Levofloxacin sustained release tablet and preparation method thereof

Abstract

The invention discloses a levofloxacin sustained release tablet and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The levofloxacin sustained-release tablet is prepared from the following components in parts by weight: 2 to 4 parts of modified composite microcrystalline cellulose pellet core, 24 to 26 parts of nanoscale medicine applying coating liquid, 18 to 20 parts of sustained-release coating liquid, 10 to 20 parts of total mixed particles and 4 to 6 parts of film coating liquid. According to the invention, the microcrystalline cellulose pellet core is modified, and after the modified composite microcrystalline cellulose pellet core is applied, the release speed of the medicine in the body is slowed down, so that the slow release effect of the medicine is realized, the action time of the medicine is prolonged, and the medicine taking frequency is reduced. According to the present invention, the drug application coating liquid is modified to obtain the nano-scale drug application coating liquid suspension, and the nano-scale drug application coating liquid suspension can be uniformly attached to the surface of the pellet core during the coating, and can be uniformly attached to the surface of the pellet core during the coating so as to ensure that the drug can maintain the relatively stable blood concentration within a certain time, such that the treatment effect can be well performed, and the disease treatment effect can be improved;

Description

Technical Field

[0001] The present invention relates to pharmaceutical preparations, and particularly to a levofloxacin sustained-release tablet and a preparation method thereof. Background Art

[0002] Levofloxacin, chemically named: (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid, is a hemihydrate crystal, a quinolone compound, and the levorotatory isomer of ofloxacin. Its antibacterial activity is about twice that of ofloxacin. Its main mechanism of action is to inhibit the activity of bacterial DNA gyrase (bacterial topoisomerase II) and hinder the replication of bacterial DNA to achieve antibacterial effects.

[0003] Conventional levofloxacin ordinary preparations, such as ordinary tablets, capsules, etc., although they can exert drug effects to a certain extent, due to their relatively fast drug release rate, the blood drug concentration fluctuates significantly. This leads to the need for patients to take medicine frequently, which not only increases the medication burden on patients, but also may affect the treatment effect due to missed doses, and is not conducive to the long-term treatment and recovery of patients. Summary of the Invention

[0004] Object of the Invention: The object of the present invention is to provide a levofloxacin sustained-release tablet and a preparation method thereof; to solve the problem of the relatively fast drug release rate of traditional levofloxacin preparations.

[0005] Technical Solution: A levofloxacin sustained-release tablet comprises 2-4 parts by weight of a modified composite microcrystalline cellulose core, 24-26 parts by weight of a nano-level drug-coated solution, 18-20 parts by weight of a sustained-release coating solution, 10-20 parts by weight of a total mixing granule, and 4-6 parts by weight of a film coating solution;

[0006] The preparation method of the modified composite microcrystalline cellulose core is as follows: Dispersed 100nm Fe3O4 nanoparticles in ethanol, added amino silane, refluxed at 80°C for 6h to obtain amino-functionalized Fe3O4; Immersed the microcrystalline cellulose core in 10% NaClO solution, stirred and reacted at 20°C for 12h, filtered, rinsed with purified water, and dried in vacuum at 50°C to obtain carboxylated microcrystalline cellulose core; Dispersed the carboxylated microcrystalline cellulose core in DMF, added N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stirred for 30min, then added 4-aminoazobenzene, reacted at 60°C for 24h, filtered, and washed with purified water to obtain grafted microcrystalline cellulose core; Dispersed the amino-functionalized Fe3O4 in 2-morpholinoethanesulfonic acid buffer solution, added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, stirred and reacted at 20°C for 30min, added the grafted microcrystalline cellulose core, reacted at room temperature for 12h, filtered, washed, and dried in vacuum at 50°C to obtain the modified composite microcrystalline cellulose core;

[0007] The preparation method of the nano-level drug-loading coating solution is as follows: Added levofloxacin to DMF and stirred to dissolve, slowly added the purified water solution containing the stabilizer, a nano-level suspension was formed during the dropping process, stirred for 2h, passed the nano-level suspension through an ultrafiltration system (pressure setting: 0.5MPa, pore size of the ultrafiltration membrane: 0.22um) to obtain wet nano-level levofloxacin, then rinsed with purified water 5 times, dried in vacuum at 60°C to obtain nano-level levofloxacin, and then subjected to high-pressure homogenization treatment, the homogenization pressure was 1000-2000bar, circulated 3 times, and the particle size D90 of the nano-level drug-loading coating solution suspension was ≤500nm.

[0008] Preferably, the stabilizer of the nano-level drug-loading coating solution is sodium dodecyl sulfate.

[0009] Preferably, the sustained-release coating solution contains ethyl cellulose, triethyl citrate, hypromellose and 75% ethanol solution, and the mass ratio is 6:1:1.5:120, stirred evenly to obtain the sustained-release coating solution.

[0010] Preferably, the total mixed granules are composed of sustained-release pellets, microcrystalline cellulose of model SH-101 (particle size 50μm) and microcrystalline cellulose of model SH-102 (150μm).

[0011] Preferably, the film coating solution is obtained by stirring the film coating premix and purified water.

[0012] A preparation method of levofloxacin sustained-release tablets includes the following steps:

[0013] S1. Pour the modified composite microcrystalline cellulose pill cores into the fluidized bed, turn on the blower and heating, and spray the nanoscale drug-loading coating solution onto the modified composite microcrystalline cellulose pill cores to obtain drug-loaded pills.

[0014] S2. Pour the drug-loaded pills into the fluidized bed, turn on the blower and heating, and spray the sustained-release coating solution onto the drug-loaded pills to obtain sustained-release pills.

[0015] S3. Mix the sustained-release pills, microcrystalline cellulose 1, and microcrystalline cellulose 2, and then add magnesium stearate and mix them thoroughly in a three-dimensional mixer to obtain the thoroughly mixed granules.

[0016] S4. Add the thoroughly mixed granules into a tableting machine to press tablets to obtain sustained-release tablets.

[0017] S5. Add the sustained-release tablets into a coating machine, turn on the hot air and the rotating drum, and spray the film coating solution onto the sustained-release tablets to obtain levofloxacin sustained-release tablets.

[0018] Preferably, the process parameters for spraying the nanoscale drug-loading coating solution are: the inlet air temperature of the fluidized bed is 70 - 80°C, the air volume is 130 - 140 m 3 / h, and the atomization pressure is 0.1 - 0.2 MPa.

[0019] Preferably, the process parameters for spraying the sustained-release coating solution are: the inlet air temperature of the fluidized bed is 50 - 60°C, the air volume is 160 - 180 m 3 / h, and the atomization pressure is 0.2 - 0.3 MPa.

[0020] Preferably, the process parameters for spraying the film coating solution are: set the inlet air temperature (reference set value: 60°C), the rotating speed of the coating machine drum is 2 rpm, preheat to make the tablet bed temperature reach 40°C, control the rotating speed of the drum at 3 rpm, the flow rate of the coating solution is 10 g / min, and the atomization pressure is 0.2 Mpa.

[0021] Preferably, in the tableting process, the main pressing pressure is 10 - 20 KN.

[0022] Beneficial effects:

[0023] (1) The present invention modifies the microcrystalline cellulose core: Dispersing 100nm Fe3O4 nanoparticles in ethanol, adding amino silane, and refluxing at 80°C for 6h to obtain amino-functionalized Fe3O4; Immersing the microcrystalline cellulose core in 10% NaClO solution, stirring and reacting at a system temperature of 20°C for 12h, filtering, washing with purified water, and drying in vacuum at 50°C to obtain carboxylated microcrystalline cellulose core; Dispersing the carboxylated microcrystalline cellulose core in DMF, adding N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stirring for 30min, then adding 4-aminoazobenzene, reacting at 60°C for 24h, filtering, and washing with purified water to obtain grafted microcrystalline cellulose core; Dispersing the amino-functionalized Fe3O4 in 2-morpholinoethanesulfonic acid buffer solution, adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, stirring and reacting at 20°C for 30min, adding the grafted microcrystalline cellulose core, reacting at room temperature for 12h, filtering, washing, and drying in vacuum at 50°C to obtain the modified composite microcrystalline cellulose core. After loading the drug, the release rate of the drug in the body is slowed down, thereby achieving the sustained-release effect of the drug, prolonging the drug action time, and reducing the frequency of taking medicine.

[0024] (2) The present invention modifies the coating solution for loading the drug: Dissolving levofloxacin in DMF with stirring, slowly adding an aqueous solution of purified water containing a stabilizer, forming a nano-sized suspension during the dropping process, stirring for 2h, passing the nano-sized suspension through an ultrafiltration system (pressure setting: 0.5MPa, pore size of the ultrafiltration membrane: 0.22um) to obtain wet nano-sized levofloxacin, then washing 5 times with purified water and drying in vacuum at 60°C to obtain nano-sized levofloxacin, and then performing high-pressure homogenization treatment with a homogenization pressure of 1000 - 2000 bar and circulating 3 times to obtain a nano-sized coating solution suspension for loading the drug. During coating, it can adhere more uniformly to the surface of the core, ensuring that the drug maintains a relatively stable blood drug concentration within a certain period of time, thereby better exerting the therapeutic effect and improving the treatment effect on diseases. Description of the Drawings

[0025] Figure 1 It is the dissolution result graph of the examples and the comparative examples in pH 1.2 hydrochloric acid buffer solution.

[0026] Figure 2 It is the dissolution curve graph of the examples and the comparative examples in pH 1.2 hydrochloric acid buffer solution.

[0027] Figure 3 It is the dissolution result graph of the examples and the comparative examples in pH 4.5 acetate buffer solution.

[0028] Figure 4 It is the dissolution curve graph of the examples and the comparative examples in pH 4.5 acetate buffer solution.

[0029] Figure 5It is the dissolution result graph of the example and the comparative example in pH 6.8 phosphate buffer solution.

[0030] Figure 6 It is the dissolution curve graph of the example and the comparative example in pH 6.8 phosphate buffer solution. Detailed implementation manners

[0031] To make the technical solution of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and specific examples.

[0032] Example 1

[0033] A levofloxacin sustained-release tablet is obtained by the following preparation method:

[0034] (1) Preparation of modified composite microcrystalline cellulose core:

[0035] Add 1 kg of 100 nm Fe3O4 nanoparticles, 30 kg of ethanol, and 500 g of amino silane into a 5 L reaction kettle, reflux at 80 °C for 6 h, filter, wash with 2 kg of ethanol, and vacuum dry at 60 °C for 12 h to obtain 900 g of amino-functionalized Fe3O4;

[0036] In a 50 L stainless steel reaction kettle, add 4 kg of microcrystalline cellulose core and 500 g of 10% NaClO solution, stir and react at a system temperature of 20 °C for 12 h, filter, wash with purified water, and vacuum dry at 50 °C for 12 h to obtain 3.8 kg of carboxylated microcrystalline cellulose core for standby;

[0037] In a 100 L reaction kettle, add 3.8 kg of carboxylated microcrystalline cellulose core, 70 kg of DMF, 300 g of N-hydroxysuccinimide, and 800 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir for 30 min, then add 2 kg of 4-aminoazobenzene, react at 60 °C for 24 h, filter, wash with 5 kg of purified water, and vacuum dry at 50 °C for 10 h to obtain 4.4 kg of grafted microcrystalline cellulose core.

[0038] Add 800 g of amino-functionalized Fe3O4 into a 20 L reaction kettle and 50 kg of 2-(N-morpholino)ethanesulfonic acid buffer solution, add 600 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 300 g of N-hydroxysuccinimide, stir and react at 20 °C for 30 min, add 4 kg of grafted microcrystalline cellulose core, react at room temperature for 12 h, filter, wash once with 2 kg of purified water, and vacuum dry at 50 °C for 12 h to obtain 4.6 kg of modified composite microcrystalline cellulose core.

[0039] (2) Preparation of nanoscale drug-loading coating solution: Add 4 kg of levofloxacin and 5 kg of DMF into a 50L stainless steel reactor and stir to dissolve. Slowly add the purified aqueous solution containing stabilizer (50 kg of purified water + 20 g of sodium dodecyl sulfate). During the dropping process, a nanoscale suspension is formed. Stir for 2 h. Pass the nanoscale suspension through an ultrafiltration system (pressure setting: 0.5 MPa, pore size of the ultrafiltration membrane: 0.22 um) to obtain wet nanoscale levofloxacin. Then wash it 5 times with 30 kg of purified water and dry it in vacuum at 60°C to obtain 3.1 kg of nanoscale levofloxacin. Add 3 kg of nanoscale levofloxacin, 13 g of sodium dodecyl sulfate, 9 kg of purified water, and then perform high-pressure homogenization treatment. The homogenization pressure is 1000 - 2000 bar. After circulating 3 times, 12 kg of nanoscale suspension drug-loading coating solution is obtained for standby.

[0040] (3) Coating with drugs on fluidized bed: Pour 200 g of the modified microcrystalline cellulose pellets in step (1) into the fluidized bed. Turn on the fan and heating to raise the temperature of the modified microcrystalline cellulose pellets to 30°C. Add 2.4 kg of the drug-loading coating solution in step (2). Adjust the inlet air temperature of the fluidized bed to 70°C and the inlet air volume to 130 m 3 / h. Adjust the atomization pressure to 0.1 Mpa and the liquid spraying rate to 5 - 10 mL / min. Spray it onto the modified microcrystalline cellulose pellets in step (1) and dry for 30 min to obtain 837 g of coated pills.

[0041] (4) Preparation of sustained-release coating solution: Add 240 g of ethyl cellulose, 40 g of triethyl citrate, 60 g of hydroxypropyl methylcellulose, and 4.8 kg of 75% ethanol into a tank and stir to obtain 5.1 kg of sustained-release coating solution for standby.

[0042] (5) Preparation of sustained-release pills: Pour 837 g of the coated pills in step (3) into the fluidized bed. Turn on the fan and heating to raise the temperature of the coated pills to 35°C. Add 1.8 kg of the sustained-release coating solution in step (4). Adjust the inlet air temperature of the fluidized bed to 50°C and the inlet air volume to 160 m 3 / h. Adjust the atomization pressure to 0.2 Mpa and the liquid spraying rate to 5 - 10 mL / min. Spray it onto the coated pills in step (3) and dry for 30 min to obtain 950 g of sustained-release pills.

[0043] (6) Preparation of total mixed granules: Mix 950 g of the sustained-release pills, 1633 g of microcrystalline cellulose, and 2633 g of microcrystalline cellulose in a mixer, and then add 12.6 g of magnesium stearate and mix to obtain 2.22 kg of total mixed granules.

[0044] (7) Preparation of sustained-release tablets: Add 1 kg of the total mixed granules in step (6) into a tableting machine for tableting. Set the main pressing pressure of the tableting machine to 10 KN, and then obtain the sustained-release tablets.

[0045] (8) Preparation of film coating solution: Add 80 g of film coating premix and 800 g of purified water into a 1 L single-necked flask, stir evenly to obtain 880 g of film coating solution.

[0046] (9) Finished product: Add the sustained-release tablets obtained in step (7) into a coating machine, turn on the hot air and the rotating drum, set the inlet air temperature of 400 g of the film coating solution in step (8) (reference setting value: 60 °C), the rotating speed of the coating machine drum is 2 rpm, preheat to make the tablet bed temperature reach 40 °C, control the rotating speed of the drum at 3 rpm, the flow rate of the coating solution is 10 g / min, and the atomization pressure is 0.2 Mpa. Sustained-release tablets are dried for 30 min to obtain levofloxacin sustained-release tablets.

[0047] Example 2

[0048] A levofloxacin sustained-release tablet is obtained by the following preparation method:

[0049] (1) Preparation of modified composite microcrystalline cellulose core:

[0050] Add 1 kg of 100 nm Fe3O4 nanoparticles and 30 kg of ethanol into a 5 L reactor, add 500 g of amino silane, reflux at 80 °C for 6 h, filter, wash with 2 kg of ethanol, and vacuum dry at 60 °C for 12 h to obtain 900 g of amino-functionalized Fe3O4;

[0051] In a 50 L stainless steel reactor, add 4 kg of microcrystalline cellulose core and 500 g of 10% NaClO solution, stir and react at 20 °C for 12 h, filter, wash with purified water, and vacuum dry at 50 °C for 12 h to obtain 3.8 kg of carboxylated microcrystalline cellulose core for standby;

[0052] In a 100 L reactor, add 3.8 kg of carboxylated microcrystalline cellulose core, add 70 kg of DMF, add 300 g of N-hydroxysuccinimide and 800 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir for 30 min, then add 2 kg of 4-aminoazobenzene, react at 60 °C for 24 h, filter, wash with 5 kg of purified water, and vacuum dry at 50 °C for 10 h to obtain 4.4 kg of grafted microcrystalline cellulose core;

[0053] In a 20 L reactor, add 800 g of amino-functionalized Fe3O4 into 50 kg of 2-morpholinoethanesulfonic acid buffer solution, add 600 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 300 g of N-hydroxysuccinimide, stir and react at 20 °C for 30 min, add 4 kg of grafted microcrystalline cellulose core, react at room temperature for 12 h, filter, wash once with 2 kg of purified water, and vacuum dry at 50 °C for 12 h to obtain 4.6 kg of modified composite microcrystalline cellulose core.

[0054] (2) Preparation of nanoscale drug-loading coating solution: Add 4 kg of levofloxacin and 5 kg of DMF to a 50L stainless steel reactor and stir to dissolve. Slowly add the purified aqueous solution containing stabilizer (50 kg of purified water + 20 g of sodium dodecyl sulfate). During the dropping process, a nanoscale suspension is formed. Stir for 2 h. Pass the nanoscale suspension through an ultrafiltration system (pressure setting: 0.5 MPa, pore size of ultrafiltration membrane: 0.22 μm) to obtain wet nanoscale levofloxacin. Then wash it 5 times with 30 kg of purified water and dry it under vacuum at 60 °C to obtain 3.1 kg of nanoscale levofloxacin. Add 3 kg of nanoscale levofloxacin, 13 g of sodium dodecyl sulfate, 9 kg of purified water, and then perform high-pressure homogenization treatment at a homogenization pressure of 1000 - 2000 bar for 3 cycles to obtain 12 kg of nanoscale suspension drug-loading coating solution for standby.

[0055] (3) Drug loading on fluidized bed: Pour 300 g of the modified microcrystalline cellulose pellets in step (1) into the fluidized bed. Turn on the fan and heater to raise the temperature of the modified microcrystalline cellulose pellets to 35 °C. Add 2.5 kg of the drug-loading coating solution in step (2). Adjust the inlet air temperature of the fluidized bed to 75 °C and the inlet air volume to 135 m 3 / h. Adjust the atomization pressure to 0.15 Mpa and the liquid spraying rate to 5 - 10 mL / min. Spray it onto the modified microcrystalline cellulose pellets in step (1) and dry for 30 min to obtain 963 g of drug-loaded pellets.

[0056] (4) Preparation of sustained-release coating solution: Add 240 g of ethyl cellulose, 40 g of triethyl citrate, 60 g of hypromellose, and 4.8 kg of 75% ethanol to a tank and stir to obtain 5.1 kg of sustained-release coating solution for standby.

[0057] (5) Preparation of sustained-release pellets: Pour 963 g of the drug-loaded pellets in step (3) into the fluidized bed. Turn on the fan and heater to raise the temperature of the drug-loaded pellets to 40 °C. Add 1.9 kg of the sustained-release coating solution in step (4). Adjust the inlet air temperature of the fluidized bed to 55 °C and the inlet air volume to 170 m 3 / h. Adjust the atomization pressure to 0.25 Mpa and the liquid spraying rate to 5 - 10 mL / min. Spray it onto the drug-loaded pellets in step (3) and dry for 30 min to obtain 1.08 kg of sustained-release pellets.

[0058] (6) Preparation of total mixed granules: Mix 1.08 kg of the sustained-release pellets, 1720 g of microcrystalline cellulose, and 720 g of microcrystalline cellulose in a mixer, and then add 14.4 g of magnesium stearate and mix to obtain 2.52 kg of total mixed granules.

[0059] (7) Preparation of sustained-release tablets: Add 1.5 kg of the total mixed granules in step (6) to a tableting machine for tableting. Set the main pressing pressure of the tableting machine to 10 KN to obtain the sustained-release tablets.

[0060] (8) Preparation of film coating solution: Add 80 g of film coating premix and 800 g of purified water into a 1 L single-necked flask, stir evenly to obtain 880 g of film coating solution.

[0061] (9) Finished product: Add the sustained-release tablets obtained in step (7) into a coating machine, turn on the hot air and the rotating drum. Set the inlet air temperature of 500 g of the film coating solution obtained in step (8) (reference set value: 60 °C), the rotating speed of the coating machine drum is 2 rpm, preheat to make the tablet bed temperature reach 40 °C, control the rotating speed of the drum at 3 rpm, the flow rate of the coating solution is 10 g / min, and the atomization pressure is 0.2 Mpa. Sustained-release tablets, and obtain levofloxacin sustained-release tablets after drying for 30 min.

[0062] Example 3

[0063] A levofloxacin sustained-release tablet is obtained by the following preparation method:

[0064] (1) Preparation of modified composite microcrystalline cellulose cores:

[0065] Add 1 kg of 100 nm Fe3O4 nanoparticles and 30 kg of ethanol into a 5 L reactor, add 500 g of amino silane, reflux at 80 °C for 6 h, filter, wash with 2 kg of ethanol, and vacuum dry at 60 °C for 12 h to obtain 900 g of amino-functionalized Fe3O4 for standby;

[0066] In a 50 L stainless steel reactor, add 4 kg of microcrystalline cellulose cores and 500 g of 10% NaClO solution, stir and react at a system temperature of 20 °C for 12 h, filter, wash with purified water, and vacuum dry at 50 °C for 12 h to obtain 3.8 kg of carboxylated microcrystalline cellulose cores for standby;

[0067] In a 100 L reactor, add 3.8 kg of carboxylated microcrystalline cellulose cores, add 70 kg of DMF, add 300 g of N-hydroxysuccinimide and 800 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir for 30 min, then add 2 kg of 4-aminoazobenzene, react at 60 °C for 24 h, filter, wash with 5 kg of purified water, and vacuum dry at 50 °C for 10 h to obtain 4.4 kg of grafted microcrystalline cellulose cores;

[0068] In a 20 L reactor, add 800 g of amino-functionalized Fe3O4 into 50 kg of 2-morpholinoethanesulfonic acid buffer solution, add 600 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 300 g of N-hydroxysuccinimide, stir and react at 20 °C for 30 min, add 4 kg of grafted microcrystalline cellulose cores, react at room temperature for 12 h, filter, wash once with 2 kg of purified water, and vacuum dry at 50 °C for 12 h to obtain 4.6 kg of modified composite microcrystalline cellulose cores.

[0069] (2) Preparation of nanoscale drug-loading coating solution: Add 4 kg of levofloxacin and 5 kg of DMF to a 50L stainless steel reactor and stir to dissolve. Slowly add the purified aqueous solution containing the stabilizer (50 kg of purified water + 20 g of sodium dodecyl sulfate). A nanoscale suspension is formed during the dropping process. Stir for 2 h. Pass the nanoscale suspension through an ultrafiltration system (pressure setting: 0.5 MPa, pore size of the ultrafiltration membrane: 0.22 μm) to obtain wet nanoscale levofloxacin. Then wash it 5 times with 30 kg of purified water and dry it in vacuum at 60°C to obtain 3.1 kg of nanoscale levofloxacin. Add 3 kg of nanoscale levofloxacin, 13 g of sodium dodecyl sulfate, 9 kg of purified water, and then perform high-pressure homogenization treatment at a homogenization pressure of 1000 - 2000 bar for 3 cycles to obtain 12 kg of nanoscale suspension drug-loading coating solution for standby.

[0070] (3) Drug loading on fluidized bed: Pour 400 g of the modified microcrystalline cellulose pellets from step (1) into the fluidized bed, turn on the fan and heater, raise the temperature of the modified microcrystalline cellulose pellets to 40°C. Add 2.6 kg of the drug-loading coating solution from step (2), adjust the inlet air temperature of the fluidized bed to 80°C, adjust the inlet air volume to 140 m 3 / h, adjust the atomization pressure to 0.2 Mpa, and the liquid spraying rate to 5 - 10 mL / min. Spray it onto the modified microcrystalline cellulose pellets from step (1) and dry for 30 min to obtain 1.09 kg of drug-loaded pellets.

[0071] (4) Preparation of sustained-release coating solution: Add 240 g of ethyl cellulose, 40 g of triethyl citrate, 60 g of hypromellose, and 4.8 kg of 75% ethanol to a tank and stir to obtain 5.1 kg of sustained-release coating solution for standby.

[0072] (5) Preparation of sustained-release pellets: Pour 1.09 kg of the drug-loaded pellets from step (3) into the fluidized bed, turn on the fan and heater, raise the temperature of the drug-loaded pellets to 45°C. Add 2.0 kg of the sustained-release coating solution from step (4), adjust the inlet air temperature of the fluidized bed to 60°C, adjust the inlet air volume to 180 m 3 / h, adjust the atomization pressure to 0.3 Mpa, and the liquid spraying rate to 5 - 10 mL / min. Spray it onto the drug-loaded pellets from step (3) and dry for 30 min to obtain 1.22 kg of sustained-release pellets.

[0073] (6) Preparation of total mixed granules: Mix 1.22 kg of the sustained-release pellets, 1813 g of microcrystalline cellulose, and 2813 g of microcrystalline cellulose in a mixer, and then add 16.2 g of magnesium stearate and mix to obtain 2.85 kg of total mixed granules.

[0074] (7) Preparation of sustained-release tablets: Add 2.0 kg of the total mixed granules from step (6) to a tableting machine and tablet. Set the main pressing pressure of the tableting machine to 10 KN to obtain the sustained-release tablets.

[0075] (8) Preparation of film coating solution: Add 80 g of film coating premix and 800 g of purified water into a 1 L single-neck flask, stir evenly to obtain 880 g of film coating solution.

[0076] (9) Finished product: Add the sustained-release tablets obtained in step (7) into a coating machine, turn on the hot air and the drum, set the inlet air temperature of 600 g of the film coating solution obtained in step (8) (reference setting value: 60 °C), the rotation speed of the coating machine drum is 2 rpm, preheat to make the tablet bed temperature reach 40 °C, control the drum rotation speed at 3 rpm, the coating solution flow rate is 10 g / min, and the atomization pressure is 0.2 Mpa. Sustained-release tablets, and levofloxacin sustained-release tablets are obtained after drying for 30 min.

[0077] Comparative Example 1

[0078] A levofloxacin sustained-release tablet is obtained by the following preparation method:

[0079] (1) Preparation of nano-level drug-loading coating solution: Add 4 kg of levofloxacin and 5 kg of DMF into a 50 L stainless steel reactor, stir and dissolve, slowly add an aqueous solution of purified water containing a stabilizer (50 kg of purified water + 20 g of sodium dodecyl sulfate), a nano-level suspension is formed during the dropping process, stir for 2 h, and pass the nano-level suspension through an ultrafiltration system (pressure setting: 0.5 MPa, pore size of the ultrafiltration membrane: 0.22 um) to obtain wet nano-level levofloxacin, and then wash it 5 times with 30 kg of purified water, and vacuum dry at 60 °C to obtain 3.1 kg of nano-level levofloxacin; Add 3 kg of nano-level levofloxacin, 13 g of sodium dodecyl sulfate, 9 Kg of purified water, and then perform high-pressure homogenization treatment, the homogenization pressure is 1000 - 2000 bar, and circulate 3 times to obtain 12 kg of nano-suspension drug-loading coating solution for standby.

[0080] (2) Drug loading on fluidized bed: Pour 200 g of microcrystalline cellulose pellets into the fluidized bed, turn on the fan and heating, raise the temperature of the modified microcrystalline cellulose pellets to 30 °C, add 2.4 kg of the drug-loading coating solution obtained in step (1), adjust the inlet air temperature of the fluidized bed to 70 °C, adjust the inlet air volume to 130 m 3 / h, adjust the atomization pressure to 0.1 Mpa, and the liquid spraying rate is 5 - 10 mL / min, spray it onto the microcrystalline cellulose pellets, and dry for 30 min to obtain 837 g of drug-loaded pellets.

[0081] (3) Preparation of sustained-release coating solution: Add 240 g of ethyl cellulose, 40 g of triethyl citrate, 60 g of hypromellose, and 4.8 kg of 75% ethanol into a tank, stir to obtain 5.1 kg of sustained-release coating solution for standby.

[0082] (4) Preparation of sustained-release pills: Pour 837 g of the upper pills from step (2) into the fluidized bed, turn on the fan and heating, raise the temperature of the upper pills to 35 °C, and use 1.8 kg of the sustained-release coating solution from step (3). Adjust the inlet air temperature of the fluidized bed to 50 °C, the inlet air volume to 160 m 3 / h, adjust the atomization pressure to 0.2 Mpa, the liquid spraying rate to 5 - 10 mL / min, spray it onto the upper pills from step (2), and dry for 30 min to obtain 950 g of sustained-release pills.

[0083] (5) Preparation of total mixed granules: In a mixer, mix 950 g of the sustained-release pills from step (4), 1633 g of microcrystalline cellulose 1, and 633 g of microcrystalline cellulose 2, and then add 12.6 g of magnesium stearate and mix to obtain 2.22 kg of total mixed granules.

[0084] (6) Preparation of sustained-release tablets: Add 1 kg of the total mixed granules from step (5) into a tabletting machine for tabletting, set the main pressing pressure of the tabletting machine to 10 KN, and then obtain the sustained-release tablets

[0085] (7) Preparation of film coating solution: Add 80 g of film coating premix and 800 g of purified water into a 1 L single-necked flask, stir evenly to obtain 880 g of film coating solution.

[0086] (8) Finished product: Add the sustained-release tablets from step (6) into a coating machine, turn on the hot air and the rotating drum, set the inlet air temperature of the film coating solution from step (7) (reference setting value: 60 °C), the rotating speed of the coating machine drum to 2 rpm, preheat to make the tablet bed temperature reach 40 °C, control the rotating speed of the drum to 3 rpm, the coating solution flow rate to 10 g / min, the atomization pressure to 0.2 Mpa, spray it onto the sustained-release tablets from step (6), and after drying for 30 min, obtain levofloxacin sustained-release tablets.

[0087] Comparative Example 2

[0088] A levofloxacin sustained-release tablet is obtained by the following preparation method:

[0089] (1) Preparation of modified composite microcrystalline cellulose pill cores:

[0090] Add 1 kg of 100 nm Fe3O4 nanoparticles, 30 kg of ethanol, and 500 g of aminosilane into a 5 L reaction kettle, reflux at 80 °C for 6 h, filter, wash with 2 kg of ethanol, and dry in vacuum at 60 °C for 12 h to obtain 900 g of amino-functionalized Fe3O4 for standby;

[0091] In a 50 L stainless steel reaction kettle, add 4 kg of microcrystalline cellulose pill cores and 500 g of 10% NaClO solution, stir and react at a system temperature of 20 °C for 12 h, filter, wash with purified water, and dry in vacuum at 50 °C for 12 h to obtain 3.8 kg of carboxylated microcrystalline cellulose pill cores for standby;

[0092] In a 100 L reaction kettle, add 3.8 kg of carboxylated microcrystalline cellulose pellets, 70 kg of DMF, 300 g of N-hydroxysuccinimide, and 800 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Stir for 30 min, then add 2 kg of 4-aminoazobenzene, and react at 60 °C for 24 h. Filter, wash with 5 kg of purified water, and dry in vacuum at 50 °C for 10 h to obtain 4.4 kg of grafted microcrystalline cellulose pellets;

[0093] In a 20 L reaction kettle, add 800 g of amino-functionalized Fe3O4 and 50 kg of 2-morpholinoethanesulfonic acid buffer solution. Add 600 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 300 g of N-hydroxysuccinimide, stir and react at 20 °C for 30 min, add 4 kg of grafted microcrystalline cellulose pellets, react at room temperature for 12 h, filter, wash once with 2 kg of purified water, and dry in vacuum at 50 °C for 12 h to obtain 4.6 kg of modified composite microcrystalline cellulose pellets.

[0094] (2) Preparation of the coating solution for drug loading: Add 9 kg of purified water to a tank, then add 3 kg of levofloxacin and 20 g of sodium dodecyl sulfate, stir evenly, and obtain 12.2 kg of suspension coating solution for drug loading for standby.

[0095] (3) Drug loading on the fluidized bed: Pour 200 g of the modified microcrystalline cellulose pellets obtained in step (1) into the fluidized bed, turn on the blower and heating, raise the temperature of the modified microcrystalline cellulose pellets to 30 °C, add 2.4 kg of the coating solution for drug loading in step (2), adjust the inlet air temperature of the fluidized bed to 70 °C, adjust the inlet air volume to 130 m 3 / h, adjust the atomization pressure to 0.1 Mpa, and the liquid spraying rate is 5 - 10 mL / min. Spray onto the modified microcrystalline cellulose pellets in step (1) and dry for 30 min to obtain 837 g of drug-loaded pellets.

[0096] (4) Preparation of the sustained-release coating solution: Add 240 g of ethylcellulose, 40 g of triethyl citrate, 60 g of hypromellose, and 4.8 kg of 75% ethanol to a tank, stir to obtain 5.1 kg of sustained-release coating solution for standby.

[0097] (5) Preparation of the sustained-release pellets: Pour 837 g of the drug-loaded pellets obtained in step (3) into the fluidized bed, turn on the blower and heating, raise the temperature of the drug-loaded pellets to 30 °C, add 1.8 kg of the sustained-release coating solution in step (4), adjust the inlet air temperature of the fluidized bed to 50 °C, adjust the inlet air volume to 160 m 3 / h, adjust the atomization pressure to 0.2 Mpa, and the liquid spraying rate is 5 - 10 mL / min. Spray onto the drug-loaded pellets in step (3) and dry for 30 min to obtain 950 g of sustained-release pellets.

[0098] (6) Preparation of the total mixed granules: 950 g of sustained-release pills, 1,633 g of microcrystalline cellulose, and 2633 g of microcrystalline cellulose were mixed in a mixer, and then 12.6 g of magnesium stearate was added and mixed to obtain 2.22 kg of total mixed granules.

[0099] (7) Preparation of the sustained-release tablets: 1 kg of the total mixed granules from step (6) was added to a tableting machine for tableting. The main pressing pressure of the tableting machine was set at 10 KN, and then the sustained-release tablets were obtained.

[0100] (8) Preparation of the film coating solution: 80 g of the film coating premix and 800 g of purified water were added to a 1-L single-neck flask and stirred evenly to obtain 880 g of the film coating solution.

[0101] (9) Finished product: The sustained-release tablets from step (7) were added to a coating machine. The hot air and the rotating drum were turned on. 400 g of the film coating solution from step (8) was set with an inlet air temperature (reference setting value: 60 °C). The rotating speed of the coating machine drum was 2 rpm. The bed temperature of the tablets was preheated to 40 °C. The rotating speed of the drum was controlled at 3 rpm. The flow rate of the coating solution was 10 g / min, and the atomization pressure was 0.2 Mpa. After drying the sustained-release tablets for 30 min, levofloxacin sustained-release tablets were obtained.

[0102] Detection method:

[0103] According to the dissolution and release determination method (Method 2 of General Chapter 0931, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0104] Chromatographic method:

[0105] Instrument: High-performance liquid chromatograph;

[0106] Chromatographic column: Octadecylsilane-bonded silica gel column;

[0107] Mobile phase: Phosphate buffer solution;

[0108] Flow rate: 1.0 ml for rinsing once;

[0109] Injection volume: 40 μl;

[0110] Column temperature: 30 °C.

[0111] Dissolution method:

[0112] Instrument: Intelligent dissolution tester;

[0113] Dissolution medium: 500 ml (pH 1.2 hydrochloric acid buffer solution, pH 4.5 acetate buffer solution, pH 6.8 phosphate buffer solution);

[0114] Method: Paddle method, 50 revolutions per minute;

[0115] Sampling time: 1 h, 4 h, 8 h, 12 h, and 20 h.

[0116] The performance test comparison results of the above-mentioned embodiments and the comparative examples are as follows Figures 1 to 6 shown. The results show that a levofloxacin sustained-release tablet provided by the present invention can obtain a modified microcrystalline cellulose core through an esterification reaction, and after esterification, the hydrophilicity and pore structure can be changed, etc. After the drug is loaded, the release rate of the drug in the body is slowed down, thereby realizing the sustained-release effect of the drug, prolonging the action time of the drug, reducing the frequency of taking medicine, ensuring that the drug maintains a relatively stable blood drug concentration within a certain period of time, and thus better exerting the therapeutic effect and improving the therapeutic effect on diseases. It can be seen from Examples 1 to 3 that the RSD of the dissolution degrees at each time point of 1 h, 4 h, 8 h, 12 h, and 20 h under different acidic conditions is less than 5%, indicating good in-batch dissolution uniformity, a stable release rate in each time period, and the in vitro release rate reaching more than 80% in 12 hours. Although the dissolution uniformity of Comparative Example 1 is good, the dissolution degree reaches more than 94% after 12 h. The RSD of the dissolution degrees at each time point of Comparative Example 2 is greater than 5%, and the RSD of the dissolution degree at 1 h is greater than 19%, and the drug effect cannot be released stably.

[0117] The above-mentioned embodiments only represent several implementation manners of the present invention, and the description thereof is relatively specific and detailed, but it should not be understood as a limitation on the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Claims

1. A levofloxacin sustained-release tablet, characterized in that, It includes 2 - 4 parts of modified composite microcrystalline cellulose pill cores by weight, 24 - 26 parts of nano - level drug - loading coating solution, 18 - 20 parts of sustained - release coating solution, 10 - 20 parts of total - mixed granules, and 4 - 6 parts of film - coating solution; The preparation method of the modified composite microcrystalline cellulose pill cores is as follows: Disperse 100nm Fe3O4 nanoparticles in ethanol, add amino - silane, and reflux at 80°C for 6h to obtain amino - functionalized Fe3O4; Immerse the microcrystalline cellulose pill cores in 10% NaClO solution, stir and react at a system temperature of 20°C for 12h, filter, wash with purified water, and vacuum - dry at 50°C to obtain carboxylated microcrystalline cellulose pill cores; Disperse the carboxylated microcrystalline cellulose pill cores in DMF, add N - hydroxysuccinimide and 1 - (3 - dimethylaminopropyl) - 3 - ethylcarbodiimide hydrochloride, stir for 30min, then add 4 - aminoazobenzene, react at 60°C for 24h, filter, and wash with purified water to obtain grafted microcrystalline cellulose pill cores; Disperse the amino - functionalized Fe3O4 in 2 - morpholinoethanesulfonic acid buffer solution, add 1 - (3 - dimethylaminopropyl) - 3 - ethylcarbodiimide hydrochloride and N - hydroxysuccinimide, stir and react at 20°C for 30min, add the grafted microcrystalline cellulose pill cores, react at room temperature for 12h, filter, wash, and vacuum - dry at 50°C to obtain the modified composite microcrystalline cellulose pill cores; The preparation method of the nano - level drug - loading coating solution is as follows: Add levofloxacin to DMF and stir to dissolve it, slowly add the purified water solution containing a stabilizer, and form a nano - level suspension during the dropping process, stir for 2h, pass the nano - level suspension through an ultrafiltration system to obtain wet nano - level levofloxacin, then wash it 5 times with purified water and vacuum - dry at 60°C to obtain nano - level levofloxacin, and then perform high - pressure homogenization treatment with a homogenization pressure of 1000 - 2000 bar and cycle 3 times to obtain a nano - level drug - loading coating solution with a suspension particle size D90 ≤ 500nm.

2. The levofloxacin sustained-release tablets according to claim 1, characterized in that, The stabilizer of the nano - level drug - loading coating solution is sodium dodecyl sulfate.

3. The levofloxacin sustained-release tablets according to claim 1, characterized in that, The sustained - release coating solution contains ethyl cellulose, triethyl citrate, hydroxypropyl methylcellulose, and 75% ethanol solution, with a mass ratio of 6:1:1.5:120, and stir evenly to obtain the sustained - release coating solution.

4. The levofloxacin sustained-release tablets according to claim 1, characterized in that, The total - mixed granules are composed of sustained - release pills, microcrystalline cellulose 1, and microcrystalline cellulose 2.

5. The levofloxacin sustained-release tablets according to claim 1, characterized in that, The film - coating solution is obtained by stirring a film - coating premix and purified water.

6. A preparation method of the levofloxacin sustained-release tablets according to any one of claims 1 to 5, characterized in that, It includes the following steps: S1. Pour the modified composite microcrystalline cellulose pill cores into a fluidized bed, turn on the blower and heating, and spray the nano - level drug - loading coating solution onto the modified composite microcrystalline cellulose pill cores to obtain drug - loaded pills; S2. Pour the drug - loaded pills into a fluidized bed, turn on the blower and heating, and spray the sustained - release coating solution onto the drug - loaded pills to obtain sustained - release pills; S3. Mix the sustained - release pills, microcrystalline cellulose 1, and microcrystalline cellulose 2, and then add magnesium stearate and perform total mixing in a three - dimensional mixer to obtain total - mixed granules; S4. Add the total - mixed granules into a tablet press to press tablets to obtain sustained - release tablets; S5. Add the sustained - release tablets into a coating machine, turn on the hot air and the rotating drum, and spray the film - coating solution onto the sustained - release tablets to obtain levofloxacin sustained - release tablets.

7. The preparation method of the levofloxacin sustained-release tablets according to claim 6, wherein The process parameters for spraying the nano-level drug-coated solution are as follows: the inlet air temperature of the fluidized bed is 70 - 80 °C, the air volume is 130 - 140 m 3 / h, and the atomization pressure is 0.1 - 0.2 MPa.

8. The preparation method of the levofloxacin sustained-release tablets according to claim 6, characterized in that, The process parameters for spraying the sustained-release coating solution are as follows: the inlet air temperature of the fluidized bed is 50 - 60 °C, the air volume is 160 - 180 m 3 / h, and the atomization pressure is 0.2 - 0.3 MPa.

9. The preparation method of the levofloxacin sustained-release tablets according to claim 6, wherein, The process parameters for spraying the film coating solution are as follows: set the inlet air temperature at 60°C, the rotation speed of the coating machine drum at 2 rpm, preheat to make the tablet bed temperature reach 40°C, control the rotation speed of the drum at 3 rpm, the flow rate of the coating solution at 10 g / min, and the atomization pressure at 0.2 Mpa.

10. The preparation method of the levofloxacin sustained-release tablets according to claim 6, wherein In the tabletting process, the main pressing pressure is 10 - 20 KN.

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