Levetiracetam sustained-release micro-tablet and application thereof

Abstract

The invention discloses a levetiracetam sustained-release micro-tablet and an application of the levetiracetam sustained-release micro-tablet. The levetiracetam sustained-release micro-tablet core disclosed by the invention has good friability and tabletability, is easy to form in a tabletting processing process, and solves the difficult problems of tabletting formability of the micro-tablet core and friability of the micro-tablet core in a subsequent coating process in the prior art; the successful preparation of the levetiracetam sustained-release micro-tablet core and the sustained-release coated micro-tablet is realized. Compared with an original sustained-release tablet, the levetiracetam sustained-release micro-tablet disclosed by the invention has the advantages that the size and the volume are greatly reduced, the levetiracetam sustained-release micro-tablet is easier to swallow by a patient, and the medication compliance of the patient is greatly improved. And the sustained-release layer coating is coated on the outer layer of the tablet core, so that the levetiracetam sustained-release micro-tablet realizes stable release of a membrane control mechanism, and the long-acting and stable release effect of the sustained-release micro-tablet is achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a levetiracetam sustained-release microtablet and its application. Background Technology

[0002] Levetiracetam, chemically known as (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide, has the chemical structure shown below. Levetiracetam is a derivative of piracetam and is a novel antiepileptic drug. Marketed formulations of levetiracetam include tablets, oral solutions, concentrated solutions for injection, and sustained-release tablets.

[0003]

[0004] While sustained-release tablets address the issue of frequent dosing, their relatively large size (approximately 19.10 mm in long diameter, 9.72 mm in short diameter, and 7.78 mm in thickness) leads to poor medication adherence for children, the elderly, and other patients who are unwilling or unable to swallow large-sized sustained-release tablets. Patents CN201410670492.5 and CN200910070314.8 disclose methods for preparing levetiracetam sustained-release microspheres, which reduce the volume of the formulation and improve patient adherence. However, the significant size variation among these microspheres makes the formulation prone to uneven coating and large batch-to-batch quality variations during scale-up production, posing a significant challenge to the stable production of pharmaceutical formulations. Compared to sustained-release microcapsules, microplates are made by compression, which allows for greater control over tablet weight and size, and smaller batch-to-batch and batch-to-batch variations. For larger formulations, they are easier to prepare and combine the advantages of oral solid dosage forms and oral liquid dosage forms. They can be packaged as flexibly as liquid dosage forms, while also having the good stability of solid dosage forms. Furthermore, microplates can be highly dispersed in the gastrointestinal tract, reducing local irritation to the gastrointestinal tract and lowering the risk of drug burst release.

[0005] However, due to the small size of the micro-flakes and cores, the poor compressibility and high brittleness of the cores pose significant technical challenges to the processing. Summary of the Invention

[0006] To address the above problems, a first aspect of the present invention provides a levetiracetam sustained-release microtablet, comprising a tablet core and a coating layer covering the outer layer of the tablet core, wherein the tablet core comprises the active ingredient levetiracetam and pharmaceutical excipients, and the pharmaceutical excipients include a binder and / or a filler.

[0007] The levetiracetam sustained-release microtablets of the present invention consist only of a tablet core and a coating layer.

[0008] As a preferred technical solution, the tablet core includes the active ingredient levetiracetam and pharmaceutical excipients, wherein the pharmaceutical excipients include a binder.

[0009] As a preferred technical solution, the tablet core includes the active ingredient levetiracetam and pharmaceutical excipients, wherein the pharmaceutical excipients include a filler.

[0010] As a preferred technical solution, the tablet core includes the active ingredient levetiracetam and pharmaceutical excipients, wherein the pharmaceutical excipients include binders and fillers.

[0011] The numerical values ​​in this invention may vary by less than ±1%, such as ±0.1%, ±0.2%, ±0.3%, ±0.4%, which is a reasonable difference in the art.

[0012] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 50%–85% levetiracetam, 1%–25% binder, and 2%–45% filler.

[0013] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 55%–85% levetiracetam, 1%–25% binder, and 2%–40% filler.

[0014] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 60%–85% levetiracetam, 1%–20% binder, and 2%–30% filler, based on the total weight of the tablet core.

[0015] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 62%–82% levetiracetam, 2%–19% binder, and 4%–28% filler.

[0016] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 65%–80% levetiracetam, 2%–18% binder, and 6%–40% filler.

[0017] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 65%–80% levetiracetam, 2%–18% binder, and 6%–25% filler.

[0018] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 68%–76% levetiracetam, 3%–15% binder, and 9%–22% filler.

[0019] Examples of such active ingredients include levetiracetam, which constitute 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, and 85% of the total weight of the tablet core, including but not limited to the values ​​listed above.

[0020] Examples of the adhesives include 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, and 25% of the total weight of the core, including but not limited to the values ​​listed above.

[0021] Examples of fillers include those comprising 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, and 40% of the total weight of the core, including but not limited to the values ​​listed above.

[0022] Adhesives are solid powders or solutions that agglomerate non-adhesive or insufficiently adhesive materials into particles, promoting compression molding and possessing adhesive properties.

[0023] Fillers, also known as diluents, are components in a formulation used to increase volume or weight. They can reduce dosage deviations of the active pharmaceutical ingredient and improve the compressibility of the drug.

[0024] As a preferred technical solution, the adhesive is selected from at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, gum arabic, gelatin, shellac, pectin, polypropylene glycol-polyoxyethylene block copolymer, and dextrin.

[0025] As a preferred technical solution, the adhesive is selected from at least one of povidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

[0026] As a preferred technical solution, the adhesive is polyvinyl ketone.

[0027] The inventors discovered that by using povidone as a binder and controlling the amount added, the brittleness of the tablet core can be improved, the number of tablet cores that crack during the coating process can be reduced, and the compressibility of the tablet core can be improved.

[0028] As a preferred technical solution, the chip core further includes a lubricant, wherein the weight of the lubricant accounts for 0 to 5% of the total weight of the chip core.

[0029] Examples of the lubricant's weight percentages as a percentage of the total weight of the core are 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, respectively. 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, including but not limited to the values ​​listed above.

[0030] Lubricants are lubricating excipients used in the preparation of solid dosage forms. Their function is to reduce friction between particles and between particles and the metal contact surfaces of solid dosage form production equipment (such as tablet press punches and dies). During tableting, lubricants often have an anti-adhesion effect, reducing the adhesion between particles and the punch, preventing the tableting material from sticking to the punch surface, and improving the processability of the tablets.

[0031] As a preferred technical solution, the tablet core further includes a flow aid, wherein the weight of the flow aid accounts for 0 to 5% of the total weight of the tablet core.

[0032] Examples of gliding agents include those comprising 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4% of the total weight of the tablet core. 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, including but not limited to the values ​​listed above.

[0033] The main function of glidants is to increase the flowability of particles and improve powder flow rate. During tableting, they enhance material flowability and improve tablet processability.

[0034] As a preferred technical solution, the filler is selected from at least one of lactose, mannitol, calcium carbonate, sodium carboxymethyl cellulose, and microcrystalline cellulose; the lubricant is selected from at least one of magnesium stearate, calcium stearate, zinc stearate, sodium fumarate stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitoyl stearate, stearic acid and hydrogenated vegetable oil, sodium lauryl sulfate, and polyethylene glycol; and the flow aid is selected from at least one of talc, colloidal silica, or derivatives thereof.

[0035] As a preferred technical solution, the filler is microcrystalline cellulose.

[0036] As a preferred technical solution, the lubricant is magnesium stearate.

[0037] As a preferred technical solution, the lubricant is calcium stearate.

[0038] As a preferred technical solution, the flow aid is colloidal silica.

[0039] In this invention, colloidal silica refers to unmodified, hydrophilic silica. Hydrophobic silica is obtained by processing colloidal silica and has low hygroscopicity.

[0040] As a preferred technical solution, the brittleness of the chip core is ≤0.8%.

[0041] The inventors discovered that when the friability of the tablet core is ≤0.8%, the tablet core exhibits good quality stability. Higher friability leads to severe powder shedding during the coating process, resulting in damage to the tablet core's shape, changes in the content of active ingredients, and the shedding powder adhering to the tablet surface during coating, causing an uneven surface on the coated micro-tablets. Therefore, the inventors have adopted a friability of ≤0.8% as an internal control standard for tablet core preparation.

[0042] As a preferred technical solution, the hardness of the core is ≥1Kg.

[0043] The inventors discovered that when the core hardness is ≥1Kg, it has better brittleness.

[0044] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 50%–85% levetiracetam, 2%–45% filler, 1%–25% binder, 0%–5% lubricant, and 0%–5% flow aid.

[0045] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 55%–85% levetiracetam, 2%–40% filler, 1%–25% binder, 0%–5% lubricant, and 0%–5% flow aid.

[0046] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 60%–85% levetiracetam, 2%–30% filler, 1%–20% binder, 0%–5% lubricant, and 0%–4% flow aid.

[0047] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 62%–82% levetiracetam, 4%–28% filler, 2%–19% binder, 0%–4% lubricant, and 0%–3% flow aid.

[0048] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 65%–80% levetiracetam, 6%–28% filler, 2%–18% binder, 0%–3% lubricant, and 0%–2% flow aid.

[0049] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 65%–80% levetiracetam, 6%–40% filler, 2%–18% binder, 0%–3% lubricant, and 0%–2% flow aid.

[0050] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 65%–80% levetiracetam, 6%–25% filler, 2%–18% binder, 0%–3% lubricant, and 0%–2% flow aid.

[0051] As a preferred technical solution, the tablet core comprises the following components by weight fraction: 68%–76% levetiracetam, 9%–22% filler, 3%–15% binder, 0%–2% lubricant, and 0%–1% flow aid.

[0052] As a preferred technical solution, the micro-flake coating includes a sustained-release coating material and a pore-forming agent, wherein the weight ratio of the sustained-release coating material to the pore-forming agent is 3 to 6:1.

[0053] The microcapsule coating in this invention comprises only a sustained-release coating material and a pore-forming agent.

[0054] The weight of the sustained-release coating material is the weight of the sustained-release material solid powder or the weight of the solid content in the sustained-release material aqueous dispersion.

[0055] As a preferred technical solution, the microfilm coating includes at least a sustained-release coating material and a pore-forming agent, wherein the weight ratio of the sustained-release coating material to the pore-forming agent is 4 to 6:1.

[0056] The inventors achieved a suitable sustained-release effect for the microtablets by adding a pore-forming agent to the sustained-release coating material. They discovered that adding a certain amount of pore-forming agent to the sustained-release coating material could adjust the release effect of the sustained-release microtablets. However, adding too little pore-forming agent resulted in unsatisfactory dissolution, while adding too much resulted in excessively rapid release of the microtablets with no significant sustained-release effect. Through in-depth research, the inventors found that when the weight ratio of the sustained-release coating material to the pore-forming agent was 3–6:1 or 4–6:1, the sustained-release microtablets exhibited better dissolution and sustained-release effects.

[0057] As a preferred technical solution, the weight gain of the coating layer is 5% to 40% based on the total weight of the wafer core.

[0058] As a preferred technical solution, the weight gain of the coating layer is 10% to 35% based on the total weight of the wafer core.

[0059] In this invention, the weight gain of the coating layer refers to the percentage of the weight of the coating layer to the total weight of the core.

[0060] As a preferred technical solution, the sustained-release coating material is selected from at least one of ethyl cellulose, ethyl cellulose aqueous dispersion, ammonium methacrylate alkyl acrylate copolymer, and ethyl acrylate methyl methacrylate polymer, and the pore-forming agent is selected from at least one of hydroxypropyl methylcellulose, polyethylene glycol, and lactose.

[0061] As a preferred technical solution, the solid content of the ethyl cellulose aqueous dispersion is 25 wt%.

[0062] The inventors used an aqueous dispersion of ethyl cellulose as a sustained-release coating material to coat the outer layer of the tablet core with an ethyl cellulose membrane. By adding a pore-forming agent to the coating solution, a membrane-controlled release mechanism was achieved, resulting in the sustained-release effect of the microtablets.

[0063] As a preferred technical solution, the pore-forming agent is selected from at least one of hydroxypropyl methylcellulose, polyethylene glycol, and lactose.

[0064] A third aspect of the present invention provides a method for preparing the above-mentioned levetiracetam sustained-release microtablets, comprising at least the following steps:

[0065] (1) Preparation of levetiracetam sustained-release microtablet cores;

[0066] (2) Levetiracetam sustained-release microtablet cores were coated with sustained-release microtablets to obtain levetiracetam sustained-release coated microtablets;

[0067] (3) The levetiracetam sustained-release coated microtablets were cured in an oven at 40-70°C to obtain levetiracetam sustained-release coated microtablets with stable quality.

[0068] As a preferred technical solution, the method for preparing levetiracetam sustained-release microtablets provided by the present invention includes at least the following steps:

[0069] (1) Levetiracetam sustained-release microtablet cores were prepared by using levetiracetam, adhesive and filler;

[0070] (2) Levetiracetam sustained-release microtablets were obtained by coating the tablet core with a coating solution composed of a sustained-release coating material and a pore-forming agent.

[0071] (3) The levetiracetam sustained-release coated microtablets were cured in an oven at 40-70°C to obtain levetiracetam sustained-release coated microtablets with stable quality.

[0072] As a preferred technical solution, in the method for preparing levetiracetam sustained-release microplates, the curing time is ≥1h.

[0073] As a preferred technical solution, in the method for preparing levetiracetam sustained-release microplates, the curing time is ≥4h.

[0074] As a preferred technical solution, in the method for preparing levetiracetam sustained-release microplates, the curing time is between 4h and 48h.

[0075] As a preferred technical solution, the pore-forming agent is hydroxypropyl methylcellulose.

[0076] As a more preferred technical solution, the method for preparing the above-mentioned levetiracetam sustained-release microtablets includes at least the following steps:

[0077] (1) Adhesive preparation: Add the adhesive to purified water, stir to dissolve, and prepare an adhesive solution;

[0078] (2) Fluidized bed granulation: The filler and levetiracetam are added to the fluidized bed, and the binder solution is sprayed in for granulation. After drying, granulated particles are obtained.

[0079] (3) Granulation: granulation by sieving;

[0080] (4) Mixing: Mix the granulated particles with the gliding agent and lubricant to obtain the mixed particles;

[0081] (5) Tablet core compression: A rotary tablet press with a multi-punch micro-die is used to compress the total mixed particles into tablets;

[0082] (6) Preparation of coating solution: Add the pore-forming agent to purified water, stir to dissolve it completely, and then mix and stir with the sustained-release coating material to obtain the coating solution;

[0083] (7) Fluidized bed coating: The tablet core is added to a multi-functional granulation and coating machine for sustained-release coating to obtain sustained-release coated micro tablets;

[0084] (8) Curing: The sustained-release coated microfilms are cured in an oven at 40-70°C to obtain sustained-release coated microfilms with stable quality.

[0085] As a preferred technical solution, in the method for preparing levetiracetam sustained-release microplates, the curing time is ≥4h.

[0086] As a preferred technical solution, in the method for preparing levetiracetam sustained-release microplates, the curing time is between 4h and 48h.

[0087] As a preferred technical solution, the diameter of the multi-punch micro-die is between 1.5 and 2.5 mm.

[0088] The weight of levetiracetam in a unit dose of levetiracetam sustained-release microtablets is 750 mg or 500 mg. The unit dose of the levetiracetam sustained-release microtablets prepared according to this invention is packaged in a pouch. Multi-dose packaging is also possible, with doses taken in divided doses.

[0089] The sustained-release microplates prepared in this invention are circular with a diameter of 1.5–2.5 mm and a thickness of 1.5–2.5 mm.

[0090] The use of the levetiracetam sustained-release microplates described in this invention in the preparation of antiepileptic drugs.

[0091] In this invention, the weight and weight ratio of each component are calculated using a rounded numerical format. Differences arising from this rounded numerical format will not affect the quality of the levetiracetam sustained-release microtablet core or the levetiracetam sustained-release microtablet itself.

[0092] The levetiracetam sustained-release microtablets of this invention do not use organic solvents in the preparation process, and there are no organic solvent residues in the sustained-release microtablets, making them safer and more environmentally friendly.

[0093] Beneficial effects

[0094] The sustained-release microtablets of this invention possess good compressibility and brittleness, facilitating easy molding during tableting and enabling the successful preparation of levetiracetam sustained-release microtablet cores. This solves the problems of tablet core molding and coating brittleness in existing technologies. Compared to levetiracetam sustained-release tablets, the levetiracetam sustained-release microtablets of this invention are significantly smaller in size and volume, making them easier for patients to swallow and greatly improving patient medication adherence. By coating the outer layer of the core with a sustained-release coating, the levetiracetam sustained-release microtablets achieve a stable membrane control mechanism, resulting in a long-lasting and stable release effect. Example

[0095] The following are non-limiting examples illustrating embodiments of the present invention, and the scope of protection of the present invention is not limited to these embodiments. The pharmaceutical excipients used in the following examples are all commonly used pharmaceutical excipients in the art.

[0096] Example 1

[0097] Levetiracetam sustained-release microplate core

[0098] Prescription 1

[0099] The proportions in the prescription are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam).

[0100]

[0101] Preparation method: fluidized bed granulation

[0102] (1) Adhesive preparation: The prescribed amount of quaternary ammonium methacrylate copolymer type B aqueous dispersion was slowly added to purified water to prepare an aqueous dispersion with a concentration of 20 wt%.

[0103] (2) Fluidized bed granulation: Levetiracetam was added to a multi-functional granulation and coating machine, and quaternary ammonium methacrylate copolymer type B aqueous dispersion was sprayed into the granulation machine. After granulation, the particles were dried until the moisture content was ≤2%wt.

[0104] (3) Granulation: granulation by sieving;

[0105] (4) Total mixing: Mix the granulated particles with the prescribed amount of calcium stearate and hydrophobic colloidal silica to obtain the total mixed particles;

[0106] (5) Tablet core pressing: A rotary tablet press is used, and a multi-punch micro-die with a diameter of 2mm is used to press the total mixed particles into tablets, and the tablet hardness is controlled to be no less than 1kg.

[0107] Example 2

[0108] Levetiracetam sustained-release microplate core

[0109] Prescription 2

[0110] The proportions in the prescription are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam).

[0111]

[0112] Preparation method: fluidized bed granulation

[0113] (1) Adhesive preparation: Add povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0114] (2) Fluidized bed granulation: Levetiracetam is added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is ≤2%wt.

[0115] (3) Granulation: granulation by sieving;

[0116] (4) Mixing: Mix the granulated particles with calcium stearate and hydrophobic colloidal silica to obtain the mixed particles.

[0117] (5) Tablet core pressing: A rotary tablet press is used, and a multi-punch micro-die with a diameter of 2mm is used to press the total mixed particles into tablets, and the tablet hardness is controlled to be no less than 1kg.

[0118] Example 3

[0119] Levetiracetam sustained-release microplate core

[0120] Prescription 3

[0121] The proportions in the prescription are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam), excluding water as a wetting agent.

[0122]

[0123]

[0124] Preparation method: wet granulation

[0125] (1) Wet granulation: Add the prescribed amount of levetiracetam to a wet granulator and add purified water to form soft material;

[0126] (2) Wet granulation: The prepared soft material is sieved and wet granulated.

[0127] (3) Drying: The wet granulated granules are added to a multi-functional granulation and coating machine for drying until the moisture content is ≤2%wt;

[0128] (4) Dry granulation: granulation by sieving;

[0129] (5) Mixing: Mix the granulated particles with hydroxypropyl methylcellulose, colloidal silica and calcium stearate to obtain the mixed particles;

[0130] (6) Tablet core pressing: A rotary tablet press is used, and a multi-punch micro-die with a diameter of 2mm is used to press the total mixed particles into tablets, and the tablet hardness is controlled to be no less than 1kg.

[0131] Example 4

[0132] Levetiracetam sustained-release microplate core

[0133] Prescription 4

[0134] The proportions in the prescription are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam).

[0135]

[0136] Preparation method: fluidized bed granulation

[0137] (1) Adhesive preparation: Add polyvinyl ketone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 15wt%;

[0138] (2) Fluidized bed granulation: Levetiracetam is added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is ≤2%wt.

[0139] (3) Granulation: granulation by sieving;

[0140] (4) Mixing: Mix the granulated particles with hydroxypropyl methylcellulose and colloidal silica, and then add calcium stearate to mix to obtain the mixed particles.

[0141] (5) Tablet core pressing: A rotary tablet press is used, and a multi-punch micro-die with a diameter of 2mm is used to press the total mixed particles into tablets, and the tablet hardness is controlled to be no less than 1kg.

[0142] Example 5

[0143] Levetiracetam sustained-release microplate core

[0144] Prescription 5

[0145] The proportions in the prescription are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam).

[0146]

[0147] Preparation method: fluidized bed granulation

[0148] (1) Adhesive preparation: Add povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0149] (2) Fluidized bed granulation: Microcrystalline cellulose and levetiracetam are added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is reduced to a certain level.

[0150] ≤2%wt;

[0151] (3) Granulation: granulation by sieving;

[0152] (4) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0153] (5) Tablet core pressing: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to press the total mixed particles into tablets, and the tablet hardness is controlled to be no less than 1kg.

[0154] Example 6

[0155] Levetiracetam sustained-release microplate core

[0156] Prescription 6

[0157] The proportions in the prescription are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam).

[0158]

[0159] Preparation method: fluidized bed granulation

[0160] (1) Adhesive preparation: Add povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 15wt%;

[0161] (2) Fluidized bed granulation: Microcrystalline cellulose and levetiracetam are added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is ≤2%wt.

[0162] (3) Granulation: granulation by sieving;

[0163] (4) Total mixing: Mix the granulated particles with colloidal silica, and then add magnesium stearate to mix to obtain the total mixed particles;

[0164] (5) Tablet core pressing: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to press the total mixed particles into tablets, and the tablet hardness is controlled to be no less than 1kg.

[0165] Example 7

[0166] Levetiracetam sustained-release microplate core

[0167] Prescription 7-1

[0168] The proportions in the prescription are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam).

[0169]

[0170]

[0171] Preparation method: fluidized bed granulation

[0172] (1) Adhesive preparation: Add the adhesive to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0173] (2) Fluidized bed granulation: Microcrystalline cellulose and levetiracetam are added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is reduced to a certain level.

[0174] ≤2%wt;

[0175] (3) Granulation: granulation by sieving;

[0176] (4) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0177] (5) Tablet core compression: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to compress the total mixed particles into tablets.

[0178] Prescription 7-2

[0179] The proportions in the prescription are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam).

[0180]

[0181] The preparation method of the levetiracetam sustained-release microtablet core in this prescription is the same as that in prescription 7-1.

[0182] Prescription 7-3

[0183] The proportions in the prescription are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam).

[0184]

[0185] The preparation method of the levetiracetam sustained-release microtablet core in this prescription is the same as that in prescription 7-1.

[0186] Performance testing of Levetiracetam sustained-release microtablet core formulations 1-7

[0187] (1)Tabletting situation, evaluation method: Tablet core formation, hardness ≥ 1 kg, friability ≤ 0.8%.

[0188] (2)Hardness test method: Take 10 tablet cores, place them in a tablet hardness tester, detect the hardness. If the hardness ≥ 1 kg, it is qualified. The model of the hardness tester is: YPD - 200C. When the hardness ≥ 1 kg: Record the maximum and minimum values of the hardness for the hardness range. When the hardness < 1 kg:

[0189] The hardness tester does not display the hardness value, record it as < 1 kg.

[0190] (3)Friability test method: Weigh 6.5 g of tablet cores, blow off the powder that has fallen off the tablet cores, weigh precisely, place them in a friability tester, rotate 100 times, remove the powder in the same way, weigh precisely again. The weight loss should not exceed 0.8%, and no broken, cracked or pulverized tablets should be detected. This test is generally only carried out once.

[0191]

[0192]

[0193] From the test results in the above table, it can be seen that the tablet cores of Formulation 5, Formulation 6 and Formulation 7 - 1, 7 - 2, 7 - 3 all have good compressibility, can be tableted smoothly, and have friability and hardness properties that meet the requirements. The content of the active ingredient levetiracetam in the unit dose of the micro - tablets of Formulation 5, Formulation 6 and Formulation 7 - 1, 7 - 2, 7 - 3 is 750 mg. When the components in Formulation 5, Formulation 6 and Formulation 7 - 1, 7 - 2, 7 - 3 are proportionally converted into tablet cores with a content of 500 mg of levetiracetam per unit dose, they also have good compressibility, can be tableted smoothly, and have friability and hardness properties that meet the requirements. It can be seen that the addition of povidone and microcrystalline cellulose makes the tablet core have good hardness and friability.

[0194] Example 8

[0195] Levetiracetam Sustained - Release Micro - Tablets

[0196] Formulation 8

[0197] The proportions in the formulation are based on the weight of the levetiracetam sustained - release micro - tablet core per unit dose (750 mg of levetiracetam). The weight gain of the coating layer in this example is 33 wt%. The composition of the micro - tablets is shown in the following table. Water is not included in the weight range.

[0198]

[0199]

[0200] Preparation method of levetiracetam sustained-release microtablets:

[0201] (1) Adhesive preparation: Add povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0202] (2) Fluidized bed granulation: Microcrystalline cellulose and levetiracetam are added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is reduced to a certain level.

[0203] ≤2%wt;

[0204] (3) Granulation: granulation by sieving;

[0205] (4) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0206] (5) Tablet core compression: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to compress the total mixed particles into tablets to obtain plain tablets;

[0207] (6) Preparation of coating solution: Add triethyl citrate and talc to purified water, homogenize with a homogenizer for 10 min, then add it to the quaternary ammonium methacrylate copolymer type B aqueous dispersion, stir for about 30 min and then pass through an 80 mesh sieve for later use;

[0208] (7) Fluidized bed coating: Add the tablets to a multi-functional granulation and coating machine for slow-release coating. The coating process ends when the target coating layer is reached.

[0209] Example 9

[0210] Levetiracetam Extended-Release Microtablets

[0211] Prescription 9

[0212] The proportions in the formulation are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam), and the weight gain of the coating layer in this example is 30 wt%. Water is not included in the weight range.

[0213]

[0214]

[0215] Preparation method of levetiracetam sustained-release microtablets:

[0216] (1) Adhesive preparation: Add povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0217] (2) Fluidized bed granulation: Microcrystalline cellulose and levetiracetam are added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is reduced to a certain level.

[0218] ≤2%wt;

[0219] (3) Granulation: granulation by sieving;

[0220] (4) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0221] (5) Tablet core compression: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to compress the total mixed particles into tablets to obtain plain tablets;

[0222] (6) Preparation of coating solution: Add hydroxypropyl methylcellulose to the prescribed amount of purified water, stir to dissolve it completely, and then mix it with ethyl cellulose aqueous dispersion to obtain sustained-release coating solution;

[0223] (7) Fluidized bed coating: Add the tablets to a multi-functional granulation and coating machine for slow-release coating. The coating process ends when the target coating layer is reached.

[0224] Example 10

[0225] Levetiracetam Extended-Release Microtablets

[0226] Prescription 10

[0227] The proportions in the formulation are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam), and the weight gain of the coating layer in this example is 10 wt%. Water is not included in the weight range.

[0228]

[0229]

[0230] Preparation method of levetiracetam sustained-release microtablets:

[0231] (1) Adhesive preparation: Add povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0232] (2) Fluidized bed granulation: Microcrystalline cellulose and levetiracetam are added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is reduced to a certain level.

[0233] ≤2%wt;

[0234] (4) Granulation: Granulation by sieving;

[0235] (5) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0236] (6) Tablet core compression: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to compress the total mixed particles into tablets to obtain plain tablets;

[0237] (7) Preparation of coating solution: Slowly add polyethylene glycol to the prescribed amount of purified water, stir until completely dissolved, and then mix with ethyl cellulose aqueous dispersion to obtain sustained-release coating solution;

[0238] (8) Fluidized bed coating: Add the tablets to a multi-functional granulation and coating machine for slow-release coating. The coating process ends when the target coating layer is reached.

[0239] Example 11

[0240] Levetiracetam Extended-Release Microtablets

[0241] Prescription 11

[0242] The proportions in the formulation are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam), and the weight gain of the coating layer in this example is 23 wt%. Water is not included in the weight range.

[0243]

[0244] Preparation method of levetiracetam sustained-release microtablets:

[0245] (1) Adhesive preparation: Add povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0246] (2) Fluidized bed granulation: Microcrystalline cellulose and levetiracetam are added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is reduced to a certain level.

[0247] ≤2%wt;

[0248] (3) Granulation: granulation by sieving;

[0249] (4) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0250] (5) Tablet core compression: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to compress the total mixed particles into tablets to obtain plain tablets;

[0251] (6) Preparation of coating solution: Hydroxypropyl methylcellulose is slowly added to the prescribed amount of purified water and stirred until it is completely dissolved. Then it is mixed with ethyl cellulose aqueous dispersion to obtain sustained-release coating solution.

[0252] (7) Fluidized bed coating: Add the tablets to a multi-functional granulation and coating machine for slow-release coating. The coating process ends when the target coating layer is reached.

[0253] Example 12

[0254] Levetiracetam Extended-Release Microtablets

[0255] Prescription 12

[0256] The proportions in the formulation are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam), and the weight gain of the coating layer in this example is 18 wt%. Water is not included in the weight range.

[0257]

[0258] Preparation method of levetiracetam sustained-release microtablets:

[0259] (1) Adhesive preparation: Add povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0260] (2) Fluidized bed granulation: Microcrystalline cellulose and levetiracetam are added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is ≤2%wt.

[0261] (3) Granulation: granulation by sieving;

[0262] (4) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0263] (5) Tablet core compression: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to compress the total mixed particles into tablets to obtain plain tablets;

[0264] (6) Preparation of coating solution: Add hydroxypropyl methylcellulose to the prescribed amount of purified water, stir to dissolve it completely, and then mix it with ethyl cellulose aqueous dispersion to obtain sustained-release coating solution;

[0265] (7) Fluidized bed coating: Add the tablets to a multi-functional granulation and coating machine for slow-release coating. The coating process ends when the target coating layer is reached.

[0266] Example 13

[0267] Levetiracetam Extended-Release Microtablets

[0268] Prescription 13

[0269] The proportions in the formulation are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam), and the weight gain of the coating layer in this example is 20 wt%. Water is not included in the weight range.

[0270]

[0271] Preparation method of levetiracetam sustained-release microtablets:

[0272] (1) Adhesive preparation: Slowly add the prescribed amount of povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0273] (2) Fluidized bed granulation: Add the prescribed amount of microcrystalline cellulose and levetiracetam to a multi-functional granulation and coating machine, spray in the binder solution to granulate, and after granulation, dry the granules until the moisture content is ≤2%wt.

[0274] (3) Granulation: granulation by sieving;

[0275] (4) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0276] (5) Tablet core compression: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to compress the total mixed particles into tablets to obtain plain tablets;

[0277] (6) Preparation of coating solution: Add hydroxypropyl methylcellulose to the prescribed amount of purified water, stir to dissolve it completely, and then mix it with ethyl cellulose aqueous dispersion to obtain sustained-release coating solution;

[0278] (7) Fluidized bed coating: Add the tablets to a multi-functional granulation and coating machine for slow-release coating. The coating process ends when the target coating layer is reached.

[0279] Example 14

[0280] Levetiracetam Extended-Release Microtablets

[0281] Prescription 14

[0282] The proportions in the formulation are based on the weight of the levetiracetam sustained-release microtablet core per unit dose (750 mg levetiracetam), and the weight gain of the coating layer in this example is 16 wt%. Water is not included in the weight range.

[0283]

[0284] Preparation method of levetiracetam sustained-release microtablets:

[0285] (1) Adhesive preparation: Slowly add the prescribed amount of povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0286] (2) Fluidized bed granulation: Add the prescribed amount of microcrystalline cellulose and levetiracetam to a multi-functional granulation and coating machine, spray in the binder solution to granulate, and after granulation, dry the granules until the moisture content is ≤2%wt.

[0287] (3) Granulation: granulation by sieving;

[0288] (4) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0289] (5) Tablet core compression: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to compress the total mixed particles into tablets to obtain plain tablets;

[0290] (6) Preparation of coating solution: Add hydroxypropyl methylcellulose to the prescribed amount of purified water, stir to dissolve it completely, and then mix it with ethyl cellulose aqueous dispersion to obtain sustained-release coating solution;

[0291] (7) Fluidized bed coating: Add the tablets to a multi-functional granulation and coating machine for slow-release coating. The coating process ends when the target coating layer is reached.

[0292] Performance testing of Levetiracetam Extended-Release Microtablet Formulation 8-14

[0293] Specific methods for dissolution performance testing: according to USP <711> (Instrument: basket method, 100 rpm, pH 6.0 medium, 900 ml) Dissolution test was performed on the levetiracetam sustained-release microtablets obtained from formulations 8-14.

[0294]

[0295] Formula 8, with its sustained-release coating material, showed no sustained-release effect. Formula 9, with the addition of hydroxypropyl methylcellulose as a pore-forming agent, failed to release the active ingredient levetiracetam due to its small proportion of pore-forming agent. Formula 10, even after changing the pore-forming agent to polyethylene glycol, still exhibited a slow release curve. Formula 11, with 50% hydroxypropyl methylcellulose as a pore-forming agent, lacked the sustained-release effect of tablets. Formulas 12, 13, and 14 all achieved good release and sustained-release effects, meeting the dissolution limit. This indicates that when the sustained-release coating material is an aqueous dispersion of ethyl cellulose, the pore-forming agent is hydroxypropyl methylcellulose, and the mass ratio of the aqueous dispersion of ethyl cellulose to hydroxypropyl methylcellulose is 3–6:1, and the mass of the aqueous dispersion of ethyl cellulose is based on solid content, the prepared levetiracetam sustained-release microtablets exhibit a smooth and prolonged dissolution rate. To maintain a consistent in vitro release profile with the original drug, levetiracetam extended-release tablets, the inventors set the dissolution limit standards as follows: 1h ≤ 35%, 3h 50%–75%, and 12h ≥ 80%.

[0296] Example 15

[0297] Levetiracetam Extended-Release Microtablets

[0298] Prescription 13

[0299] The proportions in the formulation are based on the weight of the levetiracetam sustained-release microtablet core, and the weight gain of the coating layer in this embodiment is 20%. Water is not included in the weight range.

[0300]

[0301] Preparation method of levetiracetam sustained-release microtablets:

[0302] (1) Adhesive preparation: Add povidone to purified water, stir to dissolve, and prepare an adhesive solution with a concentration of 10wt%;

[0303] (2) Fluidized bed granulation: Microcrystalline cellulose and levetiracetam are added to a multi-functional granulation and coating machine, and a binder solution is sprayed in for granulation. After granulation, the granules are dried until the moisture content is ≤2%wt.

[0304] (3) Granulation: granulation by sieving;

[0305] (4) Mixing: Mix the granulated particles with magnesium stearate to obtain the mixed particles;

[0306] (5) Tablet core compression: A rotary tablet press with a multi-punch micro-die with a diameter of 1.7mm is used to compress the total mixed particles into tablets to obtain plain tablets;

[0307] (6) Preparation of coating solution: Add hydroxypropyl methylcellulose to the prescribed amount of purified water, stir to dissolve it completely, and then mix it with ethyl cellulose aqueous dispersion to obtain sustained-release coating solution;

[0308] (7) Fluidized bed coating: The tablets are added to a multi-functional granulation and coating machine for sustained-release coating. The coating is stopped when the target coating layer is reached, and levetiracetam sustained-release coated micro tablets are obtained.

[0309] (8) The levetiracetam sustained-release coated microtablets were cured in an oven at 60°C for 24 hours to obtain stable levetiracetam sustained-release coated microtablets.

[0310] Dissolution performance test

[0311] According to USP <711> (Instrument: basket method, 100 rpm, pH 6.0 medium, 900 ml) The dissolution characteristics of the levetiracetam sustained-release microtablets obtained in Example 13 and Example 15 were compared, and the comparison results are shown below.

[0312]

[0313] The results showed that dissolution accelerated after heating and curing, indicating that the coated microplates were unstable before curing. Therefore, curing is necessary during the preparation of levetiracetam sustained-release microplates to improve their stability.

[0314] Example 16

[0315] Levetiracetam Extended-Release Microtablets

[0316] The weight gain ratio of the coating layer and the ratio in the formulation were based on the weight of the levetiracetam sustained-release microtablet core. The release behavior of levetiracetam sustained-release microtablets with different coating layer weight gains (weight ratio between ethyl cellulose aqueous dispersion and hydroxypropyl methylcellulose = 4.6:1, the weight of the ethyl cellulose aqueous dispersion is based on solid content) was investigated. The formulation composition is as follows.

[0317]

[0318] The preparation method of the levetiracetam sustained-release microtablets with 25% and 30% weight gain of the coating layer in this embodiment is the same as the preparation method in Example 15.

[0319] According to USP <711> (Instrument: basket method, 100 rpm, pH 6.0 medium, 900 ml) The in vitro dissolution and release characteristics of levetiracetam sustained-release microtablets with coating weight increases of 20%, 25%, and 30% are compared as follows.

[0320]

[0321]

[0322] The results showed that the weight gain of the coating layer of 20%, 25%, and 30% met the standard limits.

[0323] Example 17

[0324] Levetiracetam Extended-Release Microtablets

[0325] The weight gain ratio of the coating layer and the ratio in the formulation were based on the weight of the levetiracetam sustained-release microtablet core. The release behavior of levetiracetam sustained-release microtablets with different coating layer weight gains (weight ratio between ethyl cellulose aqueous dispersion and hydroxypropyl methylcellulose 5.2-5.3:1, the weight of the ethyl cellulose aqueous dispersion being based on solid content) was investigated. The formulation composition is as follows.

[0326]

[0327]

[0328] The preparation method of the levetiracetam sustained-release microtablets with coating weight increases of 15%, 17%, and 20% in this embodiment is the same as that in Example 15.

[0329] Dissolution profiles were analyzed for coated microflakes with weight gains of 15%, 17%, and 20% coating layers, according to USP. <711> (Instrument: basket method, 100 rpm, pH 6.0 medium, 900 ml), the dissolution results are shown below.

[0330]

[0331] Note: The above dissolution curve data were obtained using solidified coated microfilms.

[0332] The results showed that the weight gain of the coating layer of 15% to 20% met the standard limit requirements, and the levetiracetam sustained-release microtablets could still have a stable and long-lasting sustained-release dissolution effect even with the use of less coating excipients.

[0333] (2) The sample with a coating weight gain of 17% in this embodiment was placed under accelerated conditions (40℃ / 75%RH) for 3 months and under long-term test conditions (30℃ / 65%RH) for 3 months, according to USP <711> (Instrument: basket method, 100rpm, pH 6.0 medium, 900ml) To investigate the trend of dissolution.

[0334]

[0335]

[0336] The results showed that the dissolution rate of the samples did not change significantly under different conditions and remained within the limits, proving that the product quality was stable.

[0337] (3) The sample with a coating weight gain of 17% in this embodiment was placed under accelerated conditions (40℃ / 75%RH) for 3 months and under long-term test conditions (30℃ / 65%RH) for 3 months to investigate the change trend of related substances. The results are as follows.

[0338] condition Maximum single impurity (%) Total impurities (%) limit(%) ≤0.1 ≤1.0 October 0.010 0.020 Accelerate January 0.020 0.030 Accelerate February 0.020 0.040 Accelerate March 0.018 0.033 Long-term 3 months 0.014 0.040

[0339] The results show that the relevant substances in the sample did not change significantly at different times, and all remained within the limits, proving that the product quality was stable.

[0340] Example 18

[0341] The levetiracetam sustained-release microtablets in this implementation (the proportion of weight gain of the coating layer and the proportion in the prescription are calculated based on the weight of the unit-dose tablet core of the levetiracetam sustained-release microtablets) were prepared according to the method in Example 15. The prescription of the levetiracetam sustained-release microtablets is shown in the following table, and the hardness (average value of 10 tablets), friability, and dissolution performance of the prepared levetiracetam were tested.

[0342]

[0343]

[0344] The change trend of dissolution was investigated according to USP<711> (apparatus: basket method, 100 rpm, pH 6.0 medium, 900 ml).

[0345]

[0346] Animal experiment

[0347] Specific animal information: Gender: half male and half female, Quantity: 12 in total, Weight range: 7 - 8 (female) / 8 - 10 (male), Age: 12 - 15 months, Source: Mas Biotechnology (Gu'an) Co., Ltd., Quality certificate number: NO.2024028, Production license number: SCXK(Ji)2024 - 001, Use license number: SYXK(Xiang)2024 - 0002, Feeding address: Animal house of Hunan Hengxing Ruisi Pharmaceutical Technology Co., Ltd.

[0348] Animal experiment method: After intragastric administration of the control preparation (levetiracetam sustained-release tablets, trade name: KEPPRA Batch number: 918802, Specification: 750 mg, Expiry date: 2026.09, License holder: UCB INC) and the self-made preparation (levetiracetam sustained-release microtablets with a specification of 750 mg in Example 18) to beagle dogs in a two-period crossover manner, plasma was collected, and the concentration of levetiracetam in the plasma of beagle dogs was determined using a validated LC-MS / MS analytical method, and its pharmacokinetic parameters were calculated, and then the pharmacokinetic characteristics of levetiracetam in the beagle dogs for the levetiracetam sustained-release tablets and the self-made preparation were evaluated and compared.

[0349] Animal experiment process: In this experiment, 12 animals were used for the experiment, divided into 2 groups (6 animals in each group, half male and half female), and administered in a two-period crossover manner. The animal groups and administration information are as follows:

[0350]

[0351] Twelve Beagles, half male and half female, were divided into two groups, G1 and G2, according to the table above, with three males (M) and three females (F) in each group. The self-prepared formulation and the control formulation were administered via double-cycle crossover gavage. After a 7-day washout period following the first cycle of administration, the second cycle of administration was administered. All animals were fasted overnight (10–14 hours) before administration, with free access to water. Administration was done on an empty stomach, and feeding was given 4 hours after administration.

[0352] On the day of the experiment, animal weight was measured and recorded. All animals were given 15 mL of water orally after administration, and the dosage and plasma sample collection time for each animal were recorded. Approximately 1 mL of whole blood was collected from the forelimb vein or other suitable site from all animals before administration (0 h) and at 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, and 34 h after administration, and placed in heparin sodium anticoagulant tubes. All whole blood samples were centrifuged in an ice-water bath for 2 hours (centrifugation conditions: 3500 g, 6 min, 4 °C) to separate plasma. All samples were stored in an ultra-low temperature freezer and transported to the main research site under dry ice conditions. The concentration of levetiracetam in beagle plasma was determined using a validated LC-MS / MS analytical method.

[0353] Terminal half-life: T 1 / 2 Time to peak plasma concentration: Tmax; Peak plasma concentration: Cmax; Area under the plasma concentration-time curve from 0 to 34 h (plasma exposure from 0 to 34 h): AUC0-t; Area under the plasma concentration-time curve from 0 to infinity (plasma exposure from 0 to infinity): AUC0-inf; Liquid chromatography-tandem mass spectrometry: LC-MS / MS; Drug residence time in vivo: MRTInf.

[0354] After two cycles of alternating gavage administration of the self-prepared formulation, the mean half-life (T1 / 2) of levetiracetam in beagle dog plasma was 3.43±0.501 h, the mean time to peak plasma concentration (Tmax) was 4.33±0.778 h, the mean peak plasma concentration (Cmax) was 59.5±4.74 μg / mL, the mean plasma exposure (AUC0-t) was 515±52.0 h*μg / mL, and the mean plasma exposure (AUC0-inf) was 516±52.2 h*μg / mL.

[0355] After two cycles of cross-administration of the control formulation, the mean half-life (T1 / 2) of levetiracetam in beagle dog plasma was 3.53±0.874 h, the mean Tmax was 2.92±1.44 h, the mean Cmax was 57.1±11.8 μg / mL, the mean plasma exposure (AUC0-t) was 514±80.5 h*μg / mL, and the mean plasma exposure (AUC0-inf) was 516±80.5 h*μg / mL.

[0356] After beagles were administered the self-prepared formulation and the control formulation, the T-test results for the main pharmacokinetic parameters of levetiracetam in plasma of both groups of beagles were P≥0.05. This indicates that after two-cycle crossover gavage administration of the self-prepared formulation and the control formulation, there were no significant differences in T1 / 2, Cmax, MRTINf, AUC0-t, and AUC0-inf in the plasma of beagles, and they were essentially the same, as shown in the table below:

[0357]

[0358]

[0359] #: The probability value of the statistical test. T.TEST (two-tailed, paired two-sample) is used to test whether there is a significant difference between two paired comparison groups. P ≥ 0.05 indicates no significant difference; otherwise, there is a significant difference.

[0360] The animal experiments above show that the levetiracetam sustained-release microtablets prepared in this invention have the same in vivo blood drug concentration as commercially available levetiracetam sustained-release tablets. Furthermore, the levetiracetam sustained-release microtablets of this invention exhibit better medication adherence.

Claims

1. A levetiracetam sustained-release microtablet, characterized in that, The tablet comprises a tablet core and a coating layer covering the tablet core. The tablet core includes the active ingredient levetiracetam and pharmaceutical excipients, wherein the pharmaceutical excipients include binders and / or fillers.

2. The levetiracetam sustained-release microtablets according to claim 1, characterized in that, The tablet core comprises the following components by weight fraction: 50%–85% levetiracetam, 1%–25% binder, and 2%–45% filler.

3. The levetiracetam sustained-release microtablets according to claim 2, characterized in that, The adhesive is selected from at least one of the following: povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, gum arabic, gelatin, shellac, pectin, polypropylene glycol-polyoxyethylene block copolymer, and dextrin.

4. The levetiracetam sustained-release microtablets according to claim 3, characterized in that, The adhesive is selected from at least one of polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

5. The levetiracetam sustained-release microtablets according to claim 1, characterized in that, The chip core also includes a lubricant, which accounts for 0 to 5% of the total weight of the chip core.

6. The levetiracetam sustained-release microtablets according to claim 5, characterized in that, The tablet core also includes a flow aid, which accounts for 0 to 5% of the total weight of the tablet core.

7. The levetiracetam sustained-release microtablets according to claim 1, characterized in that, The friability of the chip core is ≤0.8%.

8. The levetiracetam sustained-release microtablets according to claim 1, characterized in that, The hardness of the core material is ≥1kg.

9. The levetiracetam sustained-release microtablets according to claim 6, characterized in that, Based on the total weight of the tablet core, the tablet core comprises the following components in the following weight fractions: 50%–85% levetiracetam, 2%–45% filler, 1%–25% binder, 0%–5% lubricant, and 0%–5% flow aid.

10. The levetiracetam sustained-release microtablets according to claim 6, characterized in that, Based on the total weight of the tablet core, the tablet core comprises the following components in the following weight fractions: 65%–80% levetiracetam, 6%–40% filler, 2%–18% binder, 0%–3% lubricant, and 0%–2% flow aid.

11. The levetiracetam sustained-release microtablets according to claim 1, characterized in that, The coating layer includes a sustained-release coating material and a pore-forming agent, wherein the weight ratio of the sustained-release coating material to the pore-forming agent is 3 to 6:

1.

12. The levetiracetam sustained-release microtablets according to claim 11, characterized in that, The weight gain of the coating layer is 5% to 40% based on the total weight of the core.

13. The levetiracetam sustained-release microtablets according to claim 12, characterized in that, The sustained-release coating material is selected from at least one of ethyl cellulose, ethyl cellulose aqueous dispersion, ammonium methacrylate alkyl acrylate copolymer, and ethyl acrylate methyl methacrylate polymer, and the pore-forming agent is selected from at least one of hydroxypropyl methylcellulose, polyethylene glycol, and lactose.

14. The levetiracetam sustained-release microtablets according to claim 12, characterized in that, The weight of levetiracetam in a unit dose of levetiracetam extended-release tablets is 750 mg or 500 mg.

15. The levetiracetam sustained-release microtablets according to claim 12, characterized in that, The levetiracetam sustained-release microtablets are circular, with a diameter of 1.5–2.5 mm and a thickness of 1.5–2.5 mm.

16. Use of the levetiracetam extended-release microtablets according to any one of claims 1-15 in the preparation of an antiepileptic drug.

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