Levetiracetam sustained-release micro-tablet and preparation method thereof

Abstract

The invention relates to a levetiracetam sustained-release micro-tablet and a preparation method thereof. The levetiracetam sustained-release micro-tablet is composed of a tablet core and a coating layer, and the mass ratio of the tablet core to the coating layer is (100-105): (25-30); the tablet core is prepared from the following raw materials in parts by mass: 45-65 parts of levetiracetam, 1-5 parts of a foaming retardant, 5-15 parts of a retardant reinforcing agent, 20-40 parts of a filling agent and 0.5-3 parts of a flow aid; the coating layer is prepared from the following raw materials in parts by mass: 15-25 parts of a coating material and 2-8 parts of a pore-foaming agent. According to the preparation method, magnesium stearate or analogues thereof are excessively used during preparation of the levetiracetam sustained-release micro-tablets for the first time, an organic foaming agent is added, the path length and complexity of drug release are increased, the speed of drugs passing through hydrophobic pore channels is slowed down due to the hydrophobicity of a retarding enhancer, the sustained-release effect is achieved, and the sustained-release effect is achieved. The levetiracetam sustained-release micro-tablet can uniformly release the effective component levetiracetam within 24 hours, and the sustained-release time of the levetiracetam sustained-release micro-tablet is effectively prolonged.

Description

Technical Field

[0001] The invention relates to a levetiracetam sustained-release microtablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. Background Art

[0002] Epilepsy is a common chronic neurological disease in pediatrics, with a persistent tendency to cause epilepsy. The seizures are characterized by sudden onset, abrupt cessation, short duration, and transient nature. Abnormal brain discharges cause a short-term "disorder" in the child's brain, which is the main cause of epileptic symptoms. Unclear diagnosis and inappropriate medication for children with epilepsy can easily lead to repeated seizures and even irreversible neurological damage.

[0003] Levetiracetam (LEV) is a levorotatory ethyl piracetam derivative that can bind to synaptic vesicle protein 2A (SV2A) of central neurons, inhibit the release of presynaptic neurotransmitters, and block abnormal neuronal discharges, thereby achieving the therapeutic effect of reducing the number of epileptic seizures. It is highly permeable, easily soluble, and can act quickly after oral administration. Its relative bioavailability is nearly 100%, and it is not affected by food. As one of the new anti-epileptic drugs, LEV was approved by the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of epilepsy in children aged >1 month.

[0004] At present, the related preparations launched in the United States by LEV's original research company UCB (Belgium) include film-coated tablets, solutions, injections and sustained-release tablets. The trade name of the sustained-release tablets is Keppra XR, which includes two specifications of 500mg and 750mg oval tablets with a diameter of about 19mm, which are not available in China. At present, only Shenzhen Xinlitai Pharmaceutical Co., Ltd., Yueyang Pharmaceutical Development (Guangzhou) Co., Ltd. and Zhejiang Huahai Pharmaceutical Co., Ltd. have obtained the approval documents for the listing of levetiracetam sustained-release tablets in China, and they are all oval tablets with a diameter of about 19mm.

[0005] The existing common oral solid preparations of levetiracetam have good stability and are easy to store and transport. However, there are the following major problems for the administration of levetiracetam to young children: swallowing is difficult, and there may be vomiting or choking. It is often necessary to mix it with food / beverages before taking it. This type of modulation can easily lead to inaccurate dosage, affect the efficacy of the drug, or cause toxic side effects. The poor palatability causes children to feel disgusted and refuse to take the medicine, which brings great trouble to parents or caregivers. Microtablets can improve the problem of swallowing difficulties of ordinary oral solid preparations for children, and at the same time meet the requirements of accurate dosage and flexible dosage adjustment. The content of microtablets prepared by tableting technology is accurate and controllable, and has good uniformity. Children of different ages can count and take microtablets according to individualized medication plans, using appropriate metering devices (such as microtablet counters) to achieve accurate and flexible dosing. Microtablets also have the following advantages: good chemical stability, long shelf life; small size, easy to transport, store and carry; good taste masking or taste masking can be achieved through common preparation technologies such as coating; and it provides the possibility for the development of sustained-release dosage forms. It can significantly reduce the use of excipients such as antibacterial agents, antioxidants, taste masking agents, sweeteners, solvents, etc., and reduce the safety risks introduced by related excipients.

[0006] As a BCS Class I drug, levetiracetam is highly soluble in water. It is a huge challenge to make it into sustained-release microtablets that can achieve slow release of the drug for a long time. Compared with ordinary tablets, microtablets have a larger specific surface area due to their smaller volume, which means that when skeleton sustained release is used as the sustained-release mechanism of microtablets, it will form gel after contacting the medium or digestive fluid, and the gel layer is thin, and levetiracetam will be quickly released from the pores. However, when membrane-controlled sustained release is selected, new problems will be faced: if the sustained-release effect of microtablets is to be achieved for a longer period of time, the sustained-release coating material of conventional tablets will require a thicker coating film, which also means that more coating materials will be consumed, which will undoubtedly increase production costs.

[0007] Therefore, a sustained-release mechanism suitable for levetiracetam microtablets is provided, which can effectively improve the problem of rapid drug dissolution and release caused by the small volume and huge specific surface area of ​​the microtablets, and a sustained-release material composition can enable the microtablets to achieve a sustained-release effect for a longer time at a smaller dosage, which is of great significance for the preparation of sustained-release microtablets of highly hydrophilic drugs such as levetiracetam. Summary of the invention

[0008] In view of the deficiencies in the prior art, the present invention provides a levetiracetam sustained-release microtablet and a preparation method thereof.

[0009] The technical solution of the present invention is as follows:

[0010] A levetiracetam sustained-release microtablet, consisting of a tablet core and a coating layer, wherein the mass ratio of the tablet core to the coating layer is (100-105):(25-30);

[0011] The core tablet is composed of the following raw materials in parts by weight: 45-65 parts of levetiracetam, 1-5 parts of foaming blocker, 5-15 parts of block enhancer, 20-40 parts of filler, and 0.5-3 parts of glidant;

[0012] The coating layer is composed of the following raw materials in parts by weight: 15 to 25 parts of coating material and 2 to 8 parts of pore-forming agent.

[0013] Preferably, the levetiracetam sustained-release microtablets are composed of a tablet core and a coating layer, and the mass ratio of the tablet core to the coating layer is (101-102): (26-27);

[0014] The core tablet is composed of the following raw materials in parts by weight: 50-55 parts of levetiracetam, 2-3 parts of foaming blocker, 9-11 parts of block enhancer, 30-35 parts of filler, and 1-2 parts of glidant;

[0015] The coating layer is composed of the following raw materials in parts by weight: 20 to 24 parts of coating material and 4 to 5 parts of pore-forming agent.

[0016] Preferably according to the present invention, the foaming retarder is an organic foaming agent, specifically azodicarbonamide (AC).

[0017] Preferably according to the present invention, the retardation enhancer is a mixture of one or more of zinc stearate, calcium stearate and magnesium stearate.

[0018] Further preferably, the retardation enhancer is magnesium stearate.

[0019] Preferably, according to the present invention, the mass ratio of the foaming retarder to the retarder enhancer is (2.3-2.8):(9.8-12.4).

[0020] Further preferably, the mass ratio of the foaming retarder to the retarder enhancer is 2.6:10.7.

[0021] Preferably according to the present invention, the filler is a mixture of one or more of mannitol, lactose, microcrystalline cellulose or pregelatinized starch.

[0022] Preferably according to the present invention, the glidant is colloidal silicon dioxide.

[0023] Preferably according to the present invention, the coating material is a mixture of one or more of hydroxypropyl methylcellulose, povidone, methacrylic acid, methyl methacrylate, cellulose acetate phthalate and ethyl cellulose.

[0024] Preferably according to the present invention, the porogen is a mixture of one or more of carboxypropyl methylcellulose phthalate HP50 (HPMCP-HP50), sodium chloride, polyethylene glycol, hydroxypropyl cellulose and povidone.

[0025] The preparation method of the above-mentioned levetiracetam sustained-release microtablets comprises the following steps:

[0026] (1) According to the ratio, the foaming retarder and the retarder enhancer are stirred and mixed at 40-50° C. to obtain a mixed material; then the mixed material is added to a solvent and mixed uniformly to obtain a mixed solution; the mixed solution is freeze-dried and the solvent is evaporated to obtain a sustained-release material;

[0027] (2) according to the ratio, levetiracetam, a filler and a glidant are stirred and mixed uniformly, and then atomized and sprayed into the sustained-release material obtained in step (1) for granulation, and after drying, levetiracetam tablet core particles are obtained; after the levetiracetam tablet core particles are sieved through a 50-120 mesh sieve, the levetiracetam tablet core particles are compressed with a punch to obtain levetiracetam tablet cores;

[0028] (3) adding the coating material and the porogen into the solvent according to the ratio, and mixing them evenly to obtain a coating solution;

[0029] (4) coating the levetiracetam tablet core with the coating liquid, solidifying the tablet, and packaging the tablet to obtain the levetiracetam sustained-release microtablets.

[0030] Preferably according to the present invention, in step (1), the solvent is ethanol, dichloromethane or polyethylene glycol, and the amount of the solvent is 56.3-60.6% of the volume of the mixed material.

[0031] Further preferably, the amount of the solvent used is 56.3% of the volume of the mixed material.

[0032] Preferably, in step (1), the freeze-drying process includes pre-freezing, sublimation and drying; during freeze-drying, the pre-freezing temperature is -72 to -60°C, the vacuum degree is 10 to 100 Pa, and the solvent mass proportion of the sustained-release material after freeze-drying is 3 to 6%.

[0033] Further preferably, during the freeze-drying process, the pre-freezing temperature is -65°C, the vacuum degree is 13.8 Pa, and the solvent mass proportion of the sustained-release material after freeze-drying is 3.2%.

[0034] Preferably, in step (2), the levetiracetam tablet core particles are prepared in a fluidized bed granulation tower, and the specific process is: turn on the low-temperature chiller, start the condensation spray granulation system, and perform centrifugal spray granulation with a spray frequency of 45 to 55 Hz.

[0035] Preferably, according to the present invention, in step (3), the tableting is performed by using a punch with a diameter of 1 to 3 mm to tablet the levetiracetam tablet core particles; the hardness of the obtained levetiracetam tablet core is 10 to 15N.

[0036] Preferably according to the present invention, in step (3), the solvent is ethanol, dichloromethane or polyethylene glycol, and the amount of the solvent is 35-60% of the volume of the coating material.

[0037] Further preferably, the amount of the solvent used is 57.2% of the volume of the coating material.

[0038] Preferably, in step (4), the coating is performed by placing the levetiracetam tablet cores in a coating machine, preheating the coating machine at above 30°C for 10 min, spraying the levetiracetam tablet cores with the coating liquid under the conditions of a spraying speed of 15 rpm, a pot speed of 20 rpm, an inlet air temperature of 30-50°C, an exhaust air temperature of 20-40°C, an atomization and fan pressure of 0.35 MPa.

[0039] The technical features of the present invention are as follows:

[0040] The inventor of the present application initially directly prepared levetiracetam skeleton sustained-release microtablets according to the original prescription materials and proportions of UCB Company in the prior art. When conducting sustained-release research on the original preparation of levetiracetam sustained-release tablets, it was found that the proportion of the highest viscosity hydroxypropyl methylcellulose or ethyl cellulose prescription was as high as 65%, and the sustained-release effect could not be achieved. It is considered that the microtablets may be small in size and too large in specific surface area. The drug release channels formed by the skeleton material are very short. After the microtablets come into contact with the aqueous solution, the drug will be quickly released through the drug release channels of the skeleton material, so the sustained-release effect cannot be achieved. The inventor of the present application then carried out the microtablet coating pressure method and tried membrane-controlled sustained release. After coating levetiracetam with the sustained-release coating materials commonly used on the market, even if the coating weight gain reaches about 30%, it can only achieve a sustained-release effect of 6h.

[0041] In view of the limitations of the prior art, the inventors of the present application conducted a large amount of basic research and adjusted the formulation process based on the prior art. They unexpectedly discovered that by adding an organic foaming agent and a much larger amount of magnesium stearate or its analogue than the lubricant during the preparation of the tablet core and making the two into a specific ratio, the purpose of sustained release can be effectively achieved.

[0042] The specific principle of sustained release mechanism is inferred as follows: organic foaming agents produce gas under specific conditions to form a porous structure. Excessive magnesium stearate or its analogs can be embedded in the inner wall of the pores to form a thin film under special conditions of freeze-drying. After a certain amount of magnesium stearate or its analogs are filled in the pores, levetiracetam is wrapped to form sustained-release particle microunits. The pores caused by the foaming agent increase the path length and complexity of drug release. The hydrophobicity of magnesium stearate or its analogs slows down the speed of the drug passing through the hydrophobic pores. The two interact with each other to slow down the release rate of the drug and achieve a sustained-release effect. The drug needs to pass through the tortuous channels in the porous structure and overcome the obstruction of magnesium stearate or its analogs before it can be gradually released into the surrounding environment, thereby prolonging the drug's action time. The effect of slow release for 24 hours is achieved.

[0043] Beneficial effects:

[0044] 1. The present invention is the first to use an excessive amount of magnesium stearate or its analogues when preparing levetiracetam sustained-release microtablets, and add an organic foaming agent, wherein the organic foaming agent is used as a retarder, and magnesium stearate or its analogues are used as a retarder enhancer. The pores caused by the retarder increase the path length and complexity of drug release, and the hydrophobicity of the retarder enhancer slows down the speed at which the drug passes through the hydrophobic pores. The two interact with each other, so that the migration of the drug is restricted, the release speed is slowed down, and a sustained-release effect is achieved, so that the levetiracetam sustained-release microtablets can evenly release the active ingredient levetiracetam within 24 hours, effectively prolonging the sustained-release time of the levetiracetam sustained-release microtablets.

[0045] 2. The present invention provides a new levetiracetam sustained-release microtablet, which has a tablet weight of 7.5±0.3 mg, a height of 2.3 mm, a diameter of 2 mm, and a small size, which is convenient for children and patients with dysphagia to take. In addition, the levetiracetam sustained-release microtablet provided by the present invention has better stability and durability, can stably exist in the dissolution medium for 24 hours, and continuously and slowly release the drug. The release curve shows that the cumulative drug release in 24 hours is 75-80%, which successfully achieves the effect of sustained release of levetiracetam under microtablet conditions.

[0046] 3. The present invention also provides a new method for preparing levetiracetam sustained-release microtablets, which has few steps, is simple to operate, and is suitable for industrial production. It also provides a new type of microtablet preparation reference for the preparation of other sustained-release drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The release results of the levetiracetam sustained-release microtablets prepared in Examples 1-2 and Comparative Examples 1-5 are shown. DETAILED DESCRIPTION

[0048] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0049] The raw materials used in the examples are all conventional raw materials, and the equipment used are all conventional equipment, which can be purchased commercially.

[0050] Example 1

[0051] A levetiracetam sustained-release microtablet, consisting of a tablet core and a coating layer, wherein the mass ratio of the tablet core to the coating layer is 101.5:26.5;

[0052] The tablet core is composed of the following raw materials in parts by mass: 53.2 parts of levetiracetam, 2.6 parts of azodicarbonamide, 10.7 parts of magnesium stearate, 33.5 parts of microcrystalline cellulose, and 1.5 parts of colloidal silicon dioxide;

[0053] The coating layer is composed of the following raw materials in parts by weight: 22 parts of ethyl cellulose and 4.5 parts of hydroxypropyl methylcellulose.

[0054] The preparation method of the above-mentioned levetiracetam sustained-release microtablets comprises the following steps:

[0055] (1) adding azodicarbonamide and magnesium stearate to a preheated batching tank according to the proportion, stirring for 90 minutes at a temperature of 45° C., a shear power of 50 Kw, and a stirring frequency of 35 Hz, and mixing uniformly to obtain a mixed material; then adding the mixed material to polyethylene glycol, mixing uniformly using a homogenizer to obtain a mixed solution; freeze-drying the mixed solution to combine azodicarbonamide with magnesium stearate and evaporating the solvent to obtain a sustained-release material;

[0056] The amount of polyethylene glycol used is 56.3% of the volume of the mixed material; the freeze-drying process includes pre-freezing, sublimation and drying; during freeze-drying, the pre-freezing temperature is -65°C, the vacuum degree is 13.8Pa, and the solvent mass proportion of the sustained-release material after freeze-drying is 3.2%;

[0057] (2) adding levetiracetam, microcrystalline cellulose and colloidal silicon dioxide into a fluidized bed granulation tower according to the proportion, stirring and mixing evenly, then turning on the low-temperature chiller, starting the condensation spray granulation system, spraying the sustained-release material obtained in step (1) into the fluidized bed granulation tower, the spray frequency is 50 Hz, and after drying, obtaining levetiracetam tablet core particles; after passing the levetiracetam tablet core particles through an 85-mesh sieve, using a punch to compress the levetiracetam tablet core particles to obtain levetiracetam tablet core particles with a height of 2.3 mm and a diameter of 2 mm;

[0058] (3) adding ethyl cellulose and hydroxypropyl methylcellulose to ethanol according to the ratio, stirring and mixing evenly to obtain a coating solution; wherein the amount of ethanol used is 57.2% of the total volume of ethyl cellulose and hydroxypropyl methylcellulose;

[0059] (4) The levetiracetam tablet cores were placed in a coating machine, which was preheated at 40°C for 10 min. The coating liquid for the levetiracetam tablet cores was sprayed under the conditions of a spraying speed of 15 rpm, a pan speed of 20 rpm, an inlet air temperature of 40°C, an exhaust air temperature of 40°C, and an atomization and fan pressure of 0.35 MPa. The tablet cores were then cured in an oven at 45°C for 2 h to complete the coating. After the coating was completed, talcum powder was added and mixed evenly in the coating pan to remove the strong static electricity generated by the friction between the microtablets during the coating rotation process. Finally, the tablets were packaged to obtain levetiracetam sustained-release microtablets.

[0060] Example 2

[0061] A levetiracetam sustained-release microtablet, consisting of a tablet core and a coating layer, wherein the mass ratio of the tablet core to the coating layer is 101.5:26.5;

[0062] The tablet core is composed of the following raw materials in parts by mass: 53.2 parts of levetiracetam, 2.6 parts of azodicarbonamide, 10.7 parts of calcium stearate, 33.5 parts of microcrystalline cellulose, and 1.5 parts of colloidal silicon dioxide;

[0063] The coating layer is composed of the following raw materials in parts by weight: 22 parts of ethyl cellulose and 4.5 parts of hydroxypropyl methylcellulose.

[0064] The preparation method of the above-mentioned levetiracetam sustained-release microtablets comprises the following steps:

[0065] (1) according to the ratio, azodicarbonamide and calcium stearate are added to a preheated batching tank, stirred for 90 minutes at a temperature of 45° C., a shear power of 50 kW, and a stirring frequency of 35 Hz, and mixed evenly to obtain a mixed material; then the mixed material is added to polyethylene glycol, and mixed evenly using a homogenizer to obtain a mixed solution; the mixed solution is freeze-dried to combine azodicarbonamide with calcium stearate and evaporate the solvent to obtain a sustained-release material;

[0066] The amount of polyethylene glycol used is 56.3% of the volume of the mixed material; the freeze-drying process includes pre-freezing, sublimation and drying; during freeze-drying, the pre-freezing temperature is -65°C, the vacuum degree is 13.8Pa, and the solvent mass proportion of the sustained-release material after freeze-drying is 3.2%;

[0067] (2) adding levetiracetam, microcrystalline cellulose and colloidal silicon dioxide into a fluidized bed granulation tower according to the proportion, stirring and mixing evenly, then turning on the low-temperature chiller, starting the condensation spray granulation system, spraying the sustained-release material obtained in step (1) into the fluidized bed granulation tower, the spray frequency is 50 Hz, and after drying, obtaining levetiracetam tablet core particles; after passing the levetiracetam tablet core particles through an 85-mesh sieve, using a punch to compress the levetiracetam tablet core particles to obtain levetiracetam tablet core particles with a height of 2.3 mm and a diameter of 2 mm;

[0068] (3) adding ethyl cellulose and hydroxypropyl methylcellulose to ethanol according to the ratio, stirring and mixing evenly to obtain a coating solution; wherein the amount of ethanol used is 57.2% of the total volume of ethyl cellulose and hydroxypropyl methylcellulose;

[0069] (4) The levetiracetam tablet cores were placed in a coating machine, which was preheated at 40° C. for 10 min. The coating liquid for the levetiracetam tablet cores was sprayed under the conditions of a spraying speed of 15 rpm, a pan speed of 20 rpm, an inlet air temperature of 45° C., an exhaust air temperature of 35° C., and an atomization and fan pressure of 0.35 MPa. The tablet cores were then cured in an oven at 45° C. for 2 h to complete the coating. After the coating was completed, talcum powder was added and mixed evenly in the coating pan to remove the strong static electricity generated by the friction between the microtablets during the coating rotation process. Finally, the tablets were packaged to obtain levetiracetam sustained-release microtablets.

[0070] Example 3

[0071] A levetiracetam sustained-release microtablet, consisting of a tablet core and a coating layer, wherein the mass ratio of the tablet core to the coating layer is 101.5:26.5;

[0072] The tablet core is composed of the following raw materials in parts by mass: 53.2 parts of levetiracetam, 2.6 parts of azodicarbonamide, 10.7 parts of zinc stearate, 33.5 parts of microcrystalline cellulose, and 1.5 parts of colloidal silicon dioxide;

[0073] The coating layer is composed of the following raw materials in parts by weight: 22 parts of ethyl cellulose and 4.5 parts of hydroxypropyl methylcellulose.

[0074] The preparation method of the above-mentioned levetiracetam sustained-release microtablets is as described in Example 1.

[0075] Comparative Example 1

[0076] A levetiracetam sustained-release microtablet, consisting of a tablet core and a coating layer, wherein the mass ratio of the tablet core to the coating layer is 101.5:26.5;

[0077] The tablet core is composed of the following raw materials in parts by mass: 53.2 parts of levetiracetam, 2.6 parts of azodicarbonamide, 44.2 parts of microcrystalline cellulose, and 1.5 parts of colloidal silicon dioxide;

[0078] The coating layer is composed of the following raw materials in parts by weight: 22 parts of ethyl cellulose and 4.5 parts of hydroxypropyl methylcellulose.

[0079] Compared with Example 1, magnesium stearate was not added in this comparative example.

[0080] The specific preparation method is the same as that in Example 1.

[0081] Comparative Example 2

[0082] A levetiracetam sustained-release microtablet, consisting of a tablet core and a coating layer, wherein the mass ratio of the tablet core to the coating layer is 101.5:26.5;

[0083] The tablet core is composed of the following raw materials in parts by mass: 53.2 parts of levetiracetam, 12.1 parts of azodicarbonamide, 1.2 parts of magnesium stearate, 33.5 parts of microcrystalline cellulose, and 1.5 parts of colloidal silicon dioxide;

[0084] The coating layer is composed of the following raw materials in parts by weight: 22 parts of ethyl cellulose and 4.5 parts of hydroxypropyl methylcellulose.

[0085] Compared with Example 1, the amount of magnesium stearate used in this comparative example is greatly reduced.

[0086] The specific preparation method is the same as that in Example 1.

[0087] Comparative Example 3

[0088] A levetiracetam sustained-release microtablet, the specific components and preparation method are as described in Example 1, except that freeze-drying is not performed in step (1) of the preparation method. Specifically, azodicarbonamide and magnesium stearate are added to a preheated batching tank according to a ratio, stirred for 90 minutes under the conditions of a temperature of 45° C., a shear power of 50 Kw, and a stirring frequency of 35 Hz, and mixed uniformly to obtain a mixed material; then the mixed material is added to polyethylene glycol, mixed uniformly using a homogenizer to obtain a mixed solution, and the mixed solution is used as a sustained-release material in subsequent steps.

[0089] Comparative Example 4

[0090] A levetiracetam sustained-release microtablet, consisting of a tablet core and a coating layer, wherein the mass ratio of the tablet core to the coating layer is 89.4:6.5;

[0091] The tablet core is composed of the following raw materials in parts by mass: 53.2 parts of levetiracetam, 2.1 parts of povidone K30, 31.9 parts of hypromellose, 1.1 parts of magnesium stearate, and 1.1 parts of colloidal silicon dioxide;

[0092] The coating layer is composed of the following raw materials in parts by mass: 6.5 parts of film coating premix (gastric soluble type).

[0093] In this formula, povidone K30 is a binder, hypromellose is a sustained-release matrix, and magnesium stearate and colloidal silicon dioxide are glidants.

[0094] The preparation method of the above-mentioned levetiracetam sustained-release microtablets comprises the following steps:

[0095] (1) According to the ratio, polyvidone K30 (PVP K30) is dispersed in half the volume of purified water at 85° C. After complete dispersion, the remaining purified water is added to obtain a PVP K30 aqueous solution; the amount of the purified water used is 56.3% of the volume of the polyvidone;

[0096] (2) According to the ratio, levetiracetam and hypromellose were added to the fluidized bed granulation dryer, the inlet air temperature was set to 60.0°C, and the air volume was set according to the fluidization state of the material (the initial setting was 20m 3 / h), heat the material to a temperature of 30.0°C and then spray the PVP K30 aqueous solution obtained in step (1) at a spray speed of 10 rpm and an atomization pressure of 1.0 kg / cm 2 , adjust the air inlet temperature according to the material temperature, adjust the air volume to ensure the material is in a fluidized state until the PVP K30 aqueous solution is sprayed; turn off the atomization, set the air volume to 20m 3 / h, inlet air temperature 60°C, drying until the granule moisture content is 2.0%, to obtain levetiracetam tablet core granules;

[0097] (3) Adding the levetiracetam tablet core particles to a granulator at a speed of 600 rpm and a granulator mesh size of 1.0 mm, then adding colloidal silicon dioxide, setting the speed to 6 rpm, mixing for 10 min, then adding magnesium stearate, setting the speed to 6 rpm, and mixing for 10 min; tableting using a rotary tablet press, with a single tablet weight controlled at 7.5 ± 0.3 mg and a tablet core diameter of 2 mm, to obtain levetiracetam tablet cores;

[0098] (4) adding the film coating premix (gastric soluble) to ethanol according to the ratio, stirring and mixing evenly to obtain a coating solution; wherein the amount of ethanol is 57.2% by volume of the film coating premix (gastric soluble);

[0099] (5) The levetiracetam tablet cores were placed in a coating machine, which was preheated at 40° C. for 10 min. The coating liquid for the levetiracetam tablet cores was sprayed under the conditions of a spraying speed of 15 rpm, a pan speed of 20 rpm, an inlet air temperature of 40° C., an exhaust air temperature of 30° C., and an atomization and fan pressure of 0.35 MPa. The tablet cores were then cured in an oven at 45° C. for 2 h to complete the coating. After the coating was completed, talcum powder was added and mixed evenly in the coating pan to remove the strong static electricity generated by the friction between the microtablets during the coating rotation process. Finally, the tablets were packaged to obtain levetiracetam sustained-release microtablets.

[0100] Comparative Example 5

[0101] A levetiracetam sustained-release microtablet, consisting of a tablet core and a coating layer, wherein the mass ratio of the tablet core to the coating layer is 100:31.8;

[0102] The tablet core is composed of the following raw materials in parts by mass: 60 parts of levetiracetam, 37 parts of microcrystalline cellulose, and 3 parts of magnesium stearate;

[0103] The coating layer is composed of the following raw materials in parts by mass: 6.5 parts of hydroxypropyl methylcellulose (HPMC E5), 22 parts of Eudragit NM30D, 2.2 parts of Tween 80, and 6.6 parts of talc.

[0104] In this formula, microcrystalline cellulose is a filler, magnesium stearate is a glidant, hypromellose is a pore-forming agent, Eudragit NM30D is a controlled-release material, Tween is a plasticizer, and talc is an anti-adhesive agent.

[0105] The preparation method of the above-mentioned levetiracetam sustained-release microtablets comprises the following steps:

[0106] (1) According to the ratio, levetiracetam, microcrystalline cellulose, and magnesium stearate were sieved through a 40-mesh sieve, and three-dimensional mixing was simulated for 20 minutes. The tablets were compressed using a 2 mm diameter shallow concave round punch, and the tablet weight was controlled to be 7.5 ± 0.33 mg, the tablet core hardness was 10 ± 3 N, and the friability was < 0.3%, thereby obtaining levetiracetam tablet cores;

[0107] (2) According to the ratio, Eudragit NM30D and HPMC E5 were dissolved in purified water, and then Tween 80 and talcum powder were added to obtain a coating solution; the levetiracetam tablet cores were placed in a coating machine, which was preheated at 40°C for 10 min, and the coating solution for the levetiracetam tablet cores was sprayed under the conditions of a spraying speed of 15 rpm, a pan speed of 20 rpm, an inlet air temperature of 40°C, an exhaust air temperature of 30°C, and an atomization and fan pressure of 0.35 MPa. The tablet cores were then cured in an oven at 45°C for 2 h to complete the coating. After the coating was completed, talcum powder was added and mixed evenly in the coating pan to remove the strong static electricity generated by the friction between the microtablets during the coating rotation process. Finally, the tablets were packaged to obtain levetiracetam sustained-release microtablets, and the coating weight gain of the levetiracetam sustained-release microtablets was greater than 30%.

[0108] Experimental example

[0109] The release of the levetiracetam sustained-release microtablets prepared in Examples 1 to 2 and Comparative Examples 1 to 5 was determined according to the second method of the dissolution and release determination method of the "General Rules of Part Four of the Chinese Pharmacopoeia 2020 Edition 0931". The specific method is as follows:

[0110] The paddle method test was performed using 900 ml of phosphate buffer solution with pH = 6.8 as the dissolution medium at a temperature of 37 ± 0.5 °C and a rotation speed of 50 rpm. The operation was carried out in accordance with the law. Samples were taken at 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 20 h, and 24 h to determine the concentration of levetiracetam sustained-release microtablets. The release curve was drawn with time as the horizontal axis and the cumulative release as the vertical axis. The results are shown in Figure 2. Figure 1 And as shown in Table 1.

[0111] Table 1

[0112]

[0113] Depend on Figure 1As shown in Table 1, no magnesium stearate was added in Comparative Example 1, and the amount of magnesium stearate was greatly reduced in Comparative Example 2, so the dichlorodicarbonamide in Comparative Examples 1 to 2 could not play a role in blocking sustained release, and the cumulative release of levetiracetam sustained-release microtablets in Comparative Examples 1 to 2 was significantly higher than the cumulative release of levetiracetam sustained-release microtablets in Examples 1 to 3 of the present invention at 0.5h. Although dichlorodicarbonamide and excess magnesium stearate were used in Comparative Example 3, freeze-drying treatment was not performed, and dichlorodicarbonamide and excess magnesium stearate were not effectively combined, and still could not play a role in blocking sustained release, and the cumulative release was significantly higher than that in Examples 1 to 3 of the present invention at 0.5h. Comparative Examples 4 and 5 are conventional levetiracetam sustained-release microtablets in the prior art. The cumulative release of Comparative Example 4 is significantly higher than that of Examples 1 to 3 of the present invention starting from 0.5 h. The cumulative release of Comparative Example 5 within 0.5 to 1 h is still similar to that of Examples 1 to 3. However, the cumulative release starting from 2 h is significantly higher than that of Examples 1 to 3, indicating that Comparative Example 5 cannot be uniformly sustained-released.

[0114] In summary, the present invention is the first to use an excessive amount of magnesium stearate or its analogues when preparing levetiracetam sustained-release microtablets, and add an organic foaming agent, with the organic foaming agent as a retarder, and magnesium stearate or its analogues as a retarder enhancer. The pores caused by the retarder increase the path length and complexity of drug release, and the hydrophobicity of the retarder enhancer slows down the speed of the drug passing through the hydrophobic pores. The two interact with each other, so that the migration of the drug is restricted, the release speed is slowed down, and the sustained-release effect is achieved, so that the levetiracetam sustained-release microtablets can evenly release the active ingredient levetiracetam within 24 hours, and the sustained-release time of the levetiracetam sustained-release microtablets is effectively prolonged.

Claims

1. A levetiracetam sustained-release microtablet, characterized in that: It consists of a tablet core and a coating layer, wherein the mass ratio of the tablet core to the coating layer is (100-105): (25-30); The core tablet is composed of the following raw materials in parts by weight: 45-65 parts of levetiracetam, 1-5 parts of foaming blocker, 5-15 parts of block enhancer, 20-40 parts of filler, and 0.5-3 parts of glidant; The coating layer is composed of the following raw materials in parts by weight: 15 to 25 parts of coating material and 2 to 8 parts of pore-forming agent.

2. The levetiracetam sustained-release microtablet according to claim 1, characterized in that: The levetiracetam sustained-release microtablets are composed of a tablet core and a coating layer, and the mass ratio of the tablet core to the coating layer is (101-102): (26-27); The core tablet is composed of the following raw materials in parts by weight: 50-55 parts of levetiracetam, 2-3 parts of foaming blocker, 9-11 parts of block enhancer, 30-35 parts of filler, and 1-2 parts of glidant; The coating layer is composed of the following raw materials in parts by weight: 20 to 24 parts of coating material and 4 to 5 parts of pore-forming agent.

3. The levetiracetam sustained-release microtablet according to claim 1, characterized in that: The foaming retarder is azodicarbonamide; the retardation enhancer is a mixture of one or more of zinc stearate, calcium stearate, and magnesium stearate; the mass ratio of the foaming retarder to the retardation enhancer is (2.3-2.8): (9.8-12.4).

4. The levetiracetam sustained-release microtablet according to claim 1, characterized in that: The retardation enhancer is magnesium stearate; the mass ratio of the foaming retarder to the retardation enhancer is 2.6:10.

7.

5. The levetiracetam sustained-release microtablet according to claim 1, characterized in that: The filler is a mixture of one or more of mannitol, lactose, microcrystalline cellulose or pregelatinized starch; and the glidant is colloidal silicon dioxide.

6. The levetiracetam sustained-release microtablet according to claim 1, characterized in that: The coating material is a mixture of one or more of hydroxypropyl methylcellulose, povidone, methacrylic acid, methyl methacrylate, cellulose acetate phthalate, and ethyl cellulose; The porogen is a mixture of one or more of carboxypropylmethylcellulose phthalate HP50, sodium chloride, polyethylene glycol, hydroxypropyl cellulose and povidone.

7. The method for preparing the levetiracetam sustained-release microtablets according to claim 1, characterized in that: The steps include: (1) According to the ratio, the foaming retarder and the retarder enhancer are stirred and mixed at 40-50° C. to obtain a mixed material; then the mixed material is added to a solvent and mixed uniformly to obtain a mixed solution; the mixed solution is freeze-dried and the solvent is evaporated to obtain a sustained-release material; (2) according to the ratio, levetiracetam, a filler and a glidant are stirred and mixed uniformly, and then atomized and sprayed into the sustained-release material obtained in step (1) for granulation, and after drying, levetiracetam tablet core particles are obtained; after the levetiracetam tablet core particles are sieved through a 50-120 mesh sieve, the levetiracetam tablet core particles are compressed with a punch to obtain levetiracetam tablet cores; (3) adding the coating material and the porogen into the solvent according to the ratio, and mixing them evenly to obtain a coating solution; (4) coating the levetiracetam tablet core with the coating liquid, solidifying the tablet, and packaging the tablet to obtain the levetiracetam sustained-release microtablets.

8. The preparation method according to claim 7, characterized in that: In step (1), the solvent is ethanol, dichloromethane or polyethylene glycol, and the amount of the solvent is 56.3-60.6% of the volume of the mixed material; the freeze-drying process includes pre-freezing, sublimation and drying; during freeze-drying, the pre-freezing temperature is -72 to -60°C, the vacuum degree is 10 to 100 Pa, and the mass proportion of the solvent in the sustained-release material after freeze-drying is 3 to 6%; Further preferably, the amount of the solvent is 56.3% of the volume of the mixed material; during the freeze-drying process, the pre-freezing temperature is -65°C, the vacuum degree is 13.8 Pa, and the solvent mass proportion of the sustained-release material after freeze-drying is 3.2%.

9. The preparation method according to claim 7, characterized in that: In step (2), the levetiracetam tablet core particles are prepared in a fluidized bed granulation tower, and the specific process is: turn on the low-temperature chiller, start the condensation spray granulation system, and perform centrifugal spray granulation at a spray frequency of 45 to 55 Hz; In step (3), the tableting is performed by using a punch with a diameter of 1 to 3 mm to tablet the levetiracetam tablet core particles; the hardness of the obtained levetiracetam tablet core is 10 to 15N; the solvent is ethanol, dichloromethane or polyethylene glycol, and the amount of the solvent is 35 to 60% of the volume of the coating material; further preferably, the amount of the solvent is 57.2% of the volume of the coating material.

10. The preparation method according to claim 7, characterized in that: In step (4), the coating is performed by placing the levetiracetam tablet core in a coating machine, preheating the coating machine at above 30°C for 10 minutes, spraying the levetiracetam tablet core with the coating liquid under the conditions of a spraying speed of 15 rpm, a pot speed of 20 rpm, an inlet air temperature of 30-50°C, an exhaust air temperature of 20-40°C, an atomization and fan pressure of 0.35 MPa.

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