CN118178356A

CN118178356A - Slow-release capsule containing fenofibrate acid choline and preparation method thereof

Info

Publication number: CN118178356A
Application number: CN202211605000.5A
Authority: CN
Inventors: 伍贤志; 姜飞; 韩凯
Original assignee: Jiangsu Wanjun Pharmaceutical Technology Co ltd
Current assignee: Jiangsu Wanjun Pharmaceutical Technology Co ltd
Priority date: 2022-12-14
Filing date: 2022-12-14
Publication date: 2024-06-14

Abstract

The invention belongs to the field of medicine processing, and relates to a slow-release capsule containing fenofibric acid choline and a preparation method thereof, wherein the slow-release capsule is prepared from the following raw materials in parts by weight: 60.0 to 72.0 parts of active ingredient, 20.0 to 30.0 parts of slow release material, 2.7 to 3.3 parts of internal adhesive, 20.0 to 30.0 parts of tablet core wetting agent, 2.7 to 3.3 parts of external adhesive, 0.4 to 0.6 part of glidant, 0.9 to 1.2 parts of lubricant, 40.0 to 60.0 parts of coating wetting agent, 7.5 to 10.1 parts of wrapping agent, 3.4 to 4.7 parts of anti-adhesive and 1.0 to 1.4 parts of plasticizer; the invention has good gastric acid resistance, reduces dosage loss, simultaneously releases slowly, maintains long-acting treatment time and has good patient compliance.

Description

Slow-release capsule containing fenofibrate acid choline and preparation method thereof

Technical Field

The invention belongs to the field of medicine processing, and relates to a slow-release capsule containing fenofibric acid choline and a preparation method thereof.

Background

Choline fenofibrate is a choline salt of fenofibric acid, has antihyperlipidemic activity, and is a PPARα agonist. The active moiety of choline fenofibrate is fenofibric acid. Pharmacological effects of fenofibrate in animals and humans have been widely studied by oral administration of fenofibrate. Lipid modulating effects of fenofibric acid in clinical practice have been explained in transgenic mouse in vivo and in vitro human hepatocyte cultures by activating peroxisome proliferator-activated receptor alpha (pparα). By this mechanism, fenofibric acid increases lipolysis and eliminates triglyceride-rich particles in plasma by activating lipoprotein lipase and reducing Apo CIII (an inhibitor of lipoprotein lipase activity) production. Activation of PPARα also induces increased synthesis of HDL-C and Apo AI and AII.

Choline fenofibrate is useful as a treatment for severe hypertriglyceridemia, primary hypercholesterolemia, or mixed dyslipidemia. For the treatment of severe hypertriglyceridemia, it is possible to reduce Triglyceride (TG) in severe hypertriglyceridemia patients. For use as a treatment for primary hypercholesterolemia or mixed dyslipidemia, elevated low density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG) and apolipoprotein B (Apo B) can be reduced, and cholesterol (HDL-C) in patients with high density lipoprotein primary hypercholesterolemia or mixed dyslipidemia can be increased.

At present, the fibrate drug is mainly focused on the application of fenofibrate in treating hyperlipidemia, and along with the deep research, a large number of clinical experiments and drug researches prove that the fenofibrate has poor solubility due to the hydrophobicity of the fenofibrate, has low bioavailability, and is greatly influenced by food in the absorption of human body, thus causing treatment difference. Meanwhile, because the hyperlipidemia belongs to chronic diseases, long-term administration is required. How to improve the treatment effect, prolong the action time and reduce the administration times is a problem to be solved at present.

Disclosure of Invention

The invention provides a slow-release capsule containing fenofibric acid choline and a preparation method thereof, wherein the preparation method adopts a wet granulation process, is environment-friendly, safe, simple and feasible, improves the flowability and compressibility of materials, solves the uniformity of tablet filling, and can simultaneously compress a plurality of micro tablets; the aqueous dispersion is adopted for enteric coating, no organic solvent is used, the coating is safe, and is environment-friendly and harmless to human health, and the coating effect is good. The No. 0 capsule is adopted to fill 12 enteric-coated micro tablets, the dosage is accurate, and the administration dosage can be adjusted according to the needs of patients, so that the method is simple and convenient. The invention has good gastric acid resistance, reduces dosage loss, simultaneously releases slowly, maintains long-acting treatment time and has good patient compliance.

The technical scheme provided by the invention is as follows:

The fenofibric acid choline slow-release capsule is prepared from the following raw materials in parts by weight: 60.0 to 72.0 parts of active ingredient, 20.0 to 30.0 parts of slow release material, 2.7 to 3.3 parts of internal adhesive, 20.0 to 30.0 parts of tablet core wetting agent, 2.7 to 3.3 parts of external adhesive, 0.4 to 0.6 part of glidant, 0.9 to 1.2 parts of lubricant, 40.0 to 60.00 parts of coating wetting agent, 7.5 to 10.1 parts of wrapping agent, 3.4 to 4.7 parts of anti-adhesive and 1.0 to 1.4 parts of plasticizer; the active ingredient is choline fenofibrate; the slow-release material is hypromellose; the internal adhesive is povidone K30; the tablet core wetting agent is purified water; the external adhesive is hydroxypropyl cellulose; the glidant is colloidal silicon dioxide; the lubricant is sodium stearyl fumarate, the coating wetting agent is purified water, and the coating agent is methacrylic acid-ethyl acrylate copolymer; the anti-sticking agent is talcum powder, and the plasticizer is triethyl citrate.

The invention also provides a preparation method of the slow-release capsule containing fenofibric acid choline, which adopts a wet granulation process, and the method comprises the following steps:

Premixing active ingredients, a slow-release material and an internal adhesive, adding water for wet granulation after completion, drying the materials by a fluidized bed after depolymerizing the wet granules, crushing and sieving the dried materials, adding the external adhesive, a glidant and a lubricant for total mixing, tabletting the total mixed materials, coating an enteric coating, curing and drying, and finally counting tablets and filling the tablets into capsules to complete the preparation.

Further, the active ingredient, the slow release material and the internal adhesive are mixed for 3 to 5 minutes in a high shear wet granulator at a stirring speed of 300rpm and a shearing speed of 1000rpm, water is added for 3 to 5 minutes, and granulation is continued for 3 to 5 minutes with the same parameters after the water addition is completed.

Further, the wet particles are depolymerized by a dry-wet granulator, the pore diameter is 4mm by 4mm, and the frequency is 20-50 HZ.

Further, the depolymerized particles are dried for 10-15 min, the air inlet temperature during drying is 55-65 ℃, and the final material moisture is controlled to be 1% -3%.

Further, the dry particles are crushed by a dry-wet granulator, wherein the aperture of the crushing is 0.8mm, and the crushing frequency is 30-40 HZ.

Further, the dried particles obtained after pulverization were subjected to a 30-mesh screen.

Further, the sieved dry particles, an external adhesive, a glidant and a lubricant are added into a V-shaped mixer for mixing, the mixing frequency is 35-45 Hz, and the mixing time is 9-11 min.

Further, the materials after the total mixing are subjected to tablet preparation, the theoretical tablet weight is controlled to be +/-5%, and the tablet is pressed into micro tablets, wherein the diameter of the micro tablets is 3mm.

Further, after uniformly mixing a coating wetting agent, an anti-adhesion agent, a plasticizer and a coating agent, coating enteric-coated micro-tablets by using a high-efficiency coating machine, wherein the rotating speed of a coating pot is 10-15 rpm, the atomizing pressure is 0.1-0.3 Mpa, the temperature of a tablet bed is controlled at 25-30 ℃, the coating weight is increased by 12-16%, the coated micro-tablets are put into the coating pot for drying and curing, the rotating speed of the coating pot is 2-4 rpm, the temperature of the tablet bed is 40-45 ℃, and the curing time is 2-4 hours.

Further, the coated minitablets thus cured were filled into size 0 gelatin capsules, and the amount to be filled was calculated according to the specifications.

Advantageous effects

The invention adopts the wet granulation process, the preparation prescription and the process are simple, the common wet granulation equipment can meet the granulation requirement, the premixing and the wet granulation are completed in the same equipment, the working efficiency is improved, the material loss is reduced, and the production cost is saved. The wet granulation can obtain granules with good uniformity, high granule quantity, concentrated distribution and fine granularity by controlling the water addition quantity and the granulation parameters, and can obtain good tabletting stability while improving the fluidity of the granules.

The coated tablet has even weight gain and smooth and compact tablet surface by adopting the water dispersion enteric coating process. After coating, the drying and solidifying process is directly started in the coating pot, so that the efficiency is improved, the energy is saved, the environment is protected, a plurality of intermediate circulation links are reduced, and the product quality is improved and the production cost is reduced.

The gastric acid tolerance of the product obtained by the water dispersion enteric coating process is good, the consistency of the product in batches and among batches is greatly improved, and the quality controllability and the curative effect are greatly improved.

The aqueous dispersion enteric coating process does not use an organic solvent, the cost is greatly reduced, the aqueous dispersion enteric coating process is extremely friendly to the environment and human body, the harm to the environment and the human health is avoided, and the production safety is ensured.

The invention adopts the technology of filling the micro-tablet into the capsule, the weight and the volume of the micro-tablet are smaller, and a plurality of micro-tablets can be easily filled into the capsule by using the capsule, so that capsule products with different specifications can be obtained. The process can develop products with multiple specifications at the same time, and greatly reduces development and production costs. In actual clinical application, the product can flexibly adjust the dosage according to the actual condition of a patient, and has obvious advantages.

The tablet core of the invention is coated with enteric coating, is insoluble in stomach, has little dissolution in medium with pH of 3.5, and has good gastric acid resistance and safety, and dose dumping experiments prove that the dissolution rate is very small within 2 hours, the phenomenon of sudden drug release does not occur, and sudden drug release after drinking does not occur. The tablet core is coated with enteric coating prepared by a specific process with the medicine and other auxiliary materials, and can achieve the effect of slowly releasing the medicine, thereby maintaining long-acting treatment time. Only needs to be taken once every day, and has good patient compliance.

Drawings

FIG. 1 is a dissolution release profile of a fenofibric acid choline extended release capsule in a medium of pH3.5 (acid resistant) +pH 6.8;

FIG. 2 is a dissolution release profile of a fenofibric acid choline extended release capsule in a medium of pH3.5 (acid resistant) +pH 6.8;

FIG. 3 is a graph of 40% ethanol pH1.0 hydrochloric acid medium dose dumping experiments of examples 1,2 and 3;

FIG. 4 is a graph of 40% ethanol pH1.0 hydrochloric acid medium dose dumping experiments of examples 2,4 and 5.

Detailed Description

TABLE 1 composition of slow-release capsule of fenofibric acid choline

The active ingredient is choline fenofibrate; the slow-release material is hypromellose; the internal adhesive is povidone K30; the tablet core wetting agent is purified water; the external adhesive is hydroxypropyl cellulose; the glidant is colloidal silicon dioxide; the lubricant is sodium stearyl fumarate, the coating wetting agent is purified water, and the coating agent is methacrylic acid-ethyl acrylate copolymer; the anti-sticking agent is talcum powder, and the plasticizer is triethyl citrate.

The invention mainly relates to a process comprising wet granulation, micro tablet compression, enteric coating and the like, wherein the main preparation process is as follows:

1. premixing: the weighed material components in the granules are put into a high shear wet granulator, covered and locked. Starting the premixing process, setting the stirring rotation speed to 300rpm, and cutting the stirring rotation speed to 1000rpm, wherein the premixing time is 3-5 min.

2. Wet granulation: the wet granulation adopts an atomization spraying mode to add water, peristaltic pump flow rate test experiments are carried out before the wet granulation is carried out, and the flow of spray liquid is calculated. Adding water accounting for 15-30% of the weight of the components in the granules to a wet granulator at a speed of 6-12 ml/min under the condition that stirring and chopping are started, and continuously granulating for a period of time at the stirring rotating speed and the chopping rotating speed after the water addition is completed. In the wet granulating process, stirring at 300rpm, shearing at 2000rpm, adding water for 3-5 min, and granulating for 3-5 min with the same parameters after the water addition is completed.

3. Depolymerizing: discharging the wet granules after granulating, depolymerizing the wet granules by using a dry-wet granulator, wherein the aperture is 4mm, and the frequency is 20-50 HZ.

4. And (3) drying: and (3) adding the obtained wet particles into a fluidized bed boiler after preheating, drying the particles for 10-15 min, wherein the air inlet temperature during drying is 55-65 ℃, and the final material moisture is controlled to be 1-3%.

5. Crushing: the dry particles are crushed by a dry-wet granulator, the crushing aperture is 0.8mm, and the crushing frequency is 30-40 HZ.

6. Sieving: the crushed dry particles were subjected to a 30-mesh screen and the finally obtained particles were weighed.

7. Total mixing: according to the weight of the material in the final particle, calculating and weighing corresponding amounts of hydroxypropyl cellulose, colloidal silicon dioxide and sodium stearyl fumarate, and adding the materials into a V-shaped mixer, wherein the mixing frequency is 35-45 Hz, and the mixing time is 9-11 min.

8. Tabletting: and (3) preparing tablets from the materials subjected to total mixing, tabletting by using a 3mm round shallow concave die, wherein the tablet weight is controlled to +/-5%, and the hardness is more than or equal to 20N.

9. Preparing a coating liquid: weighing a certain amount of coating wetting agent, stirring by using an emulsifying machine, weighing the prescription amount of talcum powder, gradually adding into vortex, and continuously homogenizing at high speed for at least 15min; and (3) weighing the prescription amount of triethyl citrate after the complete suspension is visually and uniformly mixed, adding the triethyl citrate into the vortex, and continuously homogenizing at a high speed for at least 15min to form uniform talcum powder and triethyl citrate suspension. And (3) weighing a certain amount of coating wetting agent, stirring by using a stirrer, weighing a prescribed amount of aqueous dispersion of methacrylic acid and ethyl acrylate copolymer (1:1), slowly adding into a vortex, slowly adding the prepared talcum powder and triethyl citrate suspension, reducing the stirring rotation speed, continuously stirring for at least 30min, and sieving by a 100-mesh sieve for later use.

10. Coating: the temperature of the air inlet is set to be 40-50 ℃, the rotation speed of the main machine is 2rpm, the preheating is carried out for 10min, the temperature of the sheet bed is controlled to be 40-45 ℃, and 10-20 sheets are taken and weighed. The air inlet temperature is set to be 35-50 ℃, the rotation speed of a main machine is set to be 10-15rpm, the spraying rotation speed is set to be 2-8rpm, the atomization pressure is set to be 0.1-0.3 MPa, the temperature of a tablet bed is controlled to be 25-30 ℃ for coating, the coating weight gain is monitored every 10 minutes in the coating process, and the coating weight gain is controlled to be 12-16%.

11. Curing: and (3) putting the coated micro-tablets into a coating pot for drying and curing, wherein the rotating speed of the coating pot is 2-4 rpm, the temperature of a tablet bed is 40-45 ℃, and the curing time is 2-4 hours. After the conversion is finished, the air inlet heating is closed, and when the temperature of the slice bed is below 30 ℃, the material is collected.

12. And (3) encapsulating: the coated minitablets after curing are filled into size 0 gelatin capsules, and the filling amount is calculated according to the specification.

Examples 1-3 are presented primarily to show differences in core prescriptions, and are primarily reflected in differences in the amount of hypromellose used in the prescriptions. Wherein the proportion of the hydroxypropyl methylcellulose in the example 1 is 20.0%, the proportion of the hydroxypropyl methylcellulose in the example 2 is 27.0%, and the proportion of the hydroxypropyl methylcellulose in the example 3 is 32.9%.

Examples 2,4,5 cores were of the same prescription composition, and were mainly characterized by differences in coating weight gain. Wherein the weight gain of the enteric coating of example 2 was 14.0%, the weight gain of the enteric coating of example 4 was 12.0%, and the weight gain of the enteric coating of example 5 was 16.0%.

Dissolution data and dissolution profile.

Example 1:

TABLE 2 composition of the Choline fenofibrate sustained-release Capsule in example 1

Example 2:

TABLE 3 composition of the Choline fenofibrate sustained-release Capsule in example 2

Example 3:

TABLE 4 composition of the Choline fenofibrate sustained-release Capsule in example 3

Example 4:

TABLE 5 composition of the Choline fenofibrate sustained-release Capsule in example 4

Example 5:

TABLE 6 composition of the Choline fenofibrate sustained-release Capsule in example 5

Comparison of mixing uniformity of two processes of wet granulation and dry granulation

Granulating with the formula of the first embodiment by wet granulating and dry granulating respectively, adding external-cross auxiliary materials after granulating, mixing, sampling at different positions at three time points of 10min, 20min and 30min respectively, and detecting the mixing uniformity, wherein the comparison result is as follows.

The wet granulation total mix was found to have significantly less RSD value than the dry granulation total mix at each time point, which showed significantly better wet granulation mixing uniformity than dry granulation.

TABLE 7 Wet granulation Total Mixed Material mixing uniformity

Table 8 wet granulation total blend mix uniformity

Comparison of oven drying and curing Process and coating machine curing and drying Process:

It can be found that the coating machine can be dried for about 2 hours to reach a constant weight state, and the same temperature is used in an oven for more than 8 hours, so that the drying and curing of the coating machine are more advantageous in terms of improving efficiency, saving energy and protecting environment.

Table 9 comparison of oven drying and curing Process and coating machine curing and drying Process

Enteric preparation burst investigation:

dose dumping studies were performed using the highest standard 40% ethanol pH1.0 hydrochloric acid medium.

Examples 1-5 did not exhibit burst release in 40% ethanol pH1.0 hydrochloric acid medium dose dumping studies, and were safe and safe for use.

Table 10 investigation of burst release of enteric formulations

Time (min)	0	15	30	45	60	75	90	105	120
										Example 1	0	0.12	0.58	0.93	1.35	1.88	2.51	3.30	4.27
Example 2	0	0.04	0.51	0.87	1.25	1.74	2.33	3.08	4.00
										Example 3	0	0.22	0.71	1.11	1.60	2.17	2.92	3.81	4.80

Time (min)	0	15	30	45	60	75	90	105	120
										Example 2	0	0.04	0.51	0.87	1.25	1.74	2.33	3.08	4.00
Example 4	0	0.09	0.54	1.04	1.60	2.18	2.81	3.69	4.69
										Example 5	0	0.03	0.45	0.75	1.15	1.55	2.09	2.78	3.72

The experimental investigation of 40% ethanol pH1.0 hydrochloric acid medium dose dumping for examples 1,2 and 3 is shown in FIG. 3; the experimental investigation of 40% ethanol pH1.0 hydrochloric acid medium dose dumping for examples 2,4 and 5 is shown in FIG. 4.

Figures 3 and 4 illustrate that the ethanol dosage dumping experiments of examples 1-5 (20.0%, 27.0%, 32.9% of the hydroxypropyl methylcellulose of examples 1-3 and 27.0% of the hydroxypropyl methylcellulose of examples 2,4,5, respectively, showed that the enteric coating weight gain was 14.0%, 12.0%, 16.0% of the weight gain) were all acceptable, and no abrupt increase in concentration occurred, indicating that no abrupt release behavior occurred in high concentration ethanol within two hours. That is, in examples 1 to 5, the medicine is taken in the drinking state of the patient, the condition that the medicine is suddenly and rapidly released to influence the safety of the patient does not occur, and the safety can be ensured. The slow-release skeleton dosage of the hydroxypropyl methylcellulose in the examples 1-3 is different, the hydroxypropyl methylcellulose is an excellent hydrophilic gel skeleton slow-release material, the ratio of the examples 1-3 is from low to high, and the higher the ratio is, the slower the drug release rate is, so that a better slow-release effect is achieved.

Acid resistance effect investigation

Examples 1-5 comparison of dissolution data and dissolution profiles in a medium at pH6.8 after 2 hours of acid resistance investigation of the enteric coated formulation in a medium at pH 3.5.

It was found that examples 1 to 5 were satisfactory in acid resistance examination in a medium of pH3.5, and that the acid resistance effects of examples 1 to 5 were good, as evidenced by little or no elution of the drug.

Table 11 examples 1-5 enteric coated formulations were acid resistant in ph3.5 medium after 2 hours of examination, dissolution data in ph6.8 medium

Investigation of sustained release effect

Examples 1-3 in a pH6.8 medium study, example 1 reached plateau earlier (dissolution over 85%), which shows that the slow release effect of examples 2 and 3 is superior to example 1, i.e., two examples with 27.0% hypromellose and 32.9% hypromellose maintained a relatively long drug release time than the 20.0% hypromellose example formulation, so that both examples can maintain a relatively long treatment time.

In the medium examination of examples 2,4 and 5 at pH6.8, there was no obvious difference in the time for 3 examples to reach the plateau (dissolution over 85%), which indicates that the slow release effects of example 2 (coating weight gain 14.0%), example 4 (coating weight gain 12.0%) and example 5 (coating weight gain 16.0%) were all good, relatively long drug release times were maintained, and relatively long treatment times could be maintained.

Table 12 investigation of sustained release effect

Claims

1. The fenofibric acid choline slow-release capsule is characterized by being prepared from the following raw materials in parts by weight: 60.0 to 72.0 parts of active ingredient, 20.0 to 30.0 parts of slow release material, 2.7 to 3.3 parts of internal adhesive, 20.0 to 30.0 parts of tablet core wetting agent, 2.7 to 3.3 parts of external adhesive, 0.4 to 0.6 part of glidant, 0.9 to 1.2 parts of lubricant, 40.0 to 60.0 parts of coating wetting agent, 7.5 to 10.1 parts of wrapping agent, 3.4 to 4.7 parts of anti-adhesive and 1.0 to 1.4 parts of plasticizer; the active ingredient is choline fenofibrate; the slow-release material is hypromellose; the internal adhesive is povidone K30; the tablet core wetting agent is purified water; the external adhesive is hydroxypropyl cellulose; the glidant is colloidal silicon dioxide; the lubricant is sodium stearyl fumarate, the coating wetting agent is purified water, and the coating agent is methacrylic acid-ethyl acrylate copolymer; the anti-sticking agent is talcum powder, and the plasticizer is triethyl citrate.

2. The method for preparing a slow release capsule containing choline fenofibrate according to claim 1, wherein a wet granulation process is used, the method comprising the steps of: premixing active ingredients, a slow-release material and an internal adhesive, adding water for wet granulation after completion, drying the materials by a fluidized bed after depolymerizing the wet granules, crushing and sieving the dried materials, adding the external adhesive, a glidant and a lubricant for total mixing, tabletting the total mixed materials, coating an enteric coating, solidifying and drying, and finally counting tablets and filling the tablets into capsules to complete the preparation.

3. The method for preparing the fenofibric acid choline containing sustained-release capsule according to claim 2, wherein the active ingredient, the sustained-release material and the internal binder are stirred at 300rpm, sheared at 1000rpm, mixed for 3 to 5 minutes in a high shearing wet granulator, and granulated for 3 to 5 minutes after the completion of the water addition.

4. The method for preparing the slow-release capsule containing fenofibric acid choline according to claim 2, wherein the wet granules are depolymerized by a mobile dry-wet granulator, and the pore size is 4mm and the frequency is 20-50 HZ.

5. The method for preparing the slow-release capsule containing the fenofibric acid choline according to claim 2, wherein the drying time is 10-15 min, the air inlet temperature during drying is 55-65 ℃, and the final material moisture is controlled to be 1% -3%.

6. The method for preparing a slow release capsule containing fenofibric acid choline according to claim 2, wherein the dry particles are crushed by a dry-wet granulator, the aperture of the crushing is 0.8mm, and the frequency of the crushing motor is 30-40 HZ.

7. The method for preparing a slow release capsule containing fenofibric acid choline according to claim 2, wherein the dry particles obtained after crushing are processed by a30 mesh screen.

8. The method for preparing the slow-release capsule containing fenofibric acid choline according to claim 2, wherein the screened dry particles, the external binder, the glidant and the lubricant are added into a V-type mixer for mixing, the mixing frequency is 35-45 Hz, and the mixing time is 9-11 min.

9. The method for preparing the slow-release capsule containing fenofibric acid choline according to claim 2, wherein the total mixed materials are subjected to tablet preparation, the theoretical tablet weight is controlled to be +/-5%, and the tablet is subjected to micro-tablet compression, wherein the diameter of the micro-tablet is 3mm.

10. The method for preparing the slow-release capsule containing fenofibric acid choline according to claim 2, wherein after uniformly mixing a coating wetting agent, an anti-adhesion agent, a plasticizer and a coating agent, coating enteric-coated tablets by using a high-efficiency coating machine, wherein the rotating speed of a coating pan is 10-15 rpm, the atomizing pressure is 0.1-0.3 Mpa, the temperature of a tablet bed is controlled at 25-30 ℃, the weight of the coating is increased by 12-16%, the coated micro-tablets are put into the coating pan for drying and curing, the rotating speed of the coating pan is 2-4 rpm, the temperature of the tablet bed is 40-45 ℃, and the curing time is 2-4 hours.