Levetiracetam sustained-release granules and a preparation process thereof

Abstract

The application discloses a levetiracetam sustained-release granule and a preparation process thereof, and relates to the technical field of pharmaceutical preparations. Specifically, the preparation process comprises the following steps: S1, preparing levetiracetam active granules; S2, preparing a transition coating liquid and a sustained-release coating liquid; and S3, sequentially performing transition layer and sustained-release layer coating on the levetiracetam active granules to obtain the levetiracetam sustained-release granules. The transition coating liquid is prepared by mixing the following raw material components in parts by weight: 3-5 parts of sodium alginate, 1-1.5 parts of a plasticizer and 100 parts of purified water; the molecular weight of the sodium alginate is 50000-100000; the sustained-release coating liquid is prepared by mixing the following raw material components in parts by weight: 5-8 parts of silicon dioxide modified chitosan, 3-5 parts of sodium alginate, 1.5-3 parts of a plasticizer and 200 parts of purified water; and the molecular weight of the sodium alginate is 150000-200000.

Description

Technical Field

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

[0002] Levetiracetam is a second-generation acetylcholine agonist developed by UCB in Belgium. It is a pyrrolidone derivative used to treat focal and secondary generalized epilepsy. Currently, levetiracetam tablets (0.25g, 0.5g, 1g), levetiracetam oral solution (10%, 150mL / bottle), and levetiracetam extended-release tablets (0.5g, 0.75g) are available in China. However, levetiracetam extended-release tablets are only suitable for children over 12 years of age and adults, and should be swallowed whole. Each tablet weighs approximately 750mg and is not suitable for patients or children with swallowing difficulties.

[0003] Based on this, the present invention specifically develops a levetiracetam sustained-release granule, which facilitates dosage adjustment and is more suitable for children and elderly patients with swallowing difficulties. Utilizing advanced coating technology, a sustained-release layer is encapsulated outside the unit cell, resulting in a better taste, fewer toxic side effects, better in vivo absorption, and absorption unaffected by food. This allows for once-daily dosing, improves patient compliance, fills a gap in the domestic market, and is of significant importance. Summary of the Invention

[0004] The purpose of this invention is to provide levetiracetam sustained-release granules and its preparation process to solve the problems mentioned in the background art.

[0005] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0006] A process for preparing levetiracetam sustained-release granules includes the following steps:

[0007] S1: Add levetiracetam, filler, binder, and purified water into a mixer and stir at 150-200 rpm for 10-20 minutes to ensure that the mixing degree RSD of the mixture is <3.0%; after processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add a flow aid for total mixing to obtain levetiracetam active granules;

[0008] S2: Preparation of transition coating solution and sustained-release coating solution:

[0009] S21: Mix sodium alginate, plasticizer, and purified water evenly to obtain a transition coating solution;

[0010] S22: Mix silica-modified chitosan, sodium alginate, plasticizer, and purified water evenly to obtain a sustained-release coating solution;

[0011] S3: Perform transition layer coating and sustained-release layer coating:

[0012] S31: After preheating the levetiracetam active particles, transfer them into a coating pan, atomize and spray the transition coating solution onto the levetiracetam active particles, and vacuum dry them at 60°C until the water content is ≤2wt% to form a transition layer.

[0013] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, and vacuum dry at 60°C until the water content is ≤2wt% to form a sustained-release layer, thus obtaining levetiracetam sustained-release particles.

[0014] Furthermore, the preparation of the levetiracetam active particles includes the following raw material components in parts by weight: 20 parts levetiracetam, 30-40 parts filler, 6-10 parts binder, 1-1.5 parts flow aid, and 10-15 parts purified water.

[0015] Furthermore, the filler is microcrystalline cellulose; the binder is polyvinyl ketone K30; and the flow aid is silica.

[0016] Further, the transition coating solution is prepared by mixing the following raw material components in parts by weight: 3-5 parts sodium alginate, 1-1.5 parts plasticizer, and 100 parts purified water; wherein the molecular weight of sodium alginate is 50,000-100,000.

[0017] Furthermore, the preparation method of the silica-modified chitosan is as follows:

[0018] (1) Add silica and 3-mercaptopropyltriethoxysilane to a 75wt% aqueous ethanol solution, add acetic acid to adjust the pH to 5-6, ultrasonically disperse for 10-30 min, filter, wash and dry to obtain mercapto-modified silica;

[0019] (2) Chitosan was added to a 5 wt% acetic acid solution and stirred to dissolve, thus obtaining a chitosan solution; (Z)-14-methyl-8-hexadecene-1-acetal was added to tetrahydrofuran and stirred to dissolve, thus obtaining a (Z)-14-methyl-8-hexadecene-1-acetal solution.

[0020] (3) At 30~50℃, (Z)-14-methyl-8-hexadecene-1-acetal solution was slowly added dropwise to chitosan solution while stirring. After the addition was completed, the reaction was continued to be stirred for 12~24h. The reaction was then stopped. Excess anhydrous ethanol was added to precipitate the precipitate. The precipitate was filtered, washed, and dried to obtain acetal-modified chitosan.

[0021] (4) Add mercapto-modified silica, acetal-modified chitosan, and photoinitiator to tetrahydrofuran, and stir at a concentration of 100~120 mW / cm 2 The reaction was initiated by ultraviolet light with high intensity and lasted for 1-2 hours, after which the reaction was terminated.

[0022] (5) Add 2,3-epoxypropyltrimethylammonium chloride aqueous solution to the reaction solution in (4), stir and heat to 60~70℃, stir and react for 6~12h, stop the reaction, filter, wash and dry to obtain silica-modified chitosan.

[0023] Furthermore, the ratio of silicon dioxide, 3-mercaptopropyltriethoxysilane, and aqueous ethanol solution is 1g:(0.5~1)g:100mL.

[0024] Furthermore, the ratio of chitosan, acetic acid solution, (Z)-14-methyl-8-hexadecene-1-acetal, and tetrahydrofuran is 1g:100mL:(0.2~0.5)g:20mL.

[0025] Furthermore, the degree of deacetylation of the chitosan is ≥85%.

[0026] Furthermore, the ratio of the mercapto-modified silica, acetal-modified chitosan, photoinitiator, and tetrahydrofuran is 1g:(5~10)g:(0.06~0.1)g:100mL.

[0027] Furthermore, the amount of 2,3-epoxypropyltrimethylammonium chloride added is 2-4% of the mass of acetal-modified chitosan.

[0028] In this invention, 3-mercaptopropyltriethoxysilane is first used to modify silica to obtain mercapto-modified silica; then (Z)-14-methyl-8-hexadecene-1-acetal is used to modify and graft chitosan, and the two are combined through a Schiff base structure to obtain acetal-modified chitosan; then, after the mercapto-modified silica and acetal-modified chitosan undergo a click reaction, they are further reacted with 2,3-epoxypropyltrimethylammonium chloride to undergo nucleophilic ring-opening to prepare silica-modified chitosan.

[0029] Furthermore, the sustained-release coating solution is prepared by mixing the following raw material components in parts by weight: 5-8 parts of silica-modified chitosan, 3-5 parts of sodium alginate, 1.5-3 parts of plasticizer, and 200 parts of purified water; wherein the molecular weight of sodium alginate is 150,000-200,000.

[0030] Furthermore, the plasticizer is triethyl citrate.

[0031] Furthermore, the parameters for the atomization spraying are: atomization pressure of 0.15~0.3MPa, spraying temperature of 50~60℃, spraying speed of 2~5mL / min, and coating pan rotation speed of 10~15r / min.

[0032] Furthermore, the transition layer is weighted by 2-5 wt%.

[0033] Furthermore, the sustained-release layer increases in weight by 4-8 wt%.

[0034] Furthermore, the levetiracetam sustained-release granules are packaged in bags; each bag contains 200 mg or 500 mg of levetiracetam.

[0035] Furthermore, the daily intake of levetiracetam should not exceed 1g in the first week; 2g in the second week; and 3g in the third week; with a maximum recommended dose of 3g / day.

[0036] Compared with the prior art, the beneficial effects achieved by the present invention are:

[0037] (1) This invention employs a multi-layered microparticle structure. First, a sodium alginate transition layer is formed on the levetiracetam active particles, and then a sustained-release layer is formed on the transition layer. The sustained-release layer uses sodium alginate with a molecular weight of 150,000-200,000, which has high viscosity and can synergistically form a dense sustained-release layer with silica-modified chitosan, thus stabilizing the sustained release. The transition layer uses sodium alginate with a molecular weight of 50,000-100,000, which has a lower molecular weight and better film-forming properties, providing a stable substrate for the subsequent sustained-release layer and also controlling the release. Through the synergistic effect of the transition layer and the sustained-release layer, stable and precise drug release within 24 hours is achieved.

[0038] (2) In this invention, the (Z)-14-methyl-8-hexadecene-1-acetal long-chain olefin introduced on chitosan enhances its hydrophobicity, thereby reducing the permeability of water molecules, preventing chitosan from swelling, greatly improving the stability of the drug, and to a certain extent achieving a sustained-release effect; further, silica is introduced, which can form a physical barrier and delay the diffusion of levetiracetam, and can further synergistically delay the release cycle of levetiracetam with acetal-modified chitosan.

[0039] (3) In this invention, an appropriate amount of 2,3-epoxypropyltrimethylammonium chloride is further added to introduce a quaternary ammonium salt structure onto chitosan; the quaternary ammonium salt structure is positively charged and can form a tight ionic bond network structure with sodium alginate through electrostatic adsorption, thereby enhancing the encapsulation ability of levetiracetam active particles and playing a role in delaying the release cycle of levetiracetam.

[0040] In summary, this invention prepares a long-acting, highly stable levetiracetam sustained-release particle through multi-layered microsphere encapsulation. Detailed Implementation

[0041] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0042] It should be noted that the following quantities are by weight, and there are no special restrictions on the suppliers of all raw materials involved in this invention. Exemplary examples include:

[0043] In the following examples, microcrystalline cellulose, povidone K30, and triethyl citrate were all purchased from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd.

[0044] Chitosan with a degree of deacetylation of 85%; 2,3-epoxypropyltrimethylammonium chloride; sodium alginate; all were purchased from Shanghai Changwei Pharmaceutical Excipients Technology Co., Ltd.

[0045] (Z)-14-methyl-8-hexadecene-1-acetal, CAS No. 60609-53-2, was purchased from Shanghai Youhe Biotechnology Co., Ltd.

[0046] 3-Mercaptopropyltriethoxysilane; photoinitiator 1173; both purchased from Hubei Qifei Pharmaceutical Chemical Co., Ltd.; the silica was colloidal silica.

[0047] All other ingredients were purchased commercially; each serving is 10g.

[0048] Example 1: A preparation process for levetiracetam sustained-release granules:

[0049] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0050] S2: Preparation of transition coating solution and sustained-release coating solution:

[0051] S21: Mix 4 parts sodium alginate (molecular weight approximately 70,000), 1.25 parts triethyl citrate, and 100 parts purified water thoroughly to obtain a transition coating solution;

[0052] S22-1: Preparation of silica-modified chitosan: (1) Add 2 parts silica and 1.5 parts 3-mercaptopropyltriethoxysilane to 2L of 75wt% ethanol aqueous solution, add acetic acid to adjust the pH to 5.5, ultrasonically disperse for 20min, filter, wash, and dry to obtain mercapto-modified silica; (2) Add 10 parts chitosan to 10L of 5wt% acetic acid solution, stir to dissolve, and obtain chitosan solution; add 4 parts (Z)-14-methyl-8-hexadecene-1-acetal to 2L of tetrahydrofuran, stir to dissolve, and obtain (Z)-14-methyl-8-hexadecene-1-acetal. (3) At 40°C, the (Z)-14-methyl-8-hexadecene-1-acetal solution was slowly added dropwise to the chitosan solution while stirring. After the addition was complete, the reaction was continued for 18 hours. The reaction was then stopped, and excess anhydrous ethanol was added to precipitate the precipitate. The precipitate was filtered, washed, and dried to obtain acetal-modified chitosan. (4) 1 part of mercapto-modified silica, 8 parts of acetal-modified chitosan, and 0.08 parts of photoinitiator 1173 were added to 1 L of tetrahydrofuran. The mixture was stirred at 110 mW / cm 2 The reaction was initiated by ultraviolet light with high intensity for 1.5 h, and the reaction was terminated; (5) 2,3-epoxypropyltrimethylammonium chloride aqueous solution (0.24 parts of 2,3-epoxypropyltrimethylammonium chloride and 200 mL of deionized water were added to the reaction solution in (4), the temperature was raised to 65℃ by stirring, the reaction was carried out for 8 h, the reaction was terminated, and after filtration, washing and drying, silica-modified chitosan was obtained;

[0053] S22-2: Mix 7 parts silica-modified chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0054] S3: Perform transition layer coating and sustained-release layer coating:

[0055] S31: After preheating the levetiracetam active particles to 55°C, place them in a coating pan and atomize the transition coating solution onto the levetiracetam active particles using process parameters of 0.2 MPa atomization pressure, 55°C spraying temperature, 4 mL / min spraying speed, and 13 r / min rotation speed. Then, vacuum dry at 60°C until the moisture content is ≤2 wt%, forming a transition layer with a weight gain of 3 wt%.

[0056] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, vacuum dry at 60°C until the water content is ≤2wt%, forming a sustained-release layer, increasing the weight by 6wt%, to obtain levetiracetam sustained-release particles, package them, each bag containing 200mg of levetiracetam.

[0057] Example 2: A preparation process for levetiracetam sustained-release granules:

[0058] Example 2 adjusted the ratio of the amounts of thiol-modified silica and acetal-modified chitosan.

[0059] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0060] S2: Preparation of transition coating solution and sustained-release coating solution:

[0061] S21: Mix 4 parts sodium alginate (molecular weight approximately 70,000), 1.25 parts triethyl citrate, and 100 parts purified water thoroughly to obtain a transition coating solution;

[0062] S22-1: Preparation of silica-modified chitosan: (1) Add 2 parts silica and 1.5 parts 3-mercaptopropyltriethoxysilane to 2L of 75wt% ethanol aqueous solution, add acetic acid to adjust the pH to 5.5, ultrasonically disperse for 20min, filter, wash, and dry to obtain mercapto-modified silica; (2) Add 10 parts chitosan to 10L of 5wt% acetic acid solution, stir to dissolve, and obtain chitosan solution; add 4 parts (Z)-14-methyl-8-hexadecene-1-acetal to 2L of tetrahydrofuran, stir to dissolve, and obtain (Z)-14-methyl-8-hexadecene-1-acetal. (3) At 40°C, the (Z)-14-methyl-8-hexadecene-1-acetal solution was slowly added dropwise to the chitosan solution while stirring. After the addition was complete, the reaction was continued for 18 hours. The reaction was then stopped, and excess anhydrous ethanol was added to precipitate the precipitate. The precipitate was filtered, washed, and dried to obtain acetal-modified chitosan. (4) 2 parts of mercapto-modified silica, 10 parts of acetal-modified chitosan, and 0.08 parts of photoinitiator 1173 were added to 1 L of tetrahydrofuran. The mixture was stirred at 110 mW / cm 2 The reaction was initiated by ultraviolet light with high intensity for 1.5 h, and the reaction was terminated; (5) 2,3-epoxypropyltrimethylammonium chloride aqueous solution (0.24 parts of 2,3-epoxypropyltrimethylammonium chloride and 200 mL of deionized water were added to the reaction solution in (4), the temperature was raised to 65℃ by stirring, the reaction was carried out for 8 h, the reaction was terminated, and after filtration, washing and drying, silica-modified chitosan was obtained;

[0063] S22-2: Mix 7 parts silica-modified chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0064] S3: Perform transition layer coating and sustained-release layer coating:

[0065] S31: After preheating the levetiracetam active particles to 55°C, place them in a coating pan and atomize the transition coating solution onto the levetiracetam active particles using process parameters of 0.2 MPa atomization pressure, 55°C spraying temperature, 4 mL / min spraying speed, and 13 r / min rotation speed. Then, vacuum dry at 60°C until the moisture content is ≤2 wt%, forming a transition layer with a weight gain of 3 wt%.

[0066] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, vacuum dry at 60°C until the water content is ≤2wt%, forming a sustained-release layer, increasing the weight by 6wt%, to obtain levetiracetam sustained-release particles, package them, each bag containing 200mg of levetiracetam.

[0067] Example 3: A preparation process for levetiracetam sustained-release granules:

[0068] Example 3 adjusted the ratio of the amounts of thiol-modified silica and acetal-modified chitosan.

[0069] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0070] S2: Preparation of transition coating solution and sustained-release coating solution:

[0071] S21: Mix 4 parts sodium alginate (molecular weight approximately 70,000), 1.25 parts triethyl citrate, and 100 parts purified water thoroughly to obtain a transition coating solution;

[0072] S22-1: Preparation of silica-modified chitosan: (1) Add 2 parts silica and 1.5 parts 3-mercaptopropyltriethoxysilane to 2L of 75wt% ethanol aqueous solution, add acetic acid to adjust the pH to 5.5, ultrasonically disperse for 20min, filter, wash, and dry to obtain mercapto-modified silica; (2) Add 10 parts chitosan to 10L of 5wt% acetic acid solution, stir to dissolve, and obtain chitosan solution; add 4 parts (Z)-14-methyl-8-hexadecene-1-acetal to 2L of tetrahydrofuran, stir to dissolve, and obtain (Z)-14-methyl-8-hexadecene-1-acetal. (3) At 40°C, the (Z)-14-methyl-8-hexadecene-1-acetal solution was slowly added dropwise to the chitosan solution while stirring. After the addition was complete, the reaction was continued for 18 hours. The reaction was then stopped, and excess anhydrous ethanol was added to precipitate the precipitate. The precipitate was filtered, washed, and dried to obtain acetal-modified chitosan. (4) 1 part of mercapto-modified silica, 10 parts of acetal-modified chitosan, and 0.08 parts of photoinitiator 1173 were added to 1 L of tetrahydrofuran. The mixture was stirred at 110 mW / cm 2 The reaction was initiated by ultraviolet light with high intensity for 1.5 h, and the reaction was terminated; (5) 2,3-epoxypropyltrimethylammonium chloride aqueous solution (0.24 parts of 2,3-epoxypropyltrimethylammonium chloride and 200 mL of deionized water were added to the reaction solution in (4), the temperature was raised to 65℃ by stirring, the reaction was carried out for 8 h, the reaction was terminated, and after filtration, washing and drying, silica-modified chitosan was obtained;

[0073] S22-2: Mix 7 parts silica-modified chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0074] S3: Perform transition layer coating and sustained-release layer coating:

[0075] S31: After preheating the levetiracetam active particles to 55°C, place them in a coating pan and atomize the transition coating solution onto the levetiracetam active particles using process parameters of 0.2 MPa atomization pressure, 55°C spraying temperature, 4 mL / min spraying speed, and 13 r / min rotation speed. Then, vacuum dry at 60°C until the moisture content is ≤2 wt%, forming a transition layer with a weight gain of 3 wt%.

[0076] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, vacuum dry at 60°C until the water content is ≤2wt%, forming a sustained-release layer, increasing the weight by 6wt%, to obtain levetiracetam sustained-release particles, package them, each bag containing 200mg of levetiracetam.

[0077] Example 4: A preparation process for levetiracetam sustained-release granules:

[0078] Example 4 adjusted the amount of silica-modified chitosan in the sustained-release coating solution;

[0079] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0080] S2: Preparation of transition coating solution and sustained-release coating solution:

[0081] S21: Mix 4 parts sodium alginate (molecular weight approximately 70,000), 1.25 parts triethyl citrate, and 100 parts purified water thoroughly to obtain a transition coating solution;

[0082] S22-1: Preparation of silica-modified chitosan: (1) Add 2 parts silica and 1.5 parts 3-mercaptopropyltriethoxysilane to 2L of 75wt% ethanol aqueous solution, add acetic acid to adjust the pH to 5.5, ultrasonically disperse for 20min, filter, wash, and dry to obtain mercapto-modified silica; (2) Add 10 parts chitosan to 10L of 5wt% acetic acid solution, stir to dissolve, and obtain chitosan solution; add 4 parts (Z)-14-methyl-8-hexadecene-1-acetal to 2L of tetrahydrofuran, stir to dissolve, and obtain (Z)-14-methyl-8-hexadecene-1-acetal. (3) At 40°C, the (Z)-14-methyl-8-hexadecene-1-acetal solution was slowly added dropwise to the chitosan solution while stirring. After the addition was complete, the reaction was continued for 18 hours. The reaction was then stopped, and excess anhydrous ethanol was added to precipitate the precipitate. The precipitate was filtered, washed, and dried to obtain acetal-modified chitosan. (4) 1 part of mercapto-modified silica, 8 parts of acetal-modified chitosan, and 0.08 parts of photoinitiator 1173 were added to 1 L of tetrahydrofuran. The mixture was stirred at 110 mW / cm 2 The reaction was initiated by ultraviolet light with high intensity for 1.5 h, and the reaction was terminated; (5) 2,3-epoxypropyltrimethylammonium chloride aqueous solution (0.24 parts of 2,3-epoxypropyltrimethylammonium chloride and 200 mL of deionized water were added to the reaction solution in (4), the temperature was raised to 65℃ by stirring, the reaction was carried out for 8 h, the reaction was terminated, and after filtration, washing and drying, silica-modified chitosan was obtained;

[0083] S22-2: Mix 5 parts silica-modified chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0084] S3: Perform transition layer coating and sustained-release layer coating:

[0085] S31: After preheating the levetiracetam active particles to 55°C, place them in a coating pan and atomize the transition coating solution onto the levetiracetam active particles using process parameters of 0.2 MPa atomization pressure, 55°C spraying temperature, 4 mL / min spraying speed, and 13 r / min rotation speed. Then, vacuum dry at 60°C until the moisture content is ≤2 wt%, forming a transition layer with a weight gain of 3 wt%.

[0086] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, vacuum dry at 60°C until the water content is ≤2wt%, forming a sustained-release layer, increasing the weight by 6wt%, to obtain levetiracetam sustained-release particles, package them, each bag containing 200mg of levetiracetam.

[0087] Example 5: A preparation process for levetiracetam sustained-release granules:

[0088] Example 5 adjusted the amount of silica-modified chitosan in the sustained-release coating solution;

[0089] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0090] S2: Preparation of transition coating solution and sustained-release coating solution:

[0091] S21: Mix 4 parts sodium alginate (molecular weight approximately 70,000), 1.25 parts triethyl citrate, and 100 parts purified water thoroughly to obtain a transition coating solution;

[0092] S22-1: Preparation of silica-modified chitosan: (1) Add 2 parts silica and 1.5 parts 3-mercaptopropyltriethoxysilane to 2L of 75wt% ethanol aqueous solution, add acetic acid to adjust the pH to 5.5, ultrasonically disperse for 20min, filter, wash, and dry to obtain mercapto-modified silica; (2) Add 10 parts chitosan to 10L of 5wt% acetic acid solution, stir to dissolve, and obtain chitosan solution; add 4 parts (Z)-14-methyl-8-hexadecene-1-acetal to 2L of tetrahydrofuran, stir to dissolve, and obtain (Z)-14-methyl-8-hexadecene-1-acetal. (3) At 40°C, the (Z)-14-methyl-8-hexadecene-1-acetal solution was slowly added dropwise to the chitosan solution while stirring. After the addition was complete, the reaction was continued for 18 hours. The reaction was then stopped, and excess anhydrous ethanol was added to precipitate the precipitate. The precipitate was filtered, washed, and dried to obtain acetal-modified chitosan. (4) 1 part of mercapto-modified silica, 8 parts of acetal-modified chitosan, and 0.08 parts of photoinitiator 1173 were added to 1 L of tetrahydrofuran. The mixture was stirred at 110 mW / cm 2 The reaction was initiated by ultraviolet light with high intensity for 1.5 h, and the reaction was terminated; (5) 2,3-epoxypropyltrimethylammonium chloride aqueous solution (0.24 parts of 2,3-epoxypropyltrimethylammonium chloride and 200 mL of deionized water were added to the reaction solution in (4), the temperature was raised to 65℃ by stirring, the reaction was carried out for 8 h, the reaction was terminated, and after filtration, washing and drying, silica-modified chitosan was obtained;

[0093] S22-2: Mix 8 parts silica-modified chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0094] S3: Perform transition layer coating and sustained-release layer coating:

[0095] S31: After preheating the levetiracetam active particles to 55°C, place them in a coating pan and atomize the transition coating solution onto the levetiracetam active particles using process parameters of 0.2 MPa atomization pressure, 55°C spraying temperature, 4 mL / min spraying speed, and 13 r / min rotation speed. Then, vacuum dry at 60°C until the moisture content is ≤2 wt%, forming a transition layer with a weight gain of 3 wt%.

[0096] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, vacuum dry at 60°C until the water content is ≤2wt%, forming a sustained-release layer, increasing the weight by 6wt%, to obtain levetiracetam sustained-release particles, package them, each bag containing 200mg of levetiracetam.

[0097] The following is a control experiment based on Example 1, with comparative examples 1 to 5, specifically:

[0098] Comparative Example 1: Comparative Example 1 is based on Example 1, with the following adjustment: no modification of chitosan is performed, while other processes remain unchanged. Specifically:

[0099] A preparation process for levetiracetam sustained-release granules:

[0100] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0101] S2: Preparation of transition coating solution and sustained-release coating solution:

[0102] S21: Mix 4 parts sodium alginate (molecular weight approximately 70,000), 1.25 parts triethyl citrate, and 100 parts purified water thoroughly to obtain a transition coating solution;

[0103] S22: Mix 7 parts chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0104] S3: Perform transition layer coating and sustained-release layer coating:

[0105] S31: After preheating the levetiracetam active particles to 55°C, place them in a coating pan and atomize the transition coating solution onto the levetiracetam active particles using process parameters of 0.2 MPa atomization pressure, 55°C spraying temperature, 4 mL / min spraying speed, and 13 r / min rotation speed. Then, vacuum dry at 60°C until the moisture content is ≤2 wt%, forming a transition layer with a weight gain of 3 wt%.

[0106] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, vacuum dry at 60°C until the water content is ≤2wt%, forming a sustained-release layer, increasing the weight by 6wt%, to obtain levetiracetam sustained-release particles, package them, each bag containing 200mg of levetiracetam.

[0107] Comparative Example 2: Comparative Example 2 is based on Example 1, with the following adjustment: silicon dioxide is not introduced, while other processes remain unchanged. Specifically:

[0108] A preparation process for levetiracetam sustained-release granules:

[0109] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0110] S2: Preparation of transition coating solution and sustained-release coating solution:

[0111] S21: Mix 4 parts sodium alginate (molecular weight approximately 70,000), 1.25 parts triethyl citrate, and 100 parts purified water thoroughly to obtain a transition coating solution;

[0112] S22-1: Preparation of modified chitosan: (1) Add 10 parts of chitosan to 10L of 5wt% acetic acid solution, stir to dissolve, and obtain chitosan solution; add 4 parts of (Z)-14-methyl-8-hexadecene-1-acetal to 2L of tetrahydrofuran, stir to dissolve, and obtain (Z)-14-methyl-8-hexadecene-1-acetal solution; (2) At 40℃, slowly add (Z)-14-methyl-8-hexadecene-1-acetal solution to chitosan solution while stirring, and after the addition is complete, Continue stirring for 18 hours, stop the reaction, add excess anhydrous ethanol, precipitate out, filter, wash and dry to obtain acetal-modified chitosan; (3) Add 8 parts of acetal-modified chitosan to 1L of tetrahydrofuran, stir and mix evenly, then add 2,3-epoxypropyltrimethylammonium chloride aqueous solution (0.24 parts of 2,3-epoxypropyltrimethylammonium chloride and 200mL of deionized water), stir and heat to 65℃, stir and react for 8 hours, stop the reaction, filter, wash and dry to obtain modified chitosan;

[0113] S22-2: Mix 7 parts modified chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0114] S3: Perform transition layer coating and sustained-release layer coating:

[0115] S31: After preheating the levetiracetam active particles to 55°C, place them in a coating pan and atomize the transition coating solution onto the levetiracetam active particles using process parameters of 0.2 MPa atomization pressure, 55°C spraying temperature, 4 mL / min spraying speed, and 13 r / min rotation speed. Then, vacuum dry at 60°C until the moisture content is ≤2 wt%, forming a transition layer with a weight gain of 3 wt%.

[0116] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, vacuum dry at 60°C until the water content is ≤2wt%, forming a sustained-release layer, increasing the weight by 6wt%, to obtain levetiracetam sustained-release particles, package them, each bag containing 200mg of levetiracetam.

[0117] Comparative Example 3: Comparative Example 3 is based on Example 1, with the following adjustment: acetal modification of chitosan is not performed, while other processes remain unchanged. Specifically:

[0118] A preparation process for levetiracetam sustained-release granules:

[0119] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0120] S2: Preparation of transition coating solution and sustained-release coating solution:

[0121] S21: Mix 4 parts sodium alginate (molecular weight approximately 70,000), 1.25 parts triethyl citrate, and 100 parts purified water thoroughly to obtain a transition coating solution;

[0122] S22-1: Preparation of silica-modified chitosan: (1) Add 2 parts silica and 1.5 parts 3-mercaptopropyltriethoxysilane to 2L of 75wt% ethanol aqueous solution, add acetic acid to adjust the pH to 5.5, ultrasonically disperse for 20min, filter, wash, and dry to obtain mercapto-modified silica; (2) Add 1 part mercapto-modified silica, 8 parts chitosan, and 0.08 parts photoinitiator 1173 to 1L of tetrahydrofuran, stir, and at 110mW / cm 2The reaction was initiated by ultraviolet light with high intensity for 1.5 h, and the reaction was terminated; (3) 2,3-epoxypropyltrimethylammonium chloride aqueous solution (0.24 parts of 2,3-epoxypropyltrimethylammonium chloride and 200 mL of deionized water were added to the reaction solution in (2), the temperature was raised to 65℃ by stirring, the reaction was carried out for 8 h, the reaction was terminated, and after filtration, washing and drying, silica-modified chitosan was obtained;

[0123] S22-2: Mix 7 parts silica-modified chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0124] S3: Perform transition layer coating and sustained-release layer coating:

[0125] S31: After preheating the levetiracetam active particles to 55°C, place them in a coating pan and atomize the transition coating solution onto the levetiracetam active particles using process parameters of 0.2 MPa atomization pressure, 55°C spraying temperature, 4 mL / min spraying speed, and 13 r / min rotation speed. Then, vacuum dry at 60°C until the moisture content is ≤2 wt%, forming a transition layer with a weight gain of 3 wt%.

[0126] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, vacuum dry at 60°C until the water content is ≤2wt%, forming a sustained-release layer, increasing the weight by 6wt%, to obtain levetiracetam sustained-release particles, package them, each bag containing 200mg of levetiracetam.

[0127] Comparative Example 4: Comparative Example 4 is based on Example 1, with the following adjustment: chitosan was not added for quaternization modification, while other processes remained unchanged. Specifically:

[0128] A preparation process for levetiracetam sustained-release granules:

[0129] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0130] S2: Preparation of transition coating solution and sustained-release coating solution:

[0131] S21: Mix 4 parts sodium alginate (molecular weight approximately 70,000), 1.25 parts triethyl citrate, and 100 parts purified water thoroughly to obtain a transition coating solution;

[0132] S22-1: Preparation of silica-modified chitosan: (1) Add 2 parts silica and 1.5 parts 3-mercaptopropyltriethoxysilane to 2L of 75wt% ethanol aqueous solution, add acetic acid to adjust the pH to 5.5, ultrasonically disperse for 20min, filter, wash, and dry to obtain mercapto-modified silica; (2) Add 10 parts chitosan to 10L of 5wt% acetic acid solution, stir to dissolve, and obtain chitosan solution; add 4 parts (Z)-14-methyl-8-hexadecene-1-acetal to 2L of tetrahydrofuran, stir to dissolve, and obtain (Z)-14-methyl-8-hexadecene-1-acetal. (3) At 40°C, the (Z)-14-methyl-8-hexadecene-1-acetal solution was slowly added dropwise to the chitosan solution while stirring. After the addition was complete, the reaction was continued for 18 hours. The reaction was then stopped, and excess anhydrous ethanol was added to precipitate the precipitate. The precipitate was filtered, washed, and dried to obtain acetal-modified chitosan. (4) 1 part of mercapto-modified silica, 8 parts of acetal-modified chitosan, and 0.08 parts of photoinitiator 1173 were added to 1 L of tetrahydrofuran. The mixture was stirred at 110 mW / cm 2 The reaction was initiated by ultraviolet light with high intensity for 1.5 h, and then terminated. After filtration, washing, and drying, silica-modified chitosan was obtained.

[0133] S22-2: Mix 7 parts silica-modified chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0134] S3: Perform transition layer coating and sustained-release layer coating:

[0135] S31: After preheating the levetiracetam active particles to 55°C, place them in a coating pan and atomize the transition coating solution onto the levetiracetam active particles using process parameters of 0.2 MPa atomization pressure, 55°C spraying temperature, 4 mL / min spraying speed, and 13 r / min rotation speed. Then, vacuum dry at 60°C until the moisture content is ≤2 wt%, forming a transition layer with a weight gain of 3 wt%.

[0136] S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating solution onto the levetiracetam active particles, vacuum dry at 60°C until the water content is ≤2wt%, forming a sustained-release layer, increasing the weight by 6wt%, to obtain levetiracetam sustained-release particles, package them, each bag containing 200mg of levetiracetam.

[0137] Comparative Example 5: Comparative Example 5 is based on Example 1, with the following adjustment: no transition layer is set, while other processes remain unchanged. Specifically:

[0138] A preparation process for levetiracetam sustained-release granules:

[0139] S1: Add 20 parts of levetiracetam, 35 parts of microcrystalline cellulose, 8 parts of povidone K30, and 12.5 parts of purified water to a mixer and stir at 200 rpm for 15 minutes to ensure that the mixing degree RSD of the mixture is <3.0%. After processing the mixture into a soft material, granulate it using a granulator, vacuum dry it at 60℃ until the moisture content is ≤2.0wt%, pass it through a 65-mesh sieve, and then add 1.5 parts of silica for total mixing to obtain levetiracetam active granules.

[0140] S2: Preparation of sustained-release coating solution:

[0141] S21-1: Preparation of silica-modified chitosan: (1) Add 2 parts silica and 1.5 parts 3-mercaptopropyltriethoxysilane to 2L of 75wt% ethanol aqueous solution, add acetic acid to adjust the pH to 5.5, ultrasonically disperse for 20min, filter, wash, and dry to obtain mercapto-modified silica; (2) Add 10 parts chitosan to 10L of 5wt% acetic acid solution, stir to dissolve, and obtain chitosan solution; add 4 parts (Z)-14-methyl-8-hexadecene-1-acetal to 2L of tetrahydrofuran, stir to dissolve, and obtain (Z)- (3) At 40°C, the (Z)-14-methyl-8-hexadecene-1-acetal solution was slowly added dropwise to the chitosan solution while stirring. After the addition was complete, the reaction was continued for 18 hours. The reaction was then stopped, and excess anhydrous ethanol was added to precipitate the precipitate. The precipitate was filtered, washed, and dried to obtain acetal-modified chitosan. (4) 1 part of mercapto-modified silica, 8 parts of acetal-modified chitosan, and 0.08 parts of photoinitiator 1173 were added to 1 L of tetrahydrofuran. The mixture was stirred at 100~120 mW / cm 2 The reaction was initiated by ultraviolet light with high intensity for 1.5 h, and the reaction was terminated; (5) 2,3-epoxypropyltrimethylammonium chloride aqueous solution (0.24 parts of 2,3-epoxypropyltrimethylammonium chloride and 200 mL of deionized water were added to the reaction solution in (4), the temperature was raised to 65℃ by stirring, the reaction was carried out for 8 h, the reaction was terminated, and after filtration, washing and drying, silica-modified chitosan was obtained;

[0142] S21-2: Mix 7 parts silica-modified chitosan, 4 parts sodium alginate (molecular weight approximately 170,000), 2 parts triethyl citrate, and 200 parts purified water evenly to obtain a sustained-release coating solution.

[0143] S3: After preheating the levetiracetam active granules to 55°C, place them in a coating pan and atomize the sustained-release coating solution onto the levetiracetam active granules using the following process parameters: atomization pressure of 0.2 MPa, spraying temperature of 55°C, spraying speed of 4 mL / min, and coating pan rotation speed of 13 r / min. Vacuum dry at 60°C until the water content is ≤2 wt% to form a sustained-release layer with a weight gain of 6 wt%, to obtain levetiracetam sustained-release granules, which are then bagged, with each bag containing 200 mg of levetiracetam.

[0144] Performance Testing: The in vitro release rate of levetiracetam sustained-release granules prepared in Examples 1-5 and Comparative Examples 1-5 was tested. The specific test method is as follows: The in vitro release rate of levetiracetam sustained-release granules was investigated according to Method I (basket method) under General Chapter 0931 Dissolution and Release Determination in the 2020 edition of the Pharmacopoeia of the People's Republic of China. One sachet of levetiracetam sustained-release granules (levetiracetam content 200 mg) was added. The release medium was phosphate buffer solution with pH=6.0, a volume of 900 mL, a temperature of 35℃, and a rotation speed of 100 r / min. Samples of 5 mL were taken at 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h, and an equal volume of isothermal release medium was added promptly. The cumulative release rate (%) at 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h was measured.

[0145] The specific test results are shown in Table 1 below:

[0146] Table 1

[0147]

[0148] Results and conclusions: Comparing the data of the examples and comparative examples in Table 1 above, it can be seen that the present invention has prepared a levetiracetam sustained-release particle that can be stably released within 24 hours by encapsulating it with a multi-layered microsphere structure.

[0149] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A preparation process for levetiracetam sustained-release granules, characterized in that: Includes the following steps: S1: Levetiracetam, filler, binder and purified water are stirred and mixed evenly, granulated, dried and sieved, and then a flow aid is added for total mixing to obtain levetiracetam active granules. S2: Preparation of transition coating solution and sustained-release coating solution: S21: Mix sodium alginate, plasticizer, and purified water evenly to obtain a transition coating solution; S22: Mix silica-modified chitosan, sodium alginate, plasticizer, and purified water evenly to obtain a sustained-release coating solution; S3: Perform transition layer coating and sustained-release layer coating: S31: After preheating the levetiracetam active particles, transfer them to a coating pan, atomize and spray the transition coating solution onto the levetiracetam active particles, and dry them to form a transition layer. S32: Keeping the coating pan parameters unchanged, atomize the sustained-release coating liquid onto the levetiracetam active particles, dry it to form a sustained-release layer, and obtain levetiracetam sustained-release particles. The transition coating solution is prepared by mixing the following raw material components in parts by weight: 3-5 parts sodium alginate, 1-1.5 parts plasticizer, and 100 parts purified water; wherein the molecular weight of sodium alginate is 50,000-100,000. The sustained-release coating solution is prepared by mixing the following raw material components in parts by weight: 7-8 parts silica-modified chitosan, 3-5 parts sodium alginate, 1.5-3 parts plasticizer, and 200 parts purified water; the molecular weight of the sodium alginate is 150,000-200,000. The preparation method of the silica-modified chitosan is as follows: (1) Add silica and 3-mercaptopropyltriethoxysilane to a 75wt% aqueous ethanol solution, add acetic acid to adjust the pH to 5-6, ultrasonically disperse for 10-30 min, filter, wash and dry to obtain mercapto-modified silica; (2) Chitosan was added to a 5 wt% acetic acid solution and stirred to dissolve, thus obtaining a chitosan solution; (Z)-14-methyl-8-hexadecene-1-acetal was added to tetrahydrofuran and stirred to dissolve, thus obtaining a (Z)-14-methyl-8-hexadecene-1-acetal solution. (3) At 30~50℃, (Z)-14-methyl-8-hexadecene-1-acetal solution was slowly added dropwise to chitosan solution while stirring. After the addition was completed, the reaction was continued to be stirred for 12~24h. The reaction was then stopped. Excess anhydrous ethanol was added to precipitate the precipitate. The precipitate was filtered, washed, and dried to obtain acetal-modified chitosan. (4) Add mercapto-modified silica, acetal-modified chitosan, and photoinitiator to tetrahydrofuran, and stir at 100~120mW / cm 2 The reaction was initiated by ultraviolet light with high intensity and lasted for 1-2 hours, after which the reaction was terminated. (5) Add 2,3-epoxypropyltrimethylammonium chloride aqueous solution to the reaction solution in (4), stir and heat to 60~70℃, stir and react for 6~12h, stop the reaction, filter, wash and dry to obtain silica-modified chitosan. The ratio of silica, 3-mercaptopropyltriethoxysilane, and aqueous ethanol solution is 1g:(0.5~1)g:100mL; the ratio of chitosan, acetic acid solution, (Z)-14-methyl-8-hexadecene-1-acetal, and tetrahydrofuran is 1g:100mL:(0.2~0.5)g:20mL; the degree of deacetylation of chitosan is ≥85%; the ratio of mercapto-modified silica, acetal-modified chitosan, photoinitiator, and tetrahydrofuran is 1g:(5~8)g:(0.06~0.1)g:100mL; and the amount of 2,3-epoxypropyltrimethylammonium chloride added is 3~5% of the mass of acetal-modified chitosan.

2. The preparation process of levetiracetam sustained-release granules according to claim 1, characterized in that: The plasticizer is triethyl citrate.

3. The preparation process of levetiracetam sustained-release granules according to claim 1, characterized in that: The parameters for atomization spraying are: atomization pressure of 0.15~0.3MPa, spraying temperature of 50~60℃, spraying speed of 2~5mL / min, and coating pan rotation speed of 10~15r / min.

4. The preparation process of levetiracetam sustained-release granules according to claim 1, characterized in that: The transition layer increases in weight by 2-5 wt%; the sustained-release layer increases in weight by 4-8 wt%.

5. The preparation process of levetiracetam sustained-release granules according to claim 1, characterized in that: The preparation of the levetiracetam active particles includes the following raw material components in parts by weight: 20 parts levetiracetam, 30-40 parts filler, 6-10 parts binder, 1-1.5 parts flow aid, and 10-15 parts purified water.

6. The preparation process of levetiracetam sustained-release granules according to claim 5, characterized in that: The filler is microcrystalline cellulose; the binder is polyvinyl ketone K30; and the flow aid is silica.

7. The levetiracetam sustained-release granules prepared by the preparation process of levetiracetam sustained-release granules according to any one of claims 1 to 6, characterized in that: The levetiracetam sustained-release granules are packaged in bags; each bag contains 200 mg or 500 mg of levetiracetam.

8. The levetiracetam sustained-release granules according to claim 7, characterized in that: The recommended daily intake of levetiracetam is no more than 1g in the first week, no more than 2g in the second week, and no more than 3g in the third week; the maximum recommended dose is 3g / day.

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