Methylprednisolone pulse microchip and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a methylprednisolone pulse micro-tablet and a preparation method thereof. The methylprednisolone pulse microtablet comprises a quick release tablet core and a coating layer, the quick-release tablet core comprises methylprednisolone, a filler, an antistatic agent A, an antistatic agent B, an adhesive and a lubricant; the coating layer comprises a coating material and a plasticizer; wherein the antistatic agent A is selected from at least one of a combination of organic acid and bicarbonate or ammonium carbonate; the antistatic agent B is selected from at least one of polyoxyethylene, carbomer, high-expansion type pregelatinized starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone. The antistatic agent A and the antistatic agent B have a synergistic effect, so that the electrostatic phenomenon can be effectively reduced, and particle adhesion and microchip agglomeration are avoided.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a methylprednisolone pulse microtablet and a preparation method thereof. BACKGROUND

[0002] Methylprednisolone is an important glucocorticoid drug, which is widely used in clinical practice and can be used for the treatment of inflammatory diseases of multiple system organs and immune diseases. However, in the preparation process of methylprednisolone microtablets, the drug needs to be micronized to meet the requirements of tabletting, and the problem of static electricity becomes a key technical problem that restricts production. Static electricity not only leads to particle agglomeration and poor flowability, but also causes quality defects such as sticking and pitting, which seriously affects product quality and production efficiency.

[0003] There are many patent applications in the field of methylprednisolone preparations, mainly involving crystal forms, prescription compositions and preparation processes. Among them, CN101804061A discloses a new crystal form I of methylprednisolone, which has characteristic peaks at 2θ of 7.9°, 13.1°, 14.6°, 17.2°, 20.3° and 21.5° in X-ray powder diffraction. The patent also provides a corresponding tablet composition, which contains crystal form I of methylprednisolone and one or more pharmaceutical excipients suitable for tablets, such as lactose, starch, sucrose, dextrin, sodium cross-linked carboxymethyl cellulose, magnesium stearate, etc. CN114681416A patent discloses another methylprednisolone tablet formula, which is composed of methylprednisolone, cellulose and lactose complex, calcium or magnesium stearate, micronized silica gel and sodium cross-linked carboxymethyl cellulose. The patent emphasizes that the particle size of methylprednisolone D 90 is maintained within 25 μm to ensure tablet quality, and 4 preparation processes are reduced by optimizing the prescription and process, effectively reducing the cost. EP0301006B1 patent relates to methylprednisolone / sodium carboxymethyl starch tablet composition, which uses sodium carboxymethyl starch as a disintegrant. The patent shows that sodium carboxymethyl starch not only has good disintegration performance, but also can improve the dissolution characteristics of the drug. From these patents, it can be seen that the existing methylprednisolone preparation patents mainly focus on crystal form control, prescription optimization and process simplification, but none of them involve the problem of static electricity elimination.

[0004] The static electricity elimination technology in the pharmaceutical process mainly focuses on equipment modification and auxiliary material addition. In terms of equipment modification, the CN207942736U patent provides a static electricity elimination structure based on a tablet press, which reduces the sticking, pitting and other adverse phenomena in the tablet pressing process by installing a fan-shaped nozzle ion generator in the tablet press bin. The patent installs a generator fixing seat on the tablet press bin table, and installs a fan-shaped nozzle ion generator on the fixing seat, which eliminates static electricity through ion neutralization. Although this scheme can reduce the occurrence of static electricity through external intervention, it also increases the equipment cost in the process of preparing the medicine. In terms of auxiliary material addition, the CN115975256B patent discloses an anti-static agent containing an ionic liquid, which includes coconut oil diethanolamide, a solubilizer, an inorganic salt ion compound, and an organic ionic liquid and a plasticizer. Although this anti-static agent can eliminate static electricity by increasing the conductivity of the material, the composition of the anti-static agent is complex and relatively expensive. SUMMARY

[0005] The present application aims to overcome the shortcomings of the prior art and provides a methylprednisolone pulse microtablet and a preparation method thereof, which can reduce the generation of static electricity during the preparation of the methylprednisolone pulse microtablet, and the preparation process is simple and low in cost.

[0006] During the mixing, sieving and granulation of hydrophobic fine powders such as methylprednisolone bulk drug and matrix excipients, friction and collision between particles, between particles and the metal inner wall of the equipment and the sieve, will generate static electricity, leading to the phenomenon of powder adsorption on the inner wall of the equipment and the occurrence of particle agglomeration and caking, which will directly affect the subsequent material supply for tabletting. At the same time, the size of the microtablet mold film hole is small, and static electricity will cause the powder particles to agglomerate or adsorb on the inner wall and edge of the punch, resulting in insufficient amount of particles entering the film hole, and finally the weight of the microtablet is insufficient and the hardness does not meet the requirements, or even the microtablet cannot be successfully formed. The extrusion and friction between the particles and the punch and die of the tablet press, combined with the structural change of the particles after being pressed, will induce static electricity, causing the microtablet to stick to the punch and be difficult to demold, or the weight difference of the microtablet is too large.

[0007] The specific technical solutions of the present application are as follows:

[0008] A methylprednisolone pulse microtablet, comprising a immediate-release tablet core and a coating layer; the immediate-release tablet core comprises methylprednisolone, a filler, an antistatic agent A, an antistatic agent B, a binder and a lubricant; the coating layer comprises a coating material and a plasticizer.

[0009] Wherein, antistatic agent A is selected from a combination of organic acid and bicarbonate or at least one of ammonium carbonate; wherein, the organic acid is selected from at least one of salicylic acid, tartaric acid, fumaric acid, malic acid, gallic acid, citric acid, and alginic acid, and the bicarbonate is selected from at least one of sodium bicarbonate and potassium bicarbonate; the molar ratio of organic acid to bicarbonate is 1:0.8 to 1:1.2.

[0010] Antistatic agent B is selected from at least one of polyoxyethylene, carbomer, high-expansion pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and croscarmellose; the high-expansion pregelatinized starch is selected from at least one of Starch1500, PCS® PC-10, Lycatab PGS, SWELSTAR™ MX-1, and Prejel PA5 PH.

[0011] Preferably, the particle size D of the methylprednisolone is... 90 ≤20μm;

[0012] Preferably, the immediate-release tablet core comprises, by weight, 20-30 parts of methylprednisolone, 50-70 parts of filler, 0.5-5 parts of antistatic agent A, 5-10 parts of antistatic agent B, 0.5-2 parts of lubricant, and 1-3 parts of binder.

[0013] Preferably, the coating layer comprises, by weight, 15-25 parts of coating material and 2-8 parts of plasticizer.

[0014] Preferably, the mass ratio of the immediate-release tablet core to the coating layer is (100~105):(20~30).

[0015] Preferably, in the immediate-release tablet core, the filler is selected from one or more of lactose, microcrystalline cellulose, starch, and mannitol; the lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, zinc stearate, and sodium stearate fumarate; and the binder is selected from one or more of starch paste, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, sucrose, and polyvinylpyrrolidone.

[0016] Preferably, in the coating layer, the coating material is selected from one or more of ethyl cellulose, cellulose acetate, Eudragit® NE 30D, cellulose acetate butyrate, and polyvinyl acetate, and the plasticizer is selected from one or more of triethyl citrate, diethyl phthalate, dibutyl phthalate, polyethylene glycol 400, and dibutyl sebacate.

[0017] The electrostatic elimination mechanism of this invention is as follows:

[0018] (1) Antistatic agent A, such as sodium bicarbonate, dissociates into sodium and bicarbonate ions after dissolving in water. These ions can form a conductive layer on the particle surface, which helps to transfer and dissipate the charge. Ionic compounds can eliminate static electricity by forming a conductive water film, which can work even in a relatively dry environment. At the same time, during the reaction of organic acids such as citric acid with sodium bicarbonate to produce carbon dioxide, proton transfer occurs. This chemical reaction changes the charge distribution on the particle surface, thereby reducing static electricity accumulation. In addition, the water produced by the reaction also helps to increase the humidity of the environment and promote the dissipation of static electricity.

[0019] (2) Antistatic agent B has a porous structure. These pores can adsorb moisture in the air and form a thin water film on the surface of the particles. This water film can not only increase the surface conductivity, but also act as a lubricant to reduce the friction between particles. At the same time, during the mixing process with drug particles, antistatic agent B forms a coating layer on the drug surface through physical adsorption or hydrogen bonding to modify the surface of the drug, change the electrical properties of the drug surface, and thus reduce the generation and accumulation of static electricity.

[0020] (3) During the tableting process, antistatic agent A and antistatic agent B will form a physical barrier on the surface of drug particles, reducing direct contact between particles and thus reducing the possibility of triboelectric charging. This effect is similar to the function of surfactants, which can effectively prevent electrostatic aggregation.

[0021] A method for preparing methylprednisolone pulsed microsheets includes the following steps:

[0022] S1 uses adhesive and water to prepare an adhesive solution;

[0023] S2 Methylprednisolone is mixed with filler, antistatic agent A and antistatic agent B, and then atomized and sprayed into the binder solution obtained in step S1 for granulation to obtain methylprednisolone granules; then lubricant is added and tableted to obtain immediate-release tablet cores.

[0024] S3 uses coating material, plasticizer and water to prepare coating solution; then the immediate release tablet core is spray-coated with coating solution, and the coating solution is uniformly deposited on the surface of the tablet core to form a coating film, and finally methylprednisolone pulse microplates are obtained.

[0025] Preferably, in step S1, the mass ratio of the adhesive to water is (1~3):(60~100).

[0026] Preferably, in step S2, methylprednisolone particles are prepared in a fluidized bed granulator;

[0027] Preferably, in step S2, the liquid supply rotation speed of the atomizing injection is 15~35 rpm / min, and the air volume is 15~30 m³ / min. 3 / h, inlet air temperature is 50~70℃, atomization pressure is 1~5 bar;

[0028] Preferably, in step S2, the methylprednisolone particles are passed through a 50-100 mesh sieve before the lubricant is added;

[0029] Preferably, in step S2, the tablet press uses a punch with a diameter of 1~3mm;

[0030] Preferably, in step S2, the hardness of the immediate-release tablet core is 5~15N;

[0031] Preferably, in step S3, the mass ratio of coating material, plasticizer and water is (15~25):(2~8):(67~83);

[0032] Preferably, in step S3, the coating machine is preheated at 30~35℃ for 10 minutes, the immediate-release tablet core is placed in the coating machine, and the coating solution is sprayed in under the following conditions: spraying speed of 5~7 rpm, pot rotation speed of 10~20 rpm, air inlet temperature of 30~50℃, air outlet temperature of 20~40℃, and atomization space pressure of 8~11 MPa.

[0033] Compared with existing technologies, the beneficial effects are as follows:

[0034] (1) By rationally selecting the types and ratios of antistatic agent A and antistatic agent B, this invention can significantly reduce the static electricity level of methylprednisolone pulse microplates, improve the tableting process, and enhance product quality;

[0035] (2) The present invention uses traditional technology to solve the problem of static electricity elimination. At the same time, the antistatic agents A and B of the present invention also have the functions of generating gas and absorbing water to expand and disintegrate, which can realize pulse release to a certain extent. Therefore, the present invention achieves the two functions of static electricity elimination and pulse release through a set of excipients. No additional excipients are required, which greatly simplifies the prescription and process and reduces the cost.

[0036] (3) The present invention does not require additional static electricity removal equipment or process steps, nor does it require changes to existing production equipment. It can reduce static electricity generation based on the original granulation and tableting process. Detailed Implementation

[0037] The embodiments of the present invention will be described in further detail below. The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0038] Example 1

[0039] A type of methylprednisolone pulsed microplate includes an immediate-release tablet core and a coating layer; the immediate-release tablet core, by weight parts, comprises 28 parts of methylprednisolone (D... 90 ≤20μm), 57.7 parts microcrystalline cellulose (filler), 8 parts crospovidone (antistatic agent B), 2.3 parts citric acid, 1 part sodium bicarbonate, 2 parts hydroxypropyl methylcellulose (binder), 1 part magnesium stearate (lubricant); coating layer, by weight, includes 20 parts ethyl cellulose (coating material) and 5 parts triethyl citrate (plasticizer).

[0040] The mass ratio of the immediate-release tablet core to the coating layer is 105:28.

[0041] The preparation method is as follows:

[0042] S1 According to the formula, add 2 parts of hydroxypropyl methylcellulose to 80 parts of purified water, stir at room temperature until completely dissolved, and obtain the adhesive solution;

[0043] S2. According to the specified ratio, methylprednisolone, microcrystalline cellulose, citric acid, sodium bicarbonate, and crospovidone are added to a fluidized bed granulator and mixed evenly. Then, the mixture is atomized and sprayed into the binder solution obtained in step S1 for granulation. The liquid supply speed is 25 rpm / min, and the air volume is 22 m³ / min. 3 / h, the inlet air temperature is 60℃, the atomization pressure is 3bar, and after drying, methylprednisolone granules are obtained; after passing the methylprednisolone granules through an 80-mesh sieve, 1 part of magnesium stearate is added according to the ratio, and the mixture is evenly mixed. The methylprednisolone granules are compressed into tablets using a punch with a diameter of 2mm to obtain methylprednisolone immediate-release tablet cores with a hardness of 10N.

[0044] S3 According to the formula, 20 parts of ethyl cellulose and 5 parts of triethyl citrate are added to 75 parts of purified water and stirred to mix evenly to obtain a coating solution. The coating machine is preheated at 35℃ for 10 minutes. The methylprednisolone immediate-release tablet core is placed in the coating machine. The coating solution is sprayed into the machine under the conditions of spraying speed of 5 rpm, pot rotation speed of 20 rpm, inlet air temperature of 40℃, exhaust air temperature of 30℃, and atomization space pressure of 10 MPa to spray and coat the immediate-release tablet core. The coating solution is evenly deposited on the surface of the tablet core to form a coating film. After coating, the tablet core is packaged to obtain methylprednisolone pulse microplates.

[0045] Example 2

[0046] A type of methylprednisolone pulsed microplate includes an immediate-release tablet core and a coating layer; the immediate-release tablet core, by weight parts, includes 22 parts of methylprednisolone (D... 90≤20μm), starch 66.9 parts (filler), carbomer 6 parts (antistatic agent B), tartaric acid 1.8 parts, sodium bicarbonate 1 part, sodium carboxymethyl cellulose 1.5 parts (binder), talc 0.8 parts (lubricant); coating layer, by weight, includes ethyl cellulose 18 parts (coating material) and triethyl citrate 3 parts (plasticizer).

[0047] The mass ratio of the immediate-release tablet core to the coating layer is 100:22.

[0048] The preparation method is as follows:

[0049] S1 According to the formula, add 1.5 parts of sodium carboxymethyl cellulose to 65 parts of purified water, stir at room temperature until completely dissolved, and obtain the adhesive solution;

[0050] S2 According to the specified ratio, methylprednisolone, starch, tartaric acid, sodium bicarbonate, and carbomer are added to a fluidized bed granulator and stirred until uniformly mixed. Then, the mixture is atomized and sprayed into the binder solution obtained in step S1 for granulation. The liquid supply speed is 18 rpm / min, and the air volume is 18 m³ / min. 3 / h, the inlet air temperature is 55℃, the atomization pressure is 2bar, and after drying, methylprednisolone granules are obtained; after passing the methylprednisolone granules through a 60-mesh sieve, 0.8 parts of talc powder are added according to the formula, mixed evenly, and the methylprednisolone granules are compressed into tablets using a punch with a diameter of 1.5mm to obtain methylprednisolone immediate-release tablet cores with a hardness of 8N.

[0051] S3 According to the formula, 18 parts of ethyl cellulose and 3 parts of triethyl citrate were added to 79 parts of purified water and stirred until uniform to obtain a coating solution. The coating machine was preheated at 32℃ for 10 minutes. The methylprednisolone immediate-release tablet core was placed in the coating machine. The coating solution was sprayed into the machine under the conditions of a spraying speed of 5 rpm, a pot rotation speed of 20 rpm, an inlet air temperature of 35℃, an exhaust air temperature of 25℃, and an atomization space pressure of 10 MPa. The immediate-release tablet core was spray-coated, and the coating solution was uniformly deposited on the surface of the tablet core to form a coating film. After the coating was completed, it was packaged to obtain methylprednisolone pulse microplates.

[0052] Example 3

[0053] A type of methylprednisolone pulsed microplate includes an immediate-release tablet core and a coating layer; the immediate-release tablet core, by weight parts, comprises 28 parts of methylprednisolone (D... 90 ≤20μm), 56.44 parts microcrystalline cellulose (filler), 9 parts croscarmellose sodium (antistatic agent B), 1.16 parts fumaric acid, 1 part potassium bicarbonate, 2.8 parts hydroxypropyl cellulose (binder), 1.6 parts calcium stearate (lubricant); coating layer, by weight, includes 24 parts ethyl cellulose (coating material) and 7 parts triethyl citrate (plasticizer).

[0054] The mass ratio of the core to the coating layer is 105:28.

[0055] The preparation method is as follows:

[0056] S1 According to the formula, add 2.8 parts of hydroxypropyl cellulose to 95 parts of purified water and stir at room temperature until completely dissolved to obtain the adhesive solution;

[0057] S2 According to the specified ratio, methylprednisolone, microcrystalline cellulose, fumaric acid, potassium bicarbonate, and croscarmellose sodium are added to a fluidized bed granulator and mixed evenly. Then, the mixture is atomized and sprayed into the binder solution obtained in step S1 for granulation. The liquid supply speed is 32 rpm / min, and the air volume is 28 m³ / min. 3 / h, the inlet air temperature is 68℃, the atomization pressure is 4.5 bar, and after drying, methylprednisolone granules are obtained; after passing the methylprednisolone granules through an 80-mesh sieve, 1.6 parts of calcium stearate are added according to the formula, mixed evenly, and the methylprednisolone granules are compressed into tablets using a punch with a diameter of 2 mm to obtain methylprednisolone immediate-release tablet cores with a hardness of 14N.

[0058] S3 According to the formula, 24 parts of ethyl cellulose and 7 parts of triethyl citrate were added to 69 parts of purified water and stirred until uniform to obtain a coating solution. The coating machine was preheated at 35℃ for 10 minutes. The methylprednisolone immediate-release tablet core was placed in the coating machine. The coating solution was sprayed into the machine under the conditions of spray speed of 5 rpm, pot rotation speed of 20 rpm, inlet air temperature of 48℃, exhaust air temperature of 38℃, and atomization space pressure of 10 MPa to spray the immediate-release tablet core. The coating solution was uniformly deposited on the surface of the tablet core to form a coating film. After the coating was completed, it was packaged to obtain methylprednisolone pulse microplates.

[0059] Comparative Example 1

[0060] A type of methylprednisolone pulsed microplate, comprising an immediate-release tablet core and a coating layer; the immediate-release tablet core, by weight parts, contains 25 parts of methylprednisolone (D... 90 ≤20μm), 52.12 parts microcrystalline cellulose (filler), 12 parts croscarmellose sodium (antistatic agent B), 3.48 parts fumaric acid, 3 parts potassium bicarbonate, 2.8 parts hydroxypropyl cellulose (binder), 1.6 parts calcium stearate (lubricant); coating layer, by weight, includes 24 parts ethyl cellulose (coating material) and 7 parts triethyl citrate (plasticizer).

[0061] The mass ratio of the immediate-release tablet core to the coating layer is 105:28.

[0062] The preparation method is as follows:

[0063] S1 According to the formula, add 2.8 parts of hydroxypropyl cellulose to 95 parts of purified water and stir at room temperature until completely dissolved to obtain the adhesive solution;

[0064] S2 According to the specified ratio, methylprednisolone, microcrystalline cellulose, fumaric acid, potassium bicarbonate, and croscarmellose sodium are added to a fluidized bed granulator and mixed evenly. Then, the mixture is atomized and sprayed into the binder solution obtained in step S1 for granulation. The liquid supply speed is 32 rpm / min, and the air volume is 28 m³ / min. 3 / h, the inlet air temperature is 68℃, the atomization pressure is 4.5 bar, and after drying, methylprednisolone granules are obtained; after passing the methylprednisolone granules through an 80-mesh sieve, 1.6 parts of calcium stearate are added according to the formula, mixed evenly, and the methylprednisolone granules are compressed into tablets using a punch with a diameter of 2.8 mm to obtain methylprednisolone immediate-release tablet cores with a hardness of 14N;

[0065] S3 According to the formula, 24 parts of ethyl cellulose and 7 parts of triethyl citrate were added to 69 parts of purified water and stirred until uniform to obtain a coating solution. The coating machine was preheated at 35℃ for 10 minutes. The methylprednisolone immediate-release tablet core was placed in the coating machine. The coating solution was sprayed into the machine under the conditions of spray speed of 5 rpm, pot rotation speed of 20 rpm, inlet air temperature of 48℃, exhaust air temperature of 38℃, and atomization space pressure of 10 MPa to spray the immediate-release tablet core. The coating solution was uniformly deposited on the surface of the tablet core to form a coating film. After the coating was completed, it was packaged to obtain methylprednisolone pulse microplates.

[0066] In Comparative Example 1, the amount of antistatic agent B (crosslinked sodium carboxymethyl cellulose) was 12 parts, and the amount of antistatic agent A (3.48 parts of fumaric acid + 3 parts of potassium bicarbonate) was 6.48 parts. This exceeded the ratio of "0.5-5 parts of antistatic agent A and 5-10 parts of antistatic agent B". This deviation in the antistatic agent ratio will disrupt the dynamic balance of the micro-coating layer rupture. The imbalance of the synergistic expansion and gas generation effect of the two may lead to the tablet core disintegration rate being too fast or too slow, which will damage the timing stability of pulsed drug release. At the same time, the electrostatic adsorption of powder will be aggravated, making it more difficult to remove static electricity, ultimately affecting the quality of the formulation and the drug release effect.

[0067] Comparative Example 2

[0068] A type of methylprednisolone pulsed microplate, comprising an immediate-release tablet core and a coating layer; the immediate-release tablet core, by weight, contains 28 parts of methylprednisolone (D... 90 ≤20μm), 61.6 parts microcrystalline cellulose (filler), 6 parts croscarmellose sodium cellulose (antistatic agent B), 2.8 parts hydroxypropyl cellulose (binder), 1.6 parts calcium stearate (lubricant); coating layer, by weight, includes 24 parts ethyl cellulose (coating material) and 7 parts triethyl citrate (plasticizer).

[0069] The mass ratio of the immediate-release tablet core to the coating layer is 105:28.

[0070] The preparation method is as follows:

[0071] S1 According to the formula, add 2.8 parts of hydroxypropyl cellulose to 95 parts of purified water and stir at room temperature until completely dissolved to obtain the adhesive solution;

[0072] S2 According to the specified ratio, methylprednisolone, microcrystalline cellulose, and croscarmellose sodium are added to a fluidized bed granulator and mixed evenly. Then, the mixture is atomized and sprayed into the binder solution obtained in step S1 for granulation. The liquid supply speed is 32 rpm / min, and the air volume is 28 m³ / min. 3 / h, the inlet air temperature is 68℃, the atomization pressure is 4.5 bar, and after drying, methylprednisolone granules are obtained; after passing the methylprednisolone granules through an 80-mesh sieve, 1.6 parts of calcium stearate are added according to the formula, mixed evenly, and the methylprednisolone granules are compressed into tablets using a punch with a diameter of 2.8 mm to obtain methylprednisolone immediate-release tablet cores with a hardness of 14N;

[0073] S3 According to the formula, 24 parts of ethyl cellulose and 7 parts of triethyl citrate were added to 69 parts of purified water and stirred until uniform to obtain a coating solution. The coating machine was preheated at 35℃ for 10 minutes. The methylprednisolone immediate-release tablet core was placed in the coating machine. The coating solution was sprayed into the machine under the conditions of spray speed of 5 rpm, pot rotation speed of 20 rpm, inlet air temperature of 48℃, exhaust air temperature of 38℃, and atomization space pressure of 10 MPa to spray the immediate-release tablet core. The coating solution was uniformly deposited on the surface of the tablet core to form a coating film. After the coating was completed, it was packaged to obtain methylprednisolone pulse microplates.

[0074] Because the immediate-release tablet core does not contain antistatic agent A, it cannot synergize with antistatic agent B (cross-linked sodium carboxymethyl cellulose). Consequently, static electricity on the surface of the methylprednisolone particles in step S2 cannot be effectively eliminated, resulting in significant adhesion and a decrease in sieving pass rate. Furthermore, during the coating process in step S3, the micro-flakes agglomerate due to electrostatic adsorption, leading to uneven coating thickness and insufficient pulse release power, resulting in a flat release curve. Therefore, in the absence of antistatic agent A, antistatic agent B alone cannot achieve effective static removal, causing problems such as particle adhesion and micro-flake agglomeration during granulation and coating, while also resulting in insufficient pulse release power. This verifies that the synergistic effect of antistatic agents A and B is crucial for simultaneously achieving static removal and pulse release.

[0075] Comparative Example 3

[0076] A type of methylprednisolone pulsed microplate, comprising an immediate-release tablet core and a coating layer; the immediate-release tablet core, by weight parts, contains 25 parts of methylprednisolone (D... 90≤20μm), 68.5 parts microcrystalline cellulose (filler), 2.3 parts citric acid, 1 part sodium bicarbonate, 2 parts polyvinylpyrrolidone (binder), 1.2 parts sodium stearate fumarate (lubricant); coating layer, by weight, includes 21 parts ethyl cellulose (coating material) and 5 parts triethyl citrate (plasticizer).

[0077] The mass ratio of the immediate-release tablet core to the coating layer is 103:25.

[0078] The preparation method is as follows:

[0079] S1 According to the formula, add 2 parts of polyvinylpyrrolidone to 85 parts of purified water, stir at room temperature until completely dissolved, and obtain the adhesive solution;

[0080] S2. According to the specified ratio, methylprednisolone, microcrystalline cellulose, citric acid, and sodium bicarbonate are added to a fluidized bed granulator and stirred until uniformly mixed. Then, the mixture is atomized and sprayed into the binder solution obtained in step S1 for granulation. The liquid supply speed is 25 rpm / min, and the air volume is 25 m³ / min. 3 / h, the inlet air temperature is 62℃, the atomization pressure is 3bar, and after drying, methylprednisolone granules are obtained; after passing the methylprednisolone granules through a 90-mesh sieve, 1.2 parts of sodium stearate fumarate are added according to the formula, mixed evenly, and the methylprednisolone granules are compressed into tablets using a punch with a diameter of 2mm to obtain methylprednisolone immediate-release tablet cores with a hardness of 11N.

[0081] S3 According to the formula, 21 parts of ethyl cellulose and 5 parts of triethyl citrate were added to 74 parts of purified water and stirred until uniform to obtain a coating solution. The coating machine was preheated at 35℃ for 10 minutes. The methylprednisolone immediate-release tablet core was placed in the coating machine. The coating solution was sprayed into the machine under the conditions of spray speed of 5 rpm, pot rotation speed of 20 rpm, air inlet temperature of 42℃, air outlet temperature of 32℃, and atomization space pressure of 10 MPa to spray the immediate-release tablet core. The coating solution was uniformly deposited on the surface of the tablet core to form a coating film. After the coating was completed, it was packaged to obtain methylprednisolone pulse microplates.

[0082] In step S2, with only antistatic agent A present, the loosening and dispersing effect of antistatic agent B cannot be utilized, preventing the effective diffusion of gases from the decomposition of antistatic agent A. This results in poor static elimination of the particles, and the particles are dense with poor flowability. In step S3, during the coating process, the microflakes experience localized excessive coating thickness due to electrostatic adsorption of coating droplets. Furthermore, without the assistance of antistatic agent B during pulsed drug release, the disintegration rate is slow. Therefore, in the absence of antistatic agent B, antistatic agent A alone cannot effectively eliminate static electricity, affecting particle flowability and coating uniformity, while also slowing the disintegration rate during pulsed drug release. This further verifies that the synergistic effect of antistatic agents A and B is the core of achieving dual functionality.

[0083] Comparative Example 4

[0084] A type of methylprednisolone pulsed microplate, comprising an immediate-release tablet core and a coating layer; the immediate-release tablet core, by weight parts, contains 25 parts of methylprednisolone (D... 90 =80μm), 60.7 parts microcrystalline cellulose (filler), 8 parts crospovidone (antistatic agent B), 2.3 parts citric acid, 1 part sodium bicarbonate, 2 parts hydroxypropyl methylcellulose (binder), 1 part magnesium stearate (lubricant); the coating layer, by weight, includes 20 parts ethyl cellulose (coating material) and 5 parts triethyl citrate (plasticizer).

[0085] The mass ratio of the immediate-release tablet core to the coating layer is 102:25.

[0086] The preparation method is as follows:

[0087] S1 According to the formula, add 2 parts of hydroxypropyl methylcellulose to 80 parts of purified water, stir at room temperature until completely dissolved, and obtain the adhesive solution;

[0088] S2. According to the specified ratio, methylprednisolone, microcrystalline cellulose, citric acid, sodium bicarbonate, and crospovidone are added to a fluidized bed granulator and mixed evenly. Then, the mixture is atomized and sprayed into the binder solution obtained in step S1 for granulation. The liquid supply speed is 25 rpm / min, and the air volume is 22 m³ / min. 3 / h, the inlet air temperature is 60℃, the atomization pressure is 3bar, and after drying, methylprednisolone granules are obtained; after passing the methylprednisolone granules through an 80-mesh sieve, 1 part of magnesium stearate is added according to the ratio, and the mixture is evenly mixed. The methylprednisolone granules are compressed into tablets using a punch with a diameter of 2mm to obtain methylprednisolone immediate-release tablet cores with a hardness of 10N.

[0089] S3 According to the formula, 20 parts of ethyl cellulose and 5 parts of triethyl citrate are added to 75 parts of purified water and stirred to mix evenly to obtain a coating solution. The coating machine is preheated at 35℃ for 10 minutes. The methylprednisolone immediate-release tablet core is placed in the coating machine. The coating solution is sprayed into the machine under the conditions of spraying speed of 5 rpm, pot rotation speed of 20 rpm, inlet air temperature of 40℃, exhaust air temperature of 30℃, and atomization space pressure of 10 MPa to spray and coat the immediate-release tablet core. The coating solution is evenly deposited on the surface of the tablet core to form a coating film. After coating, the tablet core is packaged to obtain methylprednisolone pulse microplates.

[0090] Because the particle size of methylprednisolone does not meet the technical requirements (D) 90 ≤20μm) will aggravate the accumulation of static electricity in the powder, reduce the efficiency of static removal, and also damage the drug release characteristics of the pulse microplate, resulting in uncontrolled lag time, decreased dissolution, and prolonged onset time of pulse drug release, thus failing to achieve the expected rapid onset effect.

[0091] Comparative Example 5

[0092] A type of methylprednisolone pulsed microplate, comprising an immediate-release tablet core and a coating layer; the immediate-release tablet core, by weight parts, contains 25 parts of methylprednisolone (D... 90 ≤20μm), 60.7 parts microcrystalline cellulose (filler), 8 parts crospovidone (antistatic agent B), 2.3 parts citric acid, 1 part sodium bicarbonate, 2 parts hydroxypropyl methylcellulose (binder), 1 part magnesium stearate (lubricant); coating layer, by weight, includes 20 parts ethyl cellulose (coating material) and 5 parts triethyl citrate (plasticizer).

[0093] The mass ratio of the immediate-release tablet core to the coating layer is 110:25.

[0094] The preparation method is as follows:

[0095] S1 According to the formula, add 2 parts of hydroxypropyl methylcellulose to 80 parts of purified water, stir at room temperature until completely dissolved, and obtain the adhesive solution;

[0096] S2. According to the specified ratio, methylprednisolone, microcrystalline cellulose, citric acid, sodium bicarbonate, and crospovidone are added to a fluidized bed granulator and mixed evenly. Then, the mixture is atomized and sprayed into the binder solution obtained in step S1 for granulation. The liquid supply speed is 25 rpm / min, and the air volume is 22 m³ / min. 3 / h, the inlet air temperature is 60℃, the atomization pressure is 3bar, and after drying, methylprednisolone granules are obtained; after passing the methylprednisolone granules through an 80-mesh sieve, 1 part of magnesium stearate is added according to the ratio, and the mixture is evenly mixed. The methylprednisolone granules are compressed into tablets using a punch with a diameter of 2mm to obtain methylprednisolone immediate-release tablet cores with a hardness of 10N.

[0097] S3 According to the formula, 20 parts of ethyl cellulose and 5 parts of triethyl citrate are added to 75 parts of purified water and stirred to mix evenly to obtain a coating solution. The coating machine is preheated at 35℃ for 10 minutes. The methylprednisolone immediate-release tablet core is placed in the coating machine. The coating solution is sprayed into the machine under the conditions of spraying speed of 5 rpm, pot rotation speed of 20 rpm, inlet air temperature of 40℃, exhaust air temperature of 30℃, and atomization space pressure of 10 MPa to spray and coat the immediate-release tablet core. The coating solution is evenly deposited on the surface of the tablet core to form a coating film. After coating, the tablet core is packaged to obtain methylprednisolone pulse microplates.

[0098] Because the mass ratio of the tablet core to the coating layer exceeds the technical requirements (the mass ratio of the immediate-release tablet core to the coating layer is (100~105):(20~30)), the relative amount of the coating layer is insufficient, which cannot effectively achieve the delayed control of pulsed drug release, resulting in premature drug release and failure to achieve the expected controlled release effect; the excessive mass ratio of the tablet core to the coating layer will change the powder mixing characteristics, aggravate electrostatic adsorption and charge accumulation, and at the same time affect the flowability of the coated powder, further reducing the static electricity removal efficiency.

[0099] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. 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 type of methylprednisolone pulsed microsheet, characterized in that, It includes an immediate-release tablet core and a coating layer; the immediate-release tablet core includes methylprednisolone, filler, antistatic agent A, antistatic agent B, binder, and lubricant; the coating layer includes coating material and plasticizer; Among them, antistatic agent A is selected from a combination of organic acid and bicarbonate or at least one of ammonium carbonate; Antistatic agent B is selected from at least one of polyoxyethylene, carbomer, high-expansion pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and croscarmellose.

2. The methylprednisolone pulsed microsheet according to claim 1, characterized in that, The organic acid is selected from at least one of salicylic acid, tartaric acid, fumaric acid, malic acid, gallic acid, citric acid, and alginic acid; the bicarbonate is selected from at least one of sodium bicarbonate and potassium bicarbonate; the molar ratio of organic acid to bicarbonate is 1:0.8 to 1:1.

2.

3. The methylprednisolone pulsed microsheet according to claim 1, characterized in that, The immediate-release tablet core, by weight, comprises 20-30 parts of methylprednisolone, 50-70 parts of filler, 0.5-5 parts of antistatic agent A, 5-10 parts of antistatic agent B, 0.5-2 parts of lubricant, and 1-3 parts of binder; The coating layer, by weight, comprises 15-25 parts of coating material and 2-8 parts of plasticizer; The particle size D of the methylprednisolone 90 ≤20μm.

4. The methylprednisolone pulsed microsheet according to claim 1, characterized in that, The mass ratio of the immediate-release tablet core to the coating layer is (100~105):(20~30).

5. The methylprednisolone pulsed microsheet according to claim 1, characterized in that, In the immediate-release tablet core, the filler is selected from one or more of lactose, microcrystalline cellulose, starch, and mannitol; the lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, zinc stearate, and sodium stearate fumarate; and the binder is selected from one or more of starch paste, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, sucrose, and polyvinylpyrrolidone.

6. The methylprednisolone pulsed microsheet according to claim 1, characterized in that, In the coating layer, the coating material is selected from one or more of ethyl cellulose, cellulose acetate, Eudragit® NE 30D, cellulose acetate butyrate, and polyvinyl acetate, and the plasticizer is selected from one or more of triethyl citrate, diethyl phthalate, dibutyl phthalate, polyethylene glycol 400, and dibutyl sebacate.

7. The method for preparing methylprednisolone pulsed microsheets according to any one of claims 1 to 6, characterized in that, Includes the following steps: S1 uses adhesive and water to prepare an adhesive solution; S2 Methylprednisolone is mixed with filler, antistatic agent A and antistatic agent B, and then atomized and sprayed into the binder solution obtained in step S1 for granulation to obtain methylprednisolone granules; then lubricant is added and tableted to obtain immediate-release tablet cores. S3 uses coating material, plasticizer and water to prepare coating solution; then the immediate release tablet core is spray-coated with coating solution to uniformly deposit coating solution on the surface of tablet core to form coating film, and finally obtain methylprednisolone pulse micro tablets.

8. The preparation method according to claim 7, characterized in that, In step S1, the mass ratio of adhesive to water is (1~3):(60~100).

9. The preparation method according to claim 7, characterized in that, In step S3, the mass ratio of coating material, plasticizer and water is (15~25):(2~8):(67~83).

10. The preparation method according to claim 7, characterized in that, In step S2, the hardness of the immediate-release tablet core is 5~15N.