic and side effects, and its absorption is not affected by food, enabling once-daily administration and improving patient compliance.

In one or more embodiments, levetiracetam sustained-release preparations are beneficial to patients, especially those with dysphagia, in swallowing, have a good taste, and can be swallowed without water, which improves the convenience of patients taking medication and provides patients with better formulation selection.

In one or more embodiments, levetiracetam sustained-release preparations are composed of multiple modified units, which have one or more drug release rates. These units are composed of particles, pellets, micro One or more components of the film. The unit body is composed of a core containing levetiracetam and a coating layer, wherein the coating layer is composed of at least a sustained-release layer and a modification layer from the inside to the outside.

In one or more embodiments, the sustained-release formulation dosage form may be a capsule, granule, or dry suspension.

In one or more embodiments, the diameter of the particles or pellets ranges from 200 to 2000 μm, preferably from 300 to 1500 μm.

In one or more embodiments, the diameter of the microchips ranges from 1 to 5 mm, preferably from 2 to 4 mm.

In one or more embodiments, the average roundness of the pellets is at least 0.5, preferably at least 0.7, and more preferably at least 0.8.

In one or more embodiments, the weight percentage of levetiracetam in the sustained-release preparation is 15 to 95%, preferably 25 to 85%, and more preferably 35 to 75%.

In one or more embodiments, the levetiracetam-containing core is composed of levetiracetam and one or more of fillers, adhesives, lubricants, and glidants.

In one or more embodiments, the levetiracetam-containing core is uniformly mixed with one or more of fillers, adhesives, lubricants, and glidants. composition.

In one or more embodiments, the filler is one or more of starch, microcrystalline cellulose, lactose, and mannitol.

In one or more embodiments, the weight percentage of levetiracetam in the core containing levetiracetam is 15 to 95%, preferably 25 to 85%, and more preferably 35 to 75%.

In one or more embodiments, the levetiracetam-containing core has a filler weight percentage of 10 to 80%, preferably 25 to 75%, and more preferably 35 to 65%.

In one or more embodiments, the levetiracetam-containing core has a binder weight percentage of 0.5 to 10%, preferably 0.5 to 7.5%, and more preferably 0.5 to 5%.

In one or more embodiments, the levetiracetam-containing core has a lubricant weight percentage of 0.2 to 5%, preferably 0.2 to 4%, and more preferably 0.2 to 3%.

In one or more embodiments, the levetiracetam-containing core has a weight percentage of glidant of 0.05 to 4%, preferably 0.05 to 3%, and more preferably 0.05 to 2%.

In one or more embodiments, the sustained-release layer is composed of at least one of a plasticizer, a porogen, and a sustained-release material.

In one or more embodiments, the weight of the sustained-release layer is 2-60% of the weight of the core, preferably 4-50%, and more preferably 6-40%.

In one or more embodiments, the weight of the sustained-release material is 45% to 98% of the weight of the sustained-release layer, preferably 50% to 97%, and more preferably 55% to 96%.

In one or more embodiments, the weight of the plasticizer is 2-40% of the weight of the sustained-release layer, preferably 2-35%, and more preferably 2-30%.

In one or more embodiments, the weight of the porogen is 2-40% of the weight of the sustained-release layer, preferably 2-35%, and more preferably 2-30%.

In one or more embodiments, the modification layer is composed of one or more of adhesives, flavoring agents, pH adjusters, anti-sticking agents, and flavors.

In one or more embodiments, the binder is one or more of pregelatinized starch, hydroxypropyl methylcellulose, povidone, acrylic resin, and carboxymethylcellulose sodium.

In one or more embodiments, the flavor may be one or more of apple flavor, orange flavor, lemon flavor, vanilla flavor, strawberry flavor, or other flavors available in the field of medicine and food.

In one or more embodiments, the weight of the modification layer is 2-30% of the core weight, preferably 2-20%, and more preferably 2-10%.

In one or more embodiments, the weight of the adhesive is 10% to 95% of the weight of the modified layer, preferably 20% to 85%, and more preferably 30% to 75%.

In one or more embodiments, the weight of the flavoring agent is 0.01 to 10% of the weight of the modified layer, preferably 0.02 to 8%, and more preferably 0.03 to 5%.

In one or more embodiments, the weight of the pH adjuster is 0.5% to 25% of the weight of the modification layer, preferably 1% to 20%, and more preferably 2% to 15%.

In one or more embodiments, the weight of the anti-adhesive agent is 5% to 70% of the weight of the modified layer, preferably 10% to 60%, and more preferably 15% to 50%.

In one or more embodiments, the pH of the modification layer after being dissolved in water is less than 8.0, preferably less than 7.0, and more preferably less than 6.0.

In one or more embodiments, the AUC and Cmax of the levetiracetam sustained-release preparation after a single daily administration are 80 to 125% confident when the same dosage of immediate-release tablets are administered twice daily. within the interval.

One or more embodiments of the present application provide a method for preparing the above-mentioned levetiracetam sustained-release preparation. First, a core containing levetiracetam is prepared, and then a sustained-release layer and a modified layer are sequentially wrapped to prepare a sustained-release unit. body, and finally fill the sustained-release unit body into the capsule or pharmaceutical compound bag, which specifically includes the following steps:

(1) Core containing levetiracetam: Mix levetiracetam with one or more of fillers, binders, lubricants and glidants in a granulator, add water or Aqueous solution of binder to produce wet granules. The wet particles can be directly dried to obtain granular cores, or they can be extruded, spheronized, and dried to obtain pellet-type cores. The dried particles can also be mixed with one or more of lubricants and glidants and then tableted to obtain micro-tablet cores;

(3) Prepare the sustained-release unit: Place the core containing levetiracetam obtained in step (1) into a fluidized bed or other coating equipment. After turning on the fan, the core is placed in the fluidized bed or coating equipment. The coating equipment is in a moving state, and the coating liquid is sprayed through an atomizable spray gun to obtain a sustained-release unit;

(4) Prepare the coating liquid for the modified layer: dissolve or disperse one or more of the adhesive, flavoring agent, pH regulator, anti-sticking agent, and essence in the modified layer in an appropriate solvent to make a modified coating. layer coating liquid;

(5) Prepare the modified unit: Place the sustained-release unit obtained in step (3) into a fluidized bed or other coating equipment. After turning on the fan, the core is in motion in the fluidized bed or coating equipment. In the state, spray the coating liquid of the modification layer through an atomizable spray gun to obtain the modified unit body;

(6) Preparation of sustained-release preparations: The unit obtained in step (5) is directly or mixed with a small amount of excipients with antistatic effects, and then put into capsules or pharmaceutical composite bags to prepare levetiracetam sustained-release preparations. release preparations.

In one or more embodiments, the levetiracetam sustained-release preparation of the present application is beneficial to patients, especially patients with dysphagia, and has a good mouthfeel. It can be swallowed without water, improves the convenience of patients taking medication, and provides patients with for better formulation selection.

In one or more embodiments, the levetiracetam sustained-release formulation of the present application has better stability and can solve the problem of critical quality changes during product stability.

In one or more embodiments, the levetiracetam sustained-release preparation of the present application has the characteristics of reducing the frequency of medication, reducing blood drug fluctuations, reducing toxic and side effects, and being absorbed without being affected by food, and can be administered once a day. Improve patient compliance.

In one or more embodiments, the levetiracetam sustained-release preparation is composed of multiple modified units with a maximum diameter of 5 mm, which facilitates swallowing by patients, especially patients with dysphagia.

In one or more embodiments, a modified layer is added to the outside of the levetiracetam sustained-release core, which has a good taste, stimulates saliva secretion, and can be swallowed directly, which improves the convenience of patients taking medication and provides patients with better Formulation selection.

In one or more embodiments, it was unexpectedly found that adding a modified layer outside the levetiracetam sustained-release core can improve the stability of the levetiracetam sustained-release preparation and solve the problem of dissolution changes during the product stability period. Specifically: the dissolution rate of levetiracetam sustained-release unit after sustained-release coating will change during the stability period without aging. The existing aging technology is mainly online aging and offline aging. Online aging is After coating, it is aged for a certain period of time in a fluidized bed or coating machine at a higher inlet air temperature. Offline aging is high-temperature aging in an oven. The general aging time is 12 to 48 hours or longer. By enclosing a modified layer on the body of the sustained-release unit, the present invention not only improves the patient's taste and convenience in taking medicine, but also requires only 0.5 to 1 hour of coating to achieve an aging effect that is better than that of the prior art. The prepared levetiracetam sustained-release preparation has better stability.

In one or more embodiments, the release degree of levetiracetam sustained-release preparation is 1 hour: 15-35%; 2 hours: 25-55%; 4 hours: 45-85%; 8 hours is not less than 80%.

In one or more embodiments, compared with the prior art, it has a better taste, facilitates dosage adjustment, and is more convenient for children and elderly patients with dysphagia to take.

In one or more embodiments, the levetiracetam sustained-release preparation of the present application has the characteristics of reducing blood drug fluctuations, reducing side effects, and being absorbed without being affected by food, enabling once-daily administration and improving patient compliance. sex.

In one or more embodiments, compared with the existing technology, the levetiracetam sustained-release preparation of the present application has a simple preparation process, good stability, low production cost, and is suitable for industrial large-scale production.

Description of drawings

Figure 1 is the release curve of the sustained-release capsule or granule sample prepared in Examples 1-6.

Figure 2 is the release curve of the sustained-release capsule or granule sample prepared in Comparative Examples 1-6.

Figure 3 is a drug-time curve of levetiracetam sustained-release granules and commercially available levetiracetam sustained-release tablets in Example 1.

Detailed ways

A clear and complete description will be given below in conjunction with specific embodiments. Those skilled in the art will understand that the embodiments described below are some of the embodiments, not all of them. They are only for illustration and should not be regarded as Limitations on the scope of protection.

In the following specific examples, the viscosity of hypromellose is 5±3cP, and the viscosity of ethylcellulose is 10±5cP.

Example 1 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(1) Core containing levetiracetam: Mix the prescribed amount of levetiracetam with microcrystalline cellulose and hypromellose in a granulator, and add 250g of purified water to prepare wet granules. . Add the above wet granules into the extrusion and spheronization machine, select a screen with mesh openings of 0.4~1.2mm, set the extrusion speed to 30rpm and the spheronization speed to 500rpm. After spheronization, add the wet pellet core to the fluidized bed for drying. After drying, the pellet core Sieve and select pellets between 0.3~1.5mm as the core.

(2) Prepare the sustained-release layer coating liquid: Dissolve the prescribed amounts of ethylcellulose, hydroxypropylcellulose, and triethyl citrate in the ethanol solution to prepare a sustained-release coating liquid.

(3) Prepare sustained-release unit body: Place the core containing levetiracetam obtained in step (1) into the fluidized bed, set the following parameters, the inlet air temperature is 40°C, the material temperature is 30°C, spray The speed is 12g/min, the atomization pressure is 1.5bar, and the air volume is 70m ³ /h. Spray the coating liquid through an atomizing spray gun to obtain a sustained-release unit.

(4) Prepare the coating liquid for the modified layer: Add the prescribed amounts of hypromellose, povidone, aspartame, and anhydrous citric acid in the modified layer to purified water, stir until dissolved, and add talc powder and titanium dioxide Disperse evenly to prepare a coating liquid for the modified layer.

(5) Prepare the modified unit: Place the sustained-release unit obtained in step (3) into the fluidized bed, set the following parameters, the inlet air temperature is 50°C, the material temperature is 35°C, spray The speed is 14g/min, the atomization pressure is 1.5bar, and the air volume is 80m3/h. , that is, the modified unit body is obtained.

Example 2 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(1) Core containing levetiracetam: Mix the prescribed amount of levetiracetam, microcrystalline cellulose, and micropowder silica gel in a granulator, add hydroxypropylcellulose to 400g of purified water, and stir until Dissolve to obtain a binder solution, which is added to a high-speed stirring granulator to prepare wet granules. Dry the above-mentioned wet granules in a fluidized bed, add magnesium stearate and mix evenly. Use a rotary tablet press to compress the tablets. The weight of a single tablet is controlled at 28±3mg and the core diameter is 3mm to obtain the core.

(2) Prepare the sustained-release layer coating solution: Dissolve the prescription amount of ethylcellulose, polyethylene glycol, and triethyl citrate in 400g of ethanol solution, dissolve polyethylene glycol in purified water, and mix the above two Mix the two solutions and stir evenly to prepare a sustained-release coating solution.

(3) Prepare the sustained-release unit: Place the core containing levetiracetam obtained in step (1) into the coating machine, set the following parameters, the air inlet temperature is 40°C, the material temperature is 30°C, spray The speed is 12g/min, the atomization pressure is 1.5bar, and the air volume is 90m ³ /h. Spray the coating liquid through an atomizing spray gun to obtain a sustained-release unit.

(4) Prepare the coating liquid for the modified layer: Add the prescribed amounts of hypromellose, essence, aspartame, and anhydrous citric acid in the modified layer to purified water, stir until dissolved, add talc powder, and titanium dioxide to disperse evenly , to prepare the coating liquid for the modified layer.

(5) Prepare the modified unit: Place the sustained-release unit obtained in step (3) into the coating machine and set the following parameters: air inlet temperature 50°C, material temperature 35°C, spray speed 14g/min, The atomization pressure is 1.5bar and the air volume is 90m3/h. , that is, the modified unit body is obtained.

Example 3 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(1) Core containing levetiracetam: Mix the prescribed amounts of levetiracetam, hypromellose and microcrystalline cellulose in a granulator, and add 220g of purified water to prepare wet granules. . The above-mentioned wet particles are dried in a fluidized bed. After drying, the particles are passed through 60-mesh and 18-mesh sieves, and particles between 18 and 60 mesh are selected as cores.

(2) Prepare the sustained-release layer coating liquid: Dissolve the prescribed amount of Eudragit NE30D, talc powder, and triethyl citrate in the aqueous solution to prepare a sustained-release coating liquid.

(4) Prepare the coating liquid for the modified layer: Add the prescribed amounts of hypromellose, essence, aspartame, and anhydrous citric acid in the modified layer to purified water, stir until dissolved, add talc powder and make it uniform. Get the coating liquid for the modified layer.

(5) Prepare the modified unit: Place the sustained-release unit obtained in step (3) into the fluidized bed, set the following parameters, the inlet air temperature is 50°C, the material temperature is 35°C, spray The speed is 14g/min, the atomization pressure is 1.5bar, and the air volume is 80m ³ /h. , that is, the modified unit body is obtained.

Example 4 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(2) Prepare the sustained-release layer coating liquid: Dissolve the prescribed amounts of ethylcellulose, hypromellose, and triethyl citrate in the ethanol solution to prepare a sustained-release coating liquid.

(4) Prepare the coating liquid for the modified layer: Add the prescribed amounts of hypromellose, povidone, aspartame, and anhydrous citric acid in the modified layer to purified water, stir until dissolved, and add titanium dioxide to disperse evenly. Prepare the modification layer coating liquid.

Example 5 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(1) Core containing levetiracetam: Mix the prescribed amount of levetiracetam with microcrystalline cellulose and hydroxypropylcellulose in a granulator, and add 250g of purified water to prepare wet granules. Add the above wet granules into the extrusion and spheronization machine, select a screen with mesh openings of 0.4~1.2mm, set the extrusion speed to 30rpm and the spheronization speed to 500rpm. After spheronization, add the wet pellet core to the fluidized bed for drying. After drying, the pellet core Sieve and select pellets between 0.3~1.5mm as the core.

(4) Prepare the coating liquid for the modified layer: Add the prescribed amounts of hypromellose, povidone, and aspartame in the modified layer to purified water, stir until dissolved, add titanium dioxide, and talc to disperse evenly to prepare the modified layer. layer coating liquid.

Example 6 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The preparation method is as follows:

Comparative Example 1 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(1) Core containing levetiracetam: Mix the prescribed amount of levetiracetam with microcrystalline cellulose, hypromellose, and colloidal silica in a granulator, and add purified water 250g to prepare wet granules. Add the above wet granules into the extrusion and spheronization machine, select a screen with mesh openings of 0.4~1.2mm, set the extrusion speed to 30rpm and the spheronization speed to 500rpm. After spheronization, add the wet pellet core to the fluidized bed for drying. After drying, the pellet core Sieve and select pellets between 0.3~1.5mm as the core.

(4) Preparation of sustained-release preparation: Mix the unit obtained in step (3) with a small amount of talc powder and put it into a capsule or pharmaceutical composite bag to prepare a levetiracetam sustained-release preparation.

Comparative Example 2 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(3) Prepare sustained-release unit body: Place the core containing levetiracetam obtained in step (1) into the fluidized bed, set the following parameters, the inlet air temperature is 40°C, the material temperature is 30°C, spray The speed is 12g/min, the atomization pressure is 1.5bar, and the air volume is 70m ³ /h. Spray the coating liquid through an atomizing spray gun to obtain a sustained-release unit. Put a certain amount of sustained-release units in the oven, set the temperature to 50°C, and age them for 12h and 24h respectively before taking them out.

(4) Preparation of sustained-release preparation: Mix the aged unit obtained in step (3) with a small amount of talc powder and put it into a capsule or pharmaceutical composite bag to prepare a levetiracetam sustained-release preparation.

Comparative Example 3 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(2) Prepare the sustained-release layer coating liquid: Dissolve the prescribed amounts of ethylcellulose, hydroxypropylcellulose, and triethyl citrate in 80% ethanol solution to prepare a sustained-release coating liquid.

(3) Preparation of sustained-release unit body: Place the core containing levetiracetam obtained in step (1) into the fluidized bed, set the following parameters, the inlet air temperature is 40°C, the material temperature is 30°C, spray The speed is 12g/min, the atomization pressure is 1.5bar, and the air volume is 70m ³ /h. Spray the coating liquid through an atomizing spray gun to obtain a sustained-release unit. After drying, set the inlet air temperature to 60°C in the fluidized bed and take it out after online aging for 4 hours.

Comparative Example 4 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(1) Core containing levetiracetam: Mix the prescribed amount of levetiracetam with microcrystalline cellulose, hydroxypropyl cellulose, and colloidal silica in a granulator, and add 250g of purified water. , to obtain wet granules. Add the above wet granules into the extrusion and spheronization machine, select a screen with mesh openings of 0.4~1.2mm, set the extrusion speed to 30rpm and the spheronization speed to 500rpm. After spheronization, add the wet pellet core to the fluidized bed for drying. After drying, the pellet core Sieve and select pellets between 0.3~1.5mm as the core.

(2) Prepare the isolation layer coating liquid: Dissolve the prescribed amount of hypromellose in purified water, add talc powder and disperse evenly to prepare the isolation layer coating liquid.

(3) Prepare the isolation unit: Place the core containing levetiracetam obtained in step (1) into the fluidized bed, and set the following parameters: air inlet temperature 40°C, material temperature 30°C, spray speed 10g/min, atomization pressure 1.5bar, air volume 70m ³ /h. Spray the coating liquid through an atomizing spray gun to obtain the isolation layer unit.

(4) Prepare the sustained-release layer coating liquid: Dissolve the prescribed amounts of ethylcellulose, hypromellose, and triethyl citrate in the ethanol solution to prepare a sustained-release coating liquid.

(5) Prepare sustained-release unit body: Place the core containing levetiracetam obtained in step (1) into the fluidized bed, set the following parameters, the inlet air temperature is 40°C, the material temperature is 30°C, spray The speed is 12g/min, the atomization pressure is 1.5bar, and the air volume is 70m ³ /h. Spray the coating liquid through an atomizing spray gun to obtain a sustained-release unit.

Comparative Example 5 Preparation of levetiracetam sustained-release granules/capsules (1000 bags/capsules)

The ingredients are as follows:

The preparation method is as follows:

(2) Prepare the sustained-release layer coating liquid: Disperse the prescribed amount of NE30D in purified water, add talcum powder and disperse evenly to prepare a sustained-release coating liquid.

Tests and results of effect examples

Release test:

The sustained-release capsules or granules prepared in Examples 1-6 and Comparative Examples 1-5 were used as test samples. The in vitro release experimental method was as follows: Method 2 of the Chinese Pharmacopoeia 2020 version of the dissolution and release determination method (paddle method) was used. ), use 900 mL of phosphate buffer with pH 6.8 as the release medium, and the rotation speed is 75 rpm. Samples are taken at 1, 2, 4, 8, 12, and 20 hours to determine the concentration of levetiracetam. Taking time as the abscissa and cumulative release as the ordinate, a release curve is drawn (see Figures 1 and 2). The results show that the sustained-release capsules prepared by the present invention have obvious sustained-release effects and significantly extend the release time.

Taste evaluation:

The fuzzy mathematical comprehensive evaluation method (FSEM) was used to determine the 4 taste indexes of the sample X = (overall taste, peculiar smell, sweetness, aroma) and 5 taste evaluation grades Y = (very good, good, medium, poor, very poor ), determine the weight of each quality factor, and use 0 and 1 to calculate the weight according to the importance of each factor. The important one is scored as 1 point, the minor one is scored as 0 points, and there is no score for the comparison of itself. The final result is the overall taste (0.4 ), odor (0.3), sweetness (0.2) aroma (0.1), that is, A = (0.4, 0.3, 0.2, 0.1). 20 volunteers analyzed 5 indicators under 4 indicators of samples such as Example 1, Example 2, Example 5, Comparative Example 1, Levetiracetam Sustained Release Tablets, and Levetiracetam Oral Liquid one by one. The evaluation grade is used for taste voting, and the votes obtained at each grade of the quality factors of each sample are converted into approval rates. Based on the fuzzy transformation principle, the results of each sample are analyzed by matrix synthesis to draw a comprehensive evaluation conclusion.

Table 1 Taste evaluation results

Table 2 Comprehensive evaluation results of taste evaluation

综合评定Comprehensive assessment	很好very good	好good	中middle	差Difference	很差Very bad
实施例1Example 1	0.2450.245	0.590.59	0.1650.165	00	00
实施例2Example 2	0.3650.365	0.550.55	0.0750.075	0.010.01	00
实施例5Example 5	0.050.05	0.660.66	0.270.27	0.020.02	00
对比实施例1Comparative Example 1	00	0.310.31	0.330.33	0.340.34	0.020.02
左乙拉西坦缓释片Levetiracetam extended-release tablets	00	0.120.12	0.430.43	0.340.34	0.110.11
左乙拉西坦口服液Levetiracetam Oral Liquid	00	0.030.03	0.4250.425	0.470.47	0.0750.075

Comparing the peaks appearing in each sample, the peak of Example 1 appeared in "good", accounting for 59%, and "very good" accounted for 24.5%; the peak of Example 2 also appeared in "good", accounting for 55%, and "very" "Good" accounted for 36.5%; the peak value of Example 5 also appeared in "Good", accounting for 66%, and "Very Good" accounted for 5%; the peak value of Comparative Example 1 appeared in "Poor", accounting for 34%, and "Medium" accounted for 34%. 33%, "good" accounted for 31%; the peak value of levetiracetam extended-release tablets appeared in "medium", accounting for 43%, and "poor" accounted for 34%; the peak value of levetiracetam oral liquid appeared in "poor" ", accounting for 47%, and "bad" accounting for 42.5%. The ranking order from best to worst is: Example 2>Example 1>Example 5>Comparative Example 1>Levetiracetam Sustained Release Tablets>Levetiracetam Oral Liquid.

The above results prove that the levetiracetam sustained-release preparation provided by the present invention tastes better. For products such as levetiracetam that require long-term medication, it can significantly improve patients' willingness to take medication and achieve higher compliance.

Stability test:

The sustained-release capsules or granules prepared in Examples 1-6 and Comparative Examples 1-5 were used as test samples, and were placed under the conditions of influencing factors and accelerated testing (40°C ± 2°C, relative humidity 75% ± 5%), and investigated. For changes in content, related substances, and release rates, please refer to the table below.

Table 3 Examples 1-6 stability test release test results

Table 4 Comparative Examples 1-5 Stability Test Release Test Results

It can be seen from the data in Table 3 and Table 4 that there is no significant change in the release degree during the stability period of Examples 1, 2, and 3, and the changes in the release degree during the stability test of Examples 4, 5, and 6 are all within 8%. Comparison The release changes in the examples are all greater than 10%. Generally, when the release changes are less than 10%, it can be considered that the two dissolution curves are similar and still have similar release behaviors in the body. The above results prove that the samples containing the modification layer of Examples 1-6 are more stable than the samples of Comparative Examples 1-5.

Table 5 Examples 1-6 stability test content and related test results

Table 6 Comparative Examples 1-6 Stability Test Contents and Related Test Results

The above results prove that the relevant substance levels of Examples 1-6 are lower than those of Comparative Examples 1-5. The levetiracetam sustained-release preparation provided by the present invention not only solves the problem of levetiracetam tablets and oral liquids when taking the medicine. In order to solve the problems of uncomfortable taste and large diameter tablets that are not suitable for swallowing, it was unexpectedly found that it improved the stability of levetiracetam, effectively reduced the increase of related substances, and ensured the stability and safety of the preparation.

Pharmacokinetic test:

Using the sustained-release granules prepared in Example 1 and the commercially available levetiracetam sustained-release tablets, 10 healthy volunteers were selected and randomly divided into 2 groups, with 5 people in each group, to take the sustained-release granules and the sustained-release tablets respectively. , carry out a randomized controlled trial, draw venous blood at specified time points for blood drug concentration monitoring, use time as the abscissa and concentration as the ordinate to draw a blood drug concentration-time curve.

Pharmacokinetic results show that the levetiracetam sustained-release preparation provided by the present invention has a similar exposure (AUC) to the marketed original drug levetiracetam sustained-release tablets, which meets the bioequivalence requirements, meaning The clinical efficacy is similar or the same as that of the control preparation. It can be used clinically as a substitute for sustained-release tablets. It only needs to be administered once a day. It tastes good and is more easily accepted by children. It solves the problem that there is no clinical levetitralin suitable for children. Clinical status of racetam sustained-release preparations to improve patient compliance. Compared with sustained-release tablets, the slightly lower _Cmax means a lower incidence of side effects and higher safety. The peak time for the subjects in Example 1 is 2 to 4.5 hours, and the peak time for the sustained-release tablet is 2 to 6.5 hours. Compared with sustained-release tablets, Example 1 has the characteristics of small individual differences, stable release in the body, and high reproducibility of absorption. The efficacy is more stable and the safety is higher.

Claims

Levetiracetam sustained-release preparation, which is composed of multiple unit bodies, each unit body including a core, a sustained-release layer and a modification layer from the inside to the outside;

The core contains one or more of fillers, adhesives, lubricants, glidants, and levetiracetam; preferably, the weight percentage of levetiracetam is 15% to 95% by weight, preferably 25% to 85%, more preferably 35% to 75%; preferably, the weight percentage of the filler is 10% to 80% by weight of the core, preferably 15% to 75% , more preferably 20 to 65%; preferably, the weight percentage of the binder is 0.5 to 10% of the core weight, preferably 0.5 to 7.5%, more preferably 0.5 to 5%; preferably, The weight percentage of the lubricant is 0.2-5% of the weight of the core, preferably 0.2-4%, more preferably 0.2-3%; preferably, the weight percentage of the glidant is 0.2-5% of the core weight. 0.05 to 4% by weight, preferably 0.05 to 3%, more preferably 0.05 to 2%;

The sustained-release layer contains at least one of a plasticizer, a porogen, and a sustained-release material; preferably, the weight percentage of the sustained-release layer is 2 to 60% of the weight of the core, preferably 4 to 60%. 50%, more preferably 6-40%; preferably, the weight percentage of the sustained-release material is 45-98%, preferably 50-97%, more preferably 55-96% of the weight of the sustained-release layer; Preferably, the weight percentage of the plasticizer is 2-40% by weight of the sustained-release layer, preferably 2-35%, more preferably 2-30%; preferably, the weight percentage of the porogen is It is 2-40% by weight of the sustained-release layer, preferably 2-35%, more preferably 2-30%;

The modified layer contains one or more of adhesives, flavoring agents, pH adjusters, anti-sticking agents, and flavors; preferably, the weight percentage of the modified layer is 2 to 30% of the weight of the core. %, preferably 2 to 20%, more preferably 2 to 10%; preferably, the weight percentage of the adhesive is 10 to 95% of the weight of the modified layer, preferably 20 to 85%, more preferably 30 to 75%; preferably, the weight percentage of the flavoring agent is 0.01 to 10% of the weight of the modified layer, preferably 0.02 to 8%, more preferably 0.03 to 5%; preferably, the pH adjustment The weight percentage of the anti-adhesive agent is 0.5 to 25% of the weight of the modified layer, preferably 1 to 20%, more preferably 2 to 15%; preferably, the weight percentage of the anti-adhesive agent is 5% of the weight of the modified layer. ~70%, preferably 10-60%, more preferably 15-50%; preferably, the weight percentage of the fragrance is 0.01-10% of the weight of the modified layer, preferably 0.02-8%, more preferably 0.03 to 5%, more preferably 2 to 4%.
The levetiracetam sustained-release preparation according to claim 1, wherein the filler is one of sucrose, lactose, glucose, starch, microcrystalline cellulose, mannitol, calcium dihydrogen phosphate, and sodium chloride or more; preferably one or more of starch, microcrystalline cellulose, lactose, and mannitol;

Preferably, the binder is one or more of pregelatinized starch, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, acrylic resin, and carboxymethylcellulose sodium;

Preferably, the lubricant is one or more of magnesium stearate, talc, calcium stearate, zinc stearate, and glyceryl behenate;

Preferably, the glidant is one or more of colloidal silica and sodium lauryl sulfate;

Preferably, the plasticizer is glycerin, propylene glycol, polyethylene glycol, triethyl citrate, glyceryl acetate, diethyl phthalate, tributyl citrate, and dibutyl subebate. one or more of;

Preferably, the porogen is polyethylene glycol, povidone, sucrose, lactose, salts, hypromellose, hydroxypropylcellulose, levetiracetam, talc, magnesium stearate , one or more of titanium dioxide;

Preferably, the sustained-release material is acrylic resin, ethyl cellulose, cellulose acetate, hypromellose phthalate, polyvinyl acetate phthalate, or hypromellose acetate succinate. one or more;

Preferably, the binder is one or more of pregelatinized starch, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, acrylic resin, and carboxymethylcellulose sodium;

Preferably, the flavoring agent is sucrose, aspartame, sucralose, stevia, sodium saccharin, glucose, fructose, lactose, mannitol, lactic acid, citric acid, malic acid, tartaric acid, succinic acid, acetic acid one or more of;

Preferably, the pH adjuster is one or more of lactic acid, citric acid, malic acid, tartaric acid, succinic acid, and acetic acid;

Preferably, the anti-sticking agent is one or more of talc, titanium dioxide, magnesium stearate, calcium stearate, and zinc stearate;

Preferably, the flavor is one or more of apple flavor, orange flavor, lemon flavor, vanilla flavor, strawberry flavor, or other flavors available in the pharmaceutical or food fields.
The levetiracetam sustained-release preparation according to claim 1, wherein the pH of the modified layer after being dissolved in water is 1.0 to 8.0, preferably 1.5 to 7.0, and more preferably 2.0 to 6.0.
The levetiracetam sustained-release preparation according to claim 1, which is a capsule, granule or dry suspension.
The levetiracetam sustained-release preparation according to any one of claims 1 to 4, which has the following components by weight percentage:

Preferably
The levetiracetam sustained-release preparation according to any one of claims 1 to 4, which has the following components by weight percentage:

Preferably
Method for preparing levetiracetam sustained-release preparation, comprising

(1) Preparation of core containing levetiracetam: Mix levetiracetam with one or more of fillers, binders, lubricants, and glidants in water to prepare wet granules. The wet granules are directly dried to prepare a granular core; optionally, levetiracetam is mixed with a filler, an aqueous solution of a binder is added to prepare wet granules, and the wet granules are directly dried to prepare a granular core. Granular cores are obtained, or pellet-type cores are obtained by extrusion, spheronization and drying; optionally, the dried particles are mixed with one or more of lubricants and glidants and then tableted to obtain micron cores. chip core;

(2) Prepare the sustained-release layer coating liquid: dissolve or disperse one or both of the sustained-release material, plasticizer, and porogen in an appropriate solvent to prepare a sustained-release coating liquid;

(3) Prepare the sustained-release unit: Place the core containing levetiracetam obtained in step (1) into a fluidized bed or other coating equipment. After turning on the fan, the core is placed in the fluidized bed or coating equipment. The coating equipment is in a moving state, and the sustained-release coating liquid obtained in step (2) is sprayed into the atomized spray gun to obtain a sustained-release unit;

(4) Prepare the coating liquid for the modified layer: dissolve or disperse one or more of adhesives, flavoring agents, pH regulators, anti-sticking agents, and flavors in an appropriate solvent to form a coating for the modified layer. liquid;

(5) Prepare the modified unit: Place the sustained-release unit obtained in step (3) in a fluidized bed or other coating equipment. After turning on the fan, the core is in the fluidized bed or coating equipment. In the moving state, spray the modification layer coating liquid obtained in step (4) through an atomizing spray gun to obtain a modified unit body;

(6) Preparation of sustained-release preparations: The unit obtained in step (5) is optionally mixed directly or with a small amount of excipients with antistatic effect, and then put into a capsule or pharmaceutical compound bag to prepare a left-release preparation. Etiracetam extended-release formulation.
The method according to claim 7, wherein the levetiracetam sustained-release preparation obtained in step (6) is composed of multiple units, each unit including a core, a sustained-release layer and a modification in sequence from the inside to the outside. layer;

Preferably, the weight percentage of levetiracetam is 15-95% of the core weight, preferably 25-85%, more preferably 35-75%; preferably, the weight percentage of the filler It is 10-80% of the weight of the core, preferably 15-75%, more preferably 20-65%; preferably, the weight percentage of the binder is 0.5-10% of the weight of the core, Preferably it is 0.5-7.5%, more preferably 0.5-5%; Preferably, the weight percentage of the lubricant is 0.2-5% of the weight of the core, preferably 0.2-4%, more preferably 0.2-3 %; Preferably, the weight percentage of the glidant is 0.05 to 4% of the weight of the core, preferably 0.05 to 3%, more preferably 0.05 to 2%;

Preferably, the weight percentage of the sustained release layer is 2 to 60% of the core weight, preferably 4 to 50%, more preferably 6 to 40%; preferably, the weight percentage of the sustained release material is 45-98% of the weight of the sustained-release layer, preferably 50-97%, more preferably 55-96%; preferably, the weight percentage of the plasticizer is 2-40% of the weight of the sustained-release layer , preferably 2 to 35%, more preferably 2 to 30%; preferably, the weight percentage of the porogen is 2 to 40% by weight of the sustained release layer, preferably 2 to 35%, more preferably 2～30%;

Preferably, the weight percentage of the modification layer is 2 to 30% of the weight of the core, preferably 2 to 20%, more preferably 2 to 10%; preferably, the weight percentage of the adhesive is 2 to 30% of the core weight. 10 to 95% of the weight of the modified layer, preferably 20 to 85%, more preferably 30 to 75%; preferably, the weight percentage of the flavoring agent is 0.01 to 10% of the weight of the modified layer, preferably 0.02-8%, more preferably 0.03-5%; preferably, the weight percentage of the pH adjuster is 0.5-25%, preferably 1-20%, more preferably 2-15% of the weight of the modified layer. ; Preferably, the weight percentage of the anti-adhesive agent is 5 to 70% of the weight of the modified layer, preferably 10 to 60%, more preferably 15 to 50%; Preferably, the weight percentage of the flavoring agent It is 0.01-10% by weight of the modification layer, preferably 0.02-8%, more preferably 0.03-5%, more preferably 2-4%.
The method according to claim 7 or 8, wherein the filler is one or more of sucrose, lactose, glucose, starch, microcrystalline cellulose, mannitol, calcium dihydrogen phosphate, and sodium chloride; preferably It is one or more of starch, microcrystalline cellulose, lactose, and mannitol;

Preferably, the binder is one or more of pregelatinized starch, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, acrylic resin, and carboxymethylcellulose sodium;

Preferably, the lubricant is one or more of magnesium stearate, talc, calcium stearate, zinc stearate, and glyceryl behenate;

Preferably, the glidant is one or more of colloidal silica and sodium lauryl sulfate;

Preferably, the plasticizer is glycerin, propylene glycol, polyethylene glycol, triethyl citrate, glyceryl acetate, diethyl phthalate, tributyl citrate, and dibutyl subebate. one or more of;

Preferably, the porogen is polyethylene glycol, povidone, sucrose, lactose, salts, hypromellose, hydroxypropylcellulose, levetiracetam, talc, magnesium stearate , one or more of titanium dioxide;

Preferably, the sustained-release material is acrylic resin, ethyl cellulose, cellulose acetate, hypromellose phthalate, polyvinyl acetate phthalate, or hypromellose acetate succinate. one or more;

Preferably, the binder is one or more of pregelatinized starch, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, acrylic resin, and carboxymethylcellulose sodium;

Preferably, the flavoring agent is sucrose, aspartame, sucralose, stevia, sodium saccharin, glucose, fructose, lactose, mannitol, lactic acid, citric acid, malic acid, tartaric acid, succinic acid, acetic acid one or more of;

Preferably, the pH adjuster is one or more of lactic acid, citric acid, malic acid, tartaric acid, succinic acid, and acetic acid;

Preferably, the anti-sticking agent is one or more of talc, titanium dioxide, magnesium stearate, calcium stearate, and zinc stearate;

Preferably, the flavor is one or more of apple flavor, orange flavor, lemon flavor, vanilla flavor, strawberry flavor, or other flavors available in the pharmaceutical or food fields.
The method of claim 7, wherein the pH of the modified layer obtained in step (6) after being dissolved in water is 1.0 to 8.0, preferably 1.5 to 7.0, and more preferably 2.0 to 6.0.
The method of claim 7, wherein the levetiracetam sustained-release preparation obtained in step (6) is prepared into a capsule, granule or dry suspension.
The method of claim 7, comprising:

(1) Core containing levetiracetam: Mix the prescribed amount of levetiracetam with the filler, binder and glidant in a granulator, then add purified water to prepare wet granules. Add the above wet granules into the extrusion and spheronization machine, select a screen with mesh openings of 0.4~1.2mm, set the extrusion speed to 30±10rpm, and the spheronization speed to 500±100rpm. After spheronization, add the wet pellet core to the fluidized bed for drying. After drying, the pellet core is sieved, and pellets between 0.3 and 1.5 mm are selected as the core;

(2) Prepare the sustained-release layer coating liquid: Dissolve the prescribed amount of sustained-release materials, porogens, and plasticizers in the ethanol solution to prepare a sustained-release coating liquid;

(3) Prepare the sustained-release unit body: Place the core containing levetiracetam obtained in step (1) into the fluidized bed, and set the following parameters: the inlet air temperature is 40±5°C, and the material temperature is 30± 3℃, spray speed 12±3g/min, atomization pressure 1.5±0.2bar, air volume 70±20m 3 /h. Spray the coating liquid through an atomizing spray gun to obtain a sustained-release unit;

(4) Prepare the coating liquid for the modified layer: Add the prescribed amount of adhesive, flavoring agent, and pH regulator acid in the modified layer into purified water, stir until dissolved, add anti-sticking agent and disperse evenly to prepare the modified layer coating. liquid;

(5) Prepare the modified unit: Place the sustained-release unit obtained in step (3) into the fluidized bed and set the following parameters: the inlet air temperature is 50±5°C and the material temperature is 35± 3℃, spray speed 14±3g/min, atomization pressure 1.5±0.2bar, air volume 80±20m3/h. , that is, the modified unit body is obtained;

(6) Preparation of sustained-release preparation: Mix the unit obtained in step (5) with a small amount of talc powder and put it into a capsule or pharmaceutical composite bag to prepare a levetiracetam sustained-release preparation.
Use of the levetiracetam sustained-release preparation according to any one of claims 1 to 6 in the preparation of anti-epileptic drugs.