Tiamulin fumarate tablet capable of improving bioavailability and preparation method of tiamulin fumarate tablet

Abstract

The invention discloses tiamulin fumarate tablets capable of improving bioavailability and a preparation method of the tiamulin fumarate tablets, and belongs to the technical field of veterinary drug preparations. Every 100 kg of the tiamulin fumarate tablet is mainly prepared from the following raw materials in parts by weight: 10 to 30 kg of tiamulin fumarate, 28 to 35 kg of Soluplus, 1.2 to 2.0 kg of silicon dioxide, 0.5 to 1.1 kg of N-trimethyl chitosan (TMC), 16 to 20 kg of HPMC-AS, 3.2 to 4.0 kg of triethyl citrate, 16 to 25 kg of microcrystalline cellulose (PH102) and 3.1 to 4.3 kg of croscarmellose sodium. According to the invention, a composite enteric-solubilization-infiltration promotion system is adopted, and the innovative process of a solubilization inner core adopts co-grinding of a main drug and Soluplus, so that the water solubility of the drug is fully improved; the enteric-coated layer adopts HPMC-AS (hydroxypropyl methylcellulose acetate succinate) to solve the problem of gastric acid degradation and reduce the gastric degradation rate, so that drugs are accurately released in intestinal tracts, and the bioavailability is improved; the penetration enhancer chitosan derivative N-trimethyl chitosan (TMC) is added, so that the intestinal mucosa permeability is enhanced, and the intestinal absorption rate is increased.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug formulation technology, specifically relating to a fumarate tiamulin tablet with improved bioavailability and its preparation method. Background Technology

[0002] Tiamulin fumarate is a semi-synthetic antibiotic belonging to the diterpenoid class. Its mechanism of action involves binding to the 50S subunit of bacterial ribosomes, inhibiting protein synthesis, thereby suppressing bacterial growth and reproduction. This compound exhibits good antibacterial activity against Gram-positive bacteria, mycoplasma, and certain spirochetes, but its activity against Gram-negative bacteria is weak. It is mainly used to treat diseases such as swine pneumonia, swine bloody dysentery, chronic respiratory disease in chickens, swine mycoplasmal pneumonia, and swine spirochetal dysentery.

[0003] In 2025, soluble powder / premixed formulations accounted for 92% of global tiamulin fumarate preparations, but they suffer from problems such as severe degradation by gastric acid, large fluctuations in blood drug concentration, and increased drug resistance.

[0004] To address the above issues, a fumarate tiamulin tablet has been developed that improves bioavailability, reduces stomach acid levels, and lowers drug resistance. This development has profound significance for promoting the application of fumarate tiamulin in animal husbandry. Summary of the Invention

[0005] The purpose of this invention is to provide a fumarate tiamulin tablet with improved bioavailability.

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned formulation.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: A bioavailability-enhancing fumarate tiamulin tablet is mainly made from the following raw materials in parts by weight per 100 kg of fumarate tiamulin tablet: The raw materials used in the finished product are: 10-30 kg of fumarate tiamulin, 28-35 kg of Soluplus®, 1.2-2.0 kg of silica, 0.5-1.1 kg of N-trimethyl chitosan (TMC), 16-20 kg of HPMC-AS (hydroxypropyl methylcellulose acetate succinate), 3.2-4.0 kg of triethyl citrate, 16-25 kg of microcrystalline cellulose, and 3.1-4.3 kg of croscarmellose sodium.

[0008] The preparation method of the above-mentioned bioavailability-enhancing tiamulin fumarate tablets is as follows: (1) Preparation of coating solution: HPMC-AS and triethyl citrate are added to anhydrous ethanol, homogenized under high pressure, and allowed to stand for 30-60 minutes to mature before use. (2) Take Corydalis yanhusuo telosin and Soluplus® and add them to a ball mill. Then, ball mill at high speed for 50-70 min to obtain co-ground powder. (3) After mixing the co-ground powder, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose for 10-20 min, dry granulation is performed; (4) Mix silica, N-trimethyl chitosan and the particles from step (3) for 5-15 minutes, and compress directly to obtain tablet cores; (5) The core is preheated to 38±1℃ and coated with a liquefied bed. First, (5~10)wt% HPMC ethanol solution is sprayed in as an isolation layer, then the coating liquid of step (1) is sprayed in as an enteric core functional layer, and then (0.1~1)wt% magnesium stearate ethanol suspension is sprayed in as a hydrophobic barrier layer. After the material temperature is raised to 35~45℃, polyethylene glycol melt is sprayed in as a surface smoothing agent. After the process is completed, gradient heating and drying are carried out, and the product of the present invention is obtained by cooling to room temperature.

[0009] Further, in step (1), the mass ratio of HPMC-AS to anhydrous ethanol is (0.2~0.26):1.

[0010] Further, in step (1), the high-pressure homogenization process refers to homogenizing at 145~155 bar for 3~5 minutes, then at 95~105 bar for 2~4 minutes, and finally at 45~55 bar for 1~3 minutes.

[0011] Furthermore, in step (2), the high-speed ball mill rotates at 200~300 rpm, and the particle size of the co-ground powder is D50=8.0~8.5 μm.

[0012] Further, in step (5), the ethanol solution of HPMC is sprayed at 55~65 g / min for 4~6 min; the coating solution is sprayed at 140~160 g / min for 20~25 min; the magnesium stearate ethanol suspension is sprayed at 25~35 g / min for 2~4 min; and the polyethylene glycol melt is sprayed at 25~35 g / min for 2~4 min. The molecular weight of polyethylene glycol is 4000~8000.

[0013] Furthermore, gradient temperature drying refers to drying at 40±2℃ for 2~4 minutes, 45±2℃ for 2~4 minutes, and 50±2℃ for 2~4 minutes until the moisture content is <0.8%.

[0014] Furthermore, in step (3), the particle size after granulation is 40~60 mesh.

[0015] Soluplus® is chemically known as a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0016] The advantages and beneficial effects of this invention are as follows: (1) This invention adopts a composite enteric-solubilizing-penetration-enhancing system, wherein the innovative process of the solubilizing core uses co-grinding of the active pharmaceutical ingredient and Soluplus® to fully improve the water solubility of the drug; (2) The enteric layer of this invention uses HPMC-AS (hydroxypropyl methylcellulose acetate succinate) to solve the problem of gastric acid degradation, reduce the gastric degradation rate, and enable the drug to be accurately released in the intestine, thereby improving bioavailability; (3) This invention adds the permeation enhancer chitosan derivative N-trimethyl chitosan (TMC) to enhance the permeability of the intestinal mucosa and improve the intestinal absorption rate; (4) This invention adopts a dry granulation-fluidized bed coating process, which not only improves the stability of the drug, but also has the advantages of industrial production. Detailed Implementation

[0017] The present invention will be further described below through implementation, but the scope of protection of the present invention is not limited thereto.

[0018] Examples 1, 2, and 3: A fumarate tiamulin tablet with improved bioavailability Each 100kg of tiamulin fumarate tablets is mainly made from the following raw materials in parts by weight: Preparation method: 1. Preparation of coating solution: Add HPMC-AS and triethyl citrate to 78.4 kg of anhydrous ethanol, homogenize using an APV 1000 high-pressure homogenizer (gradual pressure reduction of 150 bar for 4 minutes → 100 bar for 3 minutes → 50 bar for 2 minutes), let stand for 45 minutes to mature, and then set aside for later use. 2. Add corydalis tretinoin and Soluplus® to a ball mill and ball mill at high speed (250 rpm for 60 min) to obtain co-ground powder (particle size D50 = 8.2 μm). 3. Add the co-ground powder, microcrystalline cellulose and croscarmellose sodium to a V-type mixer, mix for 15 minutes and then transfer to a dry granulator to granulate to obtain 45 mesh particles. 4. Add silica, trimethyl chitosan and the granules from step 3 into a V-type mixer and mix for 10 minutes, then directly compress to obtain tablet cores; 5. Preheat the tablet core to 38±1℃ and use liquefied bed coating. First, spray an 8wt% HPMC-E5 ethanol solution (60g / min, 5min) as an isolation layer, then spray the coating solution from step 1 (150g / min, 22min) as an enteric core functional layer. Next, spray a 0.5wt% magnesium stearate ethanol suspension (30g / min, 3min) as a hydrophobic barrier layer. After the material temperature rises to 40℃, spray polyethylene glycol 6000 melt (30g / min, 3min) as a surface smoothing agent. After completion, perform gradient temperature drying (40℃→45℃→50℃, 3min each, moisture content <0.8%), and cool to 25℃ to obtain the product of this invention. Each tablet contains 0.16g of tiamulin fumarate.

[0019] Soluplus® is chemically known as a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0020] Comparative Example 1 [Process Adjustment] Fixed-temperature drying replaces intelligent temperature-controlled drying. Its composition and the weight of raw materials used per 100kg of finished product are as follows: 10.0kg of tiamulin fumarate, 35.0kg of Soluplus®, 1.2kg of silica, 0.5kg of N-trimethyl chitosan (TMC), 20.0kg of HPMC-AS, 4.0kg of triethyl citrate, 25.0kg of microcrystalline cellulose (PH102), and 4.3kg of croscarmellose sodium.

[0021] Preparation method: 1. Preparation of coating solution: Add HPMC-AS and triethyl citrate to 78.4 kg of anhydrous ethanol, homogenize using an APV 1000 high-pressure homogenizer (gradual pressure reduction of 150 bar for 4 minutes → 100 bar for 3 minutes → 50 bar for 2 minutes), let stand for 45 minutes to mature, and then set aside for later use. 2. Add corydalis tretinoin and Soluplus® to a ball mill and ball mill at high speed (250 rpm for 60 min) to obtain co-ground powder (particle size D50 = 8.2 μm). 3. Add the co-ground powder, microcrystalline cellulose and croscarmellose sodium to a V-type mixer, mix for 15 minutes and then transfer to a dry granulator to granulate to obtain 45 mesh particles. 4. Add silica, trimethyl chitosan and the granules from step 3 into a V-type mixer and mix for 10 minutes, then directly compress to obtain tablet cores; 5. Preheat the tablet core to 38±1℃ and use liquefied bed coating. First, spray an 8wt% HPMC-E5 ethanol solution (60g / min, 5min) as an isolation layer, then spray the coating solution from step 1 (150g / min, 22min) as an enteric core functional layer. Next, spray a 0.5wt% magnesium stearate ethanol suspension (30g / min, 3min) as a hydrophobic barrier layer. After the material temperature rises to 40℃, spray polyethylene glycol 6000 melt (30g / min, 3min) as a surface smoothing agent. After completion, heat to 50℃ and dry for 9min (moisture content <0.8%). Cool to 25℃ to obtain the product of this invention. Each tablet contains 0.16g of tiamulin fumarate.

[0022] Soluplus® is chemically known as a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0023] Comparative Example 2 [Process Adjustment] TMC penetration enhancer cancelled. Its components and the weight of raw materials used per 100kg of finished product are as follows: 20.0kg of tiamulin fumarate, 32.3kg of Soluplus®, 1.5kg of silica, 18.0kg of HPMC-AS, 3.6kg of triethyl citrate, 21.5kg of microcrystalline cellulose (PH102), and 3.1kg of croscarmellose sodium.

[0024] Preparation method: 1. Preparation of coating solution: Add HPMC-AS and triethyl citrate to 78.4 kg of anhydrous ethanol, homogenize using an APV 1000 high-pressure homogenizer (gradual pressure reduction of 150 bar for 4 minutes → 100 bar for 3 minutes → 50 bar for 2 minutes), let stand for 45 minutes to mature, and then set aside for later use. 2. Add corydalis tretinoin and Soluplus® to a ball mill and ball mill at high speed (250 rpm for 60 min) to obtain co-ground powder (particle size D50 = 8.2 μm). 3. Add the co-ground powder, microcrystalline cellulose and croscarmellose sodium to a V-type mixer, mix for 15 minutes and then transfer to a dry granulator to granulate to obtain 45 mesh particles. 4. Add the silica and the particles from step 3 to a V-type mixer and mix for 10 minutes, then directly compress to obtain the tablet core; 5. Preheat the tablet core to 38±1℃ and use liquefied bed coating. First, spray an 8wt% HPMC-E5 ethanol solution (60g / min, 5min) as an isolation layer, then spray the coating solution from step 1 (150g / min, 22min) as an enteric core functional layer. Next, spray a 0.5wt% magnesium stearate ethanol suspension (30g / min, 3min) as a hydrophobic barrier layer. After the material temperature rises to 40℃, spray polyethylene glycol 6000 melt (30g / min, 3min) as a surface smoothing agent. After completion, perform gradient temperature drying (40℃→45℃→50℃, 3min each, moisture content <0.8%), and cool to 25℃ to obtain the product of this invention. Each tablet contains 0.16g of tiamulin fumarate.

[0025] Soluplus® is chemically known as a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0026] Comparative Example 3 [Process Adjustment] Ordinary mixing replaces co-grinding Its composition and the weight of raw materials used per 100kg of finished product are as follows: 30.0kg of tiamulin fumarate, 28.0kg of Soluplus®, 2.0kg of silica, 1.1kg of N-trimethyl chitosan (TMC), 16.0kg of HPMC-AS, 3.2kg of triethyl citrate, 16.0kg of microcrystalline cellulose (PH102), and 3.7kg of croscarmellose sodium.

[0027] Preparation method: 1. Preparation of coating solution: Add HPMC-AS and triethyl citrate to 78.4 kg of anhydrous ethanol, homogenize using an APV 1000 high-pressure homogenizer (gradual pressure reduction of 150 bar for 4 minutes → 100 bar for 3 minutes → 50 bar for 2 minutes), let stand for 45 minutes to mature, and then set aside for later use. 2. Add corydalis telosin, Soluplus®, microcrystalline cellulose and croscarmellose sodium to a V-type mixer, mix for 15 minutes and then transfer to a dry granulator to granulate to obtain 45 mesh granules; 3. Add silica, trimethyl chitosan and the granules from step 2 into a V-type mixer and mix for 10 minutes, then directly compress to obtain tablet cores; 4. Preheat the tablet core to 38±1℃ and use liquefied bed coating. First, spray an 8wt% HPMC-E5 ethanol solution (60g / min, 5min) as an isolation layer, then spray the coating solution from step 1 (150g / min, 22min) as an enteric core functional layer. Next, spray a 0.5wt% magnesium stearate ethanol suspension (5%, 30g / min, 3min) as a hydrophobic barrier layer. After the material temperature rises to 40℃, spray polyethylene glycol 6000 melt (30g / min, 3min) as a surface smoothing agent. After completion, perform gradient temperature drying (40℃→45℃→50℃, 3min each, moisture content <0.8%), and cool to 25℃ to obtain the product of this invention. Each tablet contains 0.16g of tiamulin fumarate.

[0028] Soluplus® is chemically known as a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0029] Comparative Example 4: A commercially available brand of fumarate tiamulin soluble powder The content of fumarate tiamulin is 10 wt%.

[0030] Test case 1. Test materials Products prepared in Examples 1, 2, and 3 Comparative Example 1: Fixed-temperature drying as a substitute for intelligent variable-temperature drying (10% fumarate and tiamulin content) Comparative Example 2: TMC penetration enhancer (20% fumarate tiamulin content) was removed. Comparative Example 3: Ordinary mixed alternative to co-grinding (tiamulin fumarate content 30%) Comparative Example 4: A commercially available brand of tiamulin fumarate soluble powder (tiamulin fumarate content is 10%) 2. Experimental methods and results 2.1 Pharmacokinetic Studies Eighty-four healthy Landrace pigs (weighing 25±2kg) were randomly divided into seven groups of 12 pigs each, with half males and half females. The pigs were kept in a constant-temperature pig house (25℃) with free access to water and were fasted for 12 hours before medication.

[0031] Dosage regimen: A single oral dose of 40 mg of tiamulin fumarate per kg of body weight (equivalent to 2 times the single tablet dose in Example 2). After drug administration, an indwelling needle was placed in the forelimb vein, and blood samples were collected at 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, and 24h to detect the blood drug concentration.

[0032] The relative bioavailability was determined using Comparative Example 4 as the reference preparation.

[0033] Table 1 Pharmacokinetic test data As shown in Table 1, compared with Comparative Example 1, the blood drug concentration of Example 1 was 39.6% higher, the time to peak concentration was shortened by 38.1%, the area under the curve (AUC) of 0-24 hours was 53.7% higher, and the relative bioavailability was increased by 54.1%; compared with Comparative Example 2, the blood drug concentration of Example 2 was 115.4% higher, the time to peak concentration was shortened by 50.0%, the AUC of 0-24 hours was 105.6% higher, and the relative bioavailability was increased by 105.3%; compared with Comparative Example 3, the blood drug concentration of Example 3 was 104.1% higher, the time to peak concentration was shortened by 54.8%, the AUC of 0-24 hours was 103.5% higher, and the relative bioavailability was increased by 102.9%; compared with Comparative Example 4, the blood drug concentration, AUC of 0-24 hours, and relative bioavailability were all significantly improved, and the time to peak concentration was significantly shortened.

[0034] 2.2 Dissolution and Degradation Rate Tests: Appendix I of the 2020 Edition of the Chinese Veterinary Pharmacopoeia Table 2. Data on gastric juice degradation rate and intestinal juice dissolution rate As shown in Table 2, compared with Comparative Example 1, the gastric juice degradation rate of Example 1 was reduced by 84.8%, and the intestinal juice dissolution rate was increased by 4.7%; compared with Comparative Example 2, the gastric juice degradation rate of Example 2 was reduced by 20%, and the intestinal juice dissolution rate was not significantly different; compared with Comparative Example 3, the gastric juice degradation rate of Example 3 was reduced by 90.3%, and the intestinal juice dissolution rate was increased by 23.6%. All examples showed a significant decrease in gastric juice degradation rate and a significant increase in intestinal juice dissolution rate compared with Comparative Example 4.

[0035] 2.3 Animal Therapeutic Effect Experiment: 160 healthy Landrace piglets of similar weight were selected as experimental animals. The animals showed no obvious disease symptoms and tested negative for pathogens such as Mycoplasma hyopneumoniae. The experimental animals were randomly divided into 8 groups of 20 piglets each and housed in separate pens.

[0036] A virulent strain of Mycoplasma hyopneumoniae CVCC 359 (ATCC 25095, China Institute of Veterinary Drug Control) was selected and anaerobically cultured at 37°C for 10 weeks. 6 CCU / mL. Take 2 mL of bacterial culture (containing 2 × 10⁻⁶ CCU / mL). 5 The virus was challenged with a solution of CCU + 2 mL sterile PBS buffer.

[0037] The blank control group did not undergo virus challenge and did not receive any drugs. The challenge control group received challenge treatment but no drugs. Group 1 underwent virus challenge treatment and was given the product from Example 1. Group 2 of Example 2 underwent virus challenge treatment and was given the product of Example 2. Group 3 of Example 3 underwent virus challenge treatment and was given the product of Example 3. Comparative Example 1 was subjected to virus challenge treatment and given the product of Comparative Example 1. Comparative Example 2 was subjected to virus challenge treatment and given the product of Comparative Example 2. Comparative group 3 underwent virus challenge treatment and was given the product of comparative group 3. Comparative group 4 was subjected to virus challenge treatment and given the product of comparative group 4. The dosage is determined based on the animal's weight 24 hours after the challenge, such as 40 mg / kg, once a day for 7 consecutive days.

[0038] The administration method is as follows: Tablets: Use an oral delivery device to accurately deliver the tablets deep into the animal's mouth to ensure swallowing.

[0039] Soluble powder: Dissolve the drug in an appropriate amount of water and administer it to the animal by gavage.

[0040] 2.3.1 Clinical treatment effect Observe respiratory symptoms daily, noting any cough or wheezing, and also monitor body temperature.

[0041] Cough: 0 = none; 1 = cough after stimulation; 2 = spontaneous cough ≤ 5 times / min; 3 = spontaneous cough > 5 times / min. Observe daily at 8:00 and 14:00.

[0042] Breathing status: 0 = normal, 1 = abdominal breathing, 2 = mouth breathing. Observe daily.

[0043] Body temperature: A temperature greater than 39.5℃ is considered abnormal. Rectal temperature should be measured daily.

[0044] Table 3 Clinical efficacy observation data As shown in Table 3, in Example 1, the cough score decreased by 54.5%, the respiratory score decreased by 57.1%, and the abnormal body temperature rate decreased by 72.8% compared to Comparative Example 1; in Example 2, the cough score decreased by 66.7%, the respiratory score decreased by 60%, and the abnormal body temperature rate decreased by 75.4% compared to Comparative Example 3; in Example 3, the cough score decreased by 53.8%, the respiratory score decreased by 50%, and the abnormal body temperature rate decreased by 71% compared to Comparative Example 4; and in Example 4, the cough score, respiratory score, and abnormal body temperature rate all decreased significantly, and there was a significant improvement compared to the challenge control group.

[0045] 2.3.2 Pathological and Microbiological Experiments Euthanasia: 24 hours after the end of drug administration, administer sodium pentobarbital (30 mg / kg) intravenously. Tissue sampling was performed on the experimental animals after necropsy: the right heart lobe was fixed in 10% formalin and sectioned in paraffin (hematoxylin and eosin). Pathological changes in lung tissue and other tissues were observed; lung tissue and tracheal secretions were collected from the animals to detect the viral load of Mycoplasma hyopneumoniae and to calculate the number of CCUs per gram of tissue or per sample; blood agar culture was performed on lung lesions to detect secondary bacterial infections.

[0046] Lobar consolidation rate: 0 points = 0%, 1 point = 1-25%, 2 points = 26-50%, 3 points = 51-75%, 4 points = 76-100% Interstitial edema: 0 = none, 1 = mild, 2 = severe Table 4. Pathological and Microbiological Experimental Data As shown in Table 4, in Example 1 compared to Comparative Example 1, the lung lesion score decreased by 62.5%, the mycoplasma load decreased by 28.1%, and the secondary bacterial infection rate decreased by 70.4%; in Example 2 compared to Comparative Example 2, the lung lesion score decreased by 75.0%, the mycoplasma load decreased by 40%, and the secondary bacterial infection rate decreased by 69.1%; in Example 3 compared to Comparative Example 3, the lung lesion score decreased by 73.7%, the mycoplasma load decreased by 34.2%, and the secondary bacterial infection rate decreased by 66.9%. In Example 4 and the challenge control group, the lung lesion score, mycoplasma load, and secondary bacterial infection rate were all significantly reduced.

[0047] Therefore, it can be seen that the product of this invention, through a composite enteric-solubilizing-penetration-enhancing system, employs processes such as co-grinding of the active pharmaceutical ingredient with Soluplus®, intelligent temperature-controlled drying, and TMC permeation enhancement, which can significantly improve drug efficacy and bioavailability.

Claims

1. A fumarate tiamulin tablet with improved bioavailability, characterized in that, Each 100kg of tiamulin fumarate tablets is mainly made from the following raw materials in parts by weight: The raw materials used in the finished product are: tiamulin fumarate 10~30 kg, Soluplus® 28~35 kg, silica 1.2~2.0 kg, N-trimethyl chitosan (TMC) 0.5~1.1 kg, HPMC-AS 16~20 kg, triethyl citrate 3.2~4.0 kg, microcrystalline cellulose 16~25 kg, and croscarmellose sodium 3.1~4.3 kg.

2. The method for preparing tiamulin fumarate tablets with improved bioavailability according to claim 1, characterized in that, The process is as follows: (1) Preparation of coating solution: HPMC-AS and triethyl citrate are added to anhydrous ethanol, homogenized under high pressure, and allowed to stand for 30-60 minutes to mature before use. (2) Take Corydalis yanhusuo telosin and Soluplus® and add them to a ball mill. Then, ball mill at high speed for 50-70 min to obtain co-ground powder. (3) After mixing the co-ground powder, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose for 10-20 min, dry granulation is performed; (4) Mix silica, N-trimethyl chitosan and the particles from step (3) for 5-15 minutes, and compress directly to obtain tablet cores; (5) The core is preheated to 38±1℃ and coated with a liquefied bed. First, (5~10)wt% HPMC ethanol solution is sprayed in as an isolation layer, then the coating liquid of step (1) is sprayed in as an enteric core functional layer, and then (0.1~1)wt% magnesium stearate ethanol suspension is sprayed in as a hydrophobic barrier layer. After the material temperature is raised to 35~45℃, polyethylene glycol melt is sprayed in as a surface smoothing agent. After the process is completed, gradient heating and drying are carried out, and the product of the present invention is obtained by cooling to room temperature.

3. The preparation method according to claim 2, characterized in that, In step (1), the mass ratio of HPMC-AS to anhydrous ethanol is (0.2~0.26):

1.

4. The preparation method according to claim 2, characterized in that, In step (1), high-pressure homogenization refers to homogenizing at 145~155 bar for 3~5 minutes, then at 95~105 bar for 2~4 minutes, and finally at 45~55 bar for 1~3 minutes.

5. The preparation method according to claim 2, characterized in that, In step (2), the high-speed ball mill rotates at 200~300 rpm, and the particle size of the co-ground powder is D50=8.0~8.5 μm.

6. The preparation method according to claim 2, characterized in that, In step (5), the ethanol solution of HPMC is sprayed at 55~65 g / min for 4~6 min; the coating solution is sprayed at 140~160 g / min for 20~25 min; and the magnesium stearate ethanol suspension is sprayed at 25~35 g / min for 2~4 min. The molten polyethylene glycol is sprayed at a rate of 25-35 g / min for 2-4 minutes. The molecular weight of the polyethylene glycol is 4000-8000.

7. The preparation method according to claim 2, characterized in that, Gradient temperature drying refers to drying at 40±2℃ for 2~4 minutes, 45±2℃ for 2~4 minutes, and 50±2℃ for 2~4 minutes until the moisture content is <0.8%.

8. The preparation method according to claim 2, characterized in that, In step (3), the particle size after granulation is 40~60 mesh.

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