Apremilast tablets with good stability and high solubility and preparation method thereof

Abstract

The invention discloses an apremilast tablet with good stability and high dissolution and a preparation method thereof, belonging to the field of medicine. The present invention first mixes and grinds apremilast with fumed silica to obtain a mixed powder; then disperses the mixed powder in a low eutectic solvent solution of panthenol-choline chloride-citric acid to obtain a suspension; then the suspension, a hydrophilic filler, and a disintegrant are mixed, granulated, and particles are obtained; finally, particles, hydrophobic fillers, disintegrants, and lubricants are mixed, and tablets are pressed to obtain apremilast tablets. The apremilast tablets prepared by the present invention have good stability and high dissolution, and the present invention reduces the side effects of apremilast by the interaction of panthenol and other substances.

Description

Technical Field

[0001] The invention relates to an apremilast tablet with good stability and high solubility and a preparation method thereof, and belongs to the field of medicine. Background Art

[0002] Apremilast is a small molecule phosphodiesterase-4 (PDE-4) inhibitor that can regulate the effects of intracellular pro-inflammatory and anti-inflammatory factors, reduce joint swelling and improve the physiological function of joints. The raw material of Apremilast is a white to off-white crystalline powder with a melting point of 153.0℃-156.0℃. It is almost non-hygroscopic, easily soluble in acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, very slightly soluble in methanol, and almost insoluble in water, ethanol, isopropanol, and methyl tert-butyl ether. It is a typical poorly soluble drug; its dissolution rate limits the absorption of the drug in the body, further affecting the oral bioavailability of the drug.

[0003] Currently, apremilast is routinely prepared as tablets for use;

[0004] For example, CN114948888A discloses a method for preparing apremilast tablets, which specifically comprises the following steps: mixing raw materials and auxiliary materials, tableting and coating in sequence, wherein the mixing of raw materials and auxiliary materials includes first mixing the active ingredient, filler and lubricant by a wet granulator, then granulating by a dry granulator and then mixing with the disintegrant by a mixer; however, its stability is poor;

[0005] CN104523574A discloses an apremilast solid dispersion and a preparation method thereof, wherein the apremilast solid dispersion is obtained by uniformly dispersing apremilast in a molten auxiliary material and then rapidly cooling it; however, the temperature in the preparation method is difficult to control, and the stability is poor, which is not convenient for actual large-scale production operations;

[0006] CN104546831A discloses a pharmaceutical composition containing Apremilast, wherein the pharmaceutical composition is prepared by combining Apremilast with cyclodextrin or a cyclodextrin derivative to form an inclusion compound; however, cyclodextrin is easily soluble in water, so that the release rate of Apremilast is high and it is difficult for Apremilast to work for a long time;

[0007] CN110548015A discloses an Apremilast tablet and a preparation method thereof, wherein the Apremilast tablet is prepared by sieving active ingredients and excipients, mixing them uniformly, pressing them into tablets, and coating them; however, the Apremilast tablet has poor stability and is difficult to exert its effect for a long time.

[0008] Moreover, Apremilast has serious gastrointestinal side effects, which leads to a narrow scope of application.

[0009] In addition, Apremilast is conventionally stored at 15-30°C, which is not suitable for humid environments and environments exposed to direct sunlight, resulting in restrictions on its storage environment.

[0010] Therefore, finding apremilast tablets with good stability, improved water solubility and high bioavailability is an urgent problem that needs to be solved. Summary of the invention

[0011] In order to solve the above problems, the present invention first mixes and grinds Apremilast and fumed silica to obtain a mixed powder; then disperses the mixed powder in a low eutectic solvent solution of panthenol-choline chloride-citric acid to obtain a suspension; then mixes the suspension, a hydrophilic filler, and a disintegrant, granulates, and obtains particles; finally, mixes the particles, a hydrophobic filler, a disintegrant, and a lubricant, and compresses the particles to obtain Apremilast tablets. The Apremilast tablets prepared by the present invention have good stability and high solubility, and the present invention reduces the side effects of Apremilast through the interaction between panthenol and other substances.

[0012] The first object of the present invention is to provide a method for preparing apremilast tablets with good stability and high solubility, comprising the following steps:

[0013] (1) mixing and grinding apremilast and fumed silica to obtain a mixed powder;

[0014] (2) mixing panthenol, choline chloride, and citric acid in a molar ratio of 0.5-1:0.5-1:2, and mixing at 60-80° C. for 1-3 hours to obtain a low eutectic solvent; dissolving the low eutectic solvent in water to obtain a low eutectic solvent solution;

[0015] (3) dispersing the mixed powder in a deep eutectic solvent solution to obtain a suspension;

[0016] (4) mixing the suspension, the hydrophilic filler, and the disintegrant, and granulating to obtain granules;

[0017] (5) The granules, hydrophobic filler, disintegrant and lubricant are mixed and tableted to obtain apremilast tablets.

[0018] In one embodiment of the present invention, the particle size of the fumed silica in step (1) is 6000-10000 mesh, more preferably 8000 mesh.

[0019] In one embodiment of the present invention, the mass ratio of apremilast to fumed silica in step (1) is 1-3:1.

[0020] In one embodiment of the present invention, the grinding speed in step (1) is 20-100 rpm.

[0021] In one embodiment of the present invention, the mixing in step (2) is performed by stirring, and the stirring speed is 100-500 rpm.

[0022] In one embodiment of the present invention, the mass ratio of the low eutectic solvent to water in step (2) is 1:1-3.

[0023] In one embodiment of the present invention, the mass ratio of the mixed powder to the low eutectic solvent solution in step (3) is 10-20:10-20.

[0024] In one embodiment of the present invention, the dispersion in step (3) is stirring dispersion, and the stirring speed is 100-1000 rpm.

[0025] In one embodiment of the present invention, the dosage ratio of the suspension, the hydrophilic filler and the disintegrant in step (4) is 20-25 mg: 5-15 mg: 5-15 mg.

[0026] In one embodiment of the present invention, the hydrophilic filler in step (4) is starch, and the starch is corn starch or potato starch.

[0027] In one embodiment of the present invention, the disintegrant in step (4) is hydroxypropyl cellulose.

[0028] In one embodiment of the present invention, the particle size of the particles obtained by granulation in step (4) is 50-100 mesh.

[0029] In one embodiment of the present invention, the hydrophobic filler in step (5) is a mixture of microcrystalline cellulose and calcium hydrogen phosphate, and the mass ratio of the two is 1:1.

[0030] In one embodiment of the present invention, the disintegrant in step (5) is hydroxypropyl cellulose.

[0031] In one embodiment of the present invention, the lubricant in step (5) is magnesium stearate.

[0032] In one embodiment of the present invention, in step (5), the mass ratio of the particles, the hydrophobic filler, the disintegrant, and the lubricant is 75-85:8-12:4-6:4-6.

[0033] In one embodiment of the present invention, the tableting in step (5) is performed by a rotary tablet press, the turntable speed is 10-20 rpm, the filling pressure is 25N, the filling depth is 15mm; the mold is circular with a diameter of 6mm.

[0034] In one embodiment of the present invention, the unit weight of the Apremilast tablet in step (5) is 100 mg.

[0035] The second object of the present invention is to provide Apremilast tablets prepared by the method described in the present invention.

[0036] The third object of the present invention is to provide a method for improving the stability and dissolution performance of Apremilast tablets, comprising the following steps:

[0037] (1) mixing and grinding apremilast and fumed silica to obtain a mixed powder;

[0038] (2) mixing panthenol, choline chloride, and citric acid in a molar ratio of 0.5-1:0.5-1:2, and mixing at 60-80° C. for 1-3 hours to obtain a low eutectic solvent; dissolving the low eutectic solvent in water to obtain a low eutectic solvent solution;

[0039] (3) dispersing the mixed powder in a deep eutectic solvent solution to obtain a suspension;

[0040] (4) mixing the suspension, the hydrophilic filler, and the disintegrant, and granulating to obtain granules;

[0041] (5) The granules, hydrophobic filler, disintegrant and lubricant are mixed and tableted to obtain apremilast tablets.

[0042] The beneficial effects of the present invention are as follows:

[0043] (1) The preparation process of the apremilast tablets prepared by the present invention is simple, and has good stability and dissolution performance, can adapt to the temperature of 10-35° C., can be placed in an environment with a humidity of 0-70%, and has relatively low storage conditions.

[0044] (2) The apremilast tablets prepared by the present invention use a combination of panthenol, citric acid and fillers (a mixture of microcrystalline cellulose and calcium hydrogen phosphate, starch) to achieve low drug irritation and better human acceptance.

[0045] (3) The low eutectic solvent solution of panthenol-choline chloride-citric acid is used in the apremilast tablets prepared by the present invention to further increase the dispersibility and solubility of apremilast. DETAILED DESCRIPTION

[0046] The preferred embodiments of the present invention are described below. It should be understood that the embodiments are for better explaining the present invention and are not used to limit the present invention.

[0047] Test method:

[0048] 1. Friability:

[0049] Check according to the Appendix of Part 2 of the 2010 edition of the Chinese Pharmacopoeia. For tablets weighing 0.65g or less, take a number of tablets to make the total weight about 6.5g; for tablets weighing more than 0.65g, take 10 tablets. Use a hair dryer to blow away the fallen powder, weigh accurately, and rotate it in a cylinder 100 times. Take it out, remove the powder in the same way, weigh accurately, and the weight loss shall not exceed 1%, and no broken, cracked or crushed tablets shall be detected.

[0050] The specific calculation formula is as follows:

[0051]

[0052] 2. Hardness:

[0053] Take a tablet and place it in the jaws of the tablet hardness tester. Slowly turn the rocker to increase the pressure applied to the tablet until the tablet is cracked, thereby measuring the hardness of the tablet. A total of 10 tablets need to be checked.

[0054] 3. Angle of repose:

[0055] Also known as the natural slope angle, it refers to the maximum angle that the free surface of the particle accumulation layer can form in a static state. It can indirectly measure the friction of the powder and characterize the fluidity of the powder through the angle of repose.

[0056] 4. Dissolution:

[0057] Environment 1: 24 months stability study at a temperature of 35±2°C and a relative humidity of 50±5%;

[0058] Environment 2: 24 months stability study at a temperature of 10±2°C and a relative humidity of 50±5%;

[0059] Environment 3: 24 months stability study at a temperature of 25±2°C and a relative humidity of 70±5%;

[0060] Environment 4: 24 months stability study under simulated sunlight (125W high pressure mercury lamp) at a temperature of 25±2°C and a relative humidity of 60±5%.

[0061] Take Apremilast tablets and follow the dissolution and release determination method (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 0931 Second Method), using 900 mL of pH = 4.0 acetate buffer solution containing 0.2% sodium dodecyl sulfate (take 1.22 g of sodium acetate, add appropriate amount of water to dissolve, add 20.5 mL of 2 mol / L acetic acid solution, dilute to 1000 mL with water, add about 2 g of sodium dodecyl sulfate and stir to dissolve, and obtain) as the dissolution medium, the speed is 75 revolutions per minute, operate according to the law, and sample 10 mL at 60 minutes.

[0062] The sample was filtered through a 0.45 μm microporous filter membrane (using a hydrophilic filter material), and the filtrate was taken as the test solution, and analyzed and determined by high performance liquid chromatography (HPLC) to obtain the dissolution amount of Apremilast in each tablet.

[0063] The raw materials used in the embodiment:

[0064] Apremilast: 98%, CAS: 608141-41-9;

[0065] Choline chloride: 98%, CAS: 67-48-1;

[0066] Panthenol: 98%, D-panthenol, medical CP grade, CAS: 81-13-0;

[0067] Citric acid: 99.5%, anhydrous citric acid, CAS: 77-92-9;

[0068] Microcrystalline cellulose: CAS: 9004-34-6;

[0069] Dicalcium phosphate: anhydrous calcium phosphate, 98%, CAS: 7757-93-9;

[0070] Hydroxypropyl cellulose: low degree of substitution, CAS: 9004-64-2;

[0071] Fumed silica: 8000 mesh, purchased from Guangzhou Zedanlu New Materials Co., Ltd.;

[0072] Starch: corn starch, purchased from Wuhan Jinfeng Fuyuan Chemical Co., Ltd.;

[0073] All raw materials are of pharmaceutical grade and can be purchased commercially.

[0074] Tableting: The tablets were pressed using a rotary tablet press with a turntable speed of 15 rpm, a filling pressure of 25 N, and a filling depth of 15 mm. The mold was round with a diameter of 6 mm.

[0075] Example 1

[0076] A method for preparing apremilast tablets with good stability and high solubility comprises the following steps:

[0077] (1) mixing apremilast and fumed silica in a mass ratio of 2:1 and grinding (grinding speed of 30 rpm) to obtain a mixed powder;

[0078] (2) mixing panthenol, choline chloride, and citric acid at a molar ratio of 1:1:2 at 70° C. and 400 rpm for 2 h, and cooling to obtain a low eutectic solvent; adding water to the low eutectic solvent, with a mass ratio of the low eutectic solvent to water being 1:1, and mixing at 25° C. and 500 rpm for 30 min to obtain a low eutectic solvent solution;

[0079] (3) dispersing 20 mg of the mixed powder in 20 mg of a deep eutectic solvent solution to obtain a suspension;

[0080] (4) spraying 40 mg of the suspension onto the surface of 20 mg of corn starch and 20 mg of hydroxypropyl cellulose to obtain granules with a mesh size of 80 mesh;

[0081] (5) 80 mg of the granules, 5 mg of microcrystalline cellulose, 5 mg of calcium hydrogen phosphate, 5 mg of hydroxypropyl cellulose, and 5 mg of magnesium stearate were compressed into tablets to obtain Apremilast tablets (100 mg).

[0082] Example 2

[0083] The mass ratio of apremilast to fumed silica in step (1) of Example 1 was adjusted to 1:1, and the other ingredients were kept consistent with Example 1 to obtain apremilast tablets.

[0084] Example 3

[0085] Adjust step (3) of Example 1 to:

[0086] Disperse 15 mg of the mixed powder in 25 mg of the deep eutectic solvent solution to obtain a suspension;

[0087] The rest was consistent with Example 1 to obtain Apremilast tablets.

[0088] Example 4

[0089] The mass ratio of the low eutectic solvent to water in step (2) of Example 1 was adjusted to 1:2; the rest was kept the same as Example 1 to obtain Apremilast tablets.

[0090] Comparative Example 1

[0091] A method for preparing Apremilast tablets comprises the following steps:

[0092] 20 mg of Apremilast, 20 mg of corn starch, 20 mg of hydroxypropyl cellulose, 5 mg of microcrystalline cellulose, 5 mg of calcium hydrogen phosphate, 5 mg of hydroxypropyl cellulose, and 5 mg of magnesium stearate were tableted to obtain Apremilast tablets.

[0093] Comparative Example 2

[0094] Omit panthenol in step (2) of Example 1, adjust the molar ratio of choline chloride to citric acid to 2:2, and keep the other steps the same as Example 1 to obtain Apremilast tablets.

[0095] Comparative Example 3

[0096] Choline chloride in step (2) of Example 1 was omitted, and the molar ratio of panthenol to citric acid was adjusted to 2:2. Other steps were the same as those of Example 1 to obtain Apremilast tablets.

[0097] Comparative Example 4

[0098] The fumed silica in step (1) of Example 1 was omitted, and the rest of the steps were the same as in Example 1 to obtain Apremilast tablets.

[0099] Comparative Example 5

[0100] The microcrystalline cellulose in step (5) of Example 1 was omitted, and the amount of calcium hydrogen phosphate was adjusted to 10 mg. The other conditions were the same as in Example 1 to obtain Apremilast tablets.

[0101] Comparative Example 6

[0102] The calcium hydrogen phosphate in step (5) of Example 1 was omitted, and the amount of microcrystalline cellulose was adjusted to 10 mg. The other conditions were the same as in Example 1 to obtain Apremilast tablets.

[0103] Comparative Example 7

[0104] Combine step (4) and step (5) of Example 1, and the details are as follows:

[0105] Spray 40 mg of the suspension onto the surface of 20 mg corn starch and 20 mg hydroxypropyl cellulose; then compress the mixture with 5 mg microcrystalline cellulose, 5 mg calcium hydrogen phosphate, 5 mg hydroxypropyl cellulose and 5 mg magnesium stearate for tableting;

[0106] The rest was consistent with Example 1 to obtain Apremilast tablets.

[0107] Comparative Example 8

[0108] The hydroxypropyl cellulose in step (5) of Example 1 was adjusted to gelatin, and the rest remained the same as Example 1.

[0109] The obtained Apremilast tablets were subjected to performance tests, and the test results were as follows:

[0110] It can be seen from Tables 1 to 5 that the hardness of the Apremilast tablets prepared in Examples 1 to 4 is moderate; the friability is below 0.08%, and can be as low as 0.02%; the angle of repose is moderate, and the tableting fluidity and compressibility are good; the dissolution rate is above 93% after storage for 24 months in environment 1 (temperature of 35±2°C, relative humidity of 50±5%); the dissolution rate (%) is above 95% after storage in environment 2 (temperature of 10±2°C, relative humidity of 50±5%); the dissolution rate (%) is above 95% after storage for 24 months in environment 3 (temperature of 25±2°C, relative humidity of 70±5%); the dissolution rate (%) is above 80% after storage for 24 months in environment 4 (temperature of 25±2°C, relative humidity of 60±5%, simulated sunlight (125W high-pressure mercury lamp)); any adjustment of other parameters will affect its stability and dissolution rate.

[0111] Table 1 Properties of tablets

[0112] example hardness Friability (%) Angle of repose(°) Compressibility Example 1 6.55 0.04 25.2 good Example 2 6.35 0.08 26.2 good Example 3 6.62 0.03 24.3 good Example 4 6.25 0.02 22.5 good Comparative Example 1 - 0.26 - Poor Comparative Example 2 5.46 0.14 24.2 good Comparative Example 3 5.62 0.15 24.8 good Comparative Example 4 5.92 0.18 25.8 Poor Comparative Example 5 6.23 0.17 27.5 good Comparative Example 6 6.39 0.15 28.4 good Comparative Example 7 - 0.34 - Poor Comparative Example 8 6.57 0.12 26.8 good

[0113] Note: “-” means undetectable.

[0114] Table 2 Dissolution rate (%) of tablets in environment 1 (temperature 35±2°C, relative humidity 50±5%)

[0115] example 0 6 months 12 months 24 months Example 1 98.3 98.1 97.3 95.4 Example 2 97.4 97.0 96.6 94.7 Example 3 97.1 96.9 95.8 93.9 Example 4 97.5 97.2 96.5 95.3 Comparative Example 1 95.3 80.8 70.3 - Comparative Example 2 97.2 90.4 88.5 78.1 Comparative Example 3 97.0 90.7 86.2 74.9 Comparative Example 4 97.6 92.3 88.9 82.1 Comparative Example 5 97.5 95.1 89.4 80.8 Comparative Example 6 97.6 96.4 86.7 81.6 Comparative Example 7 95.1 88.6 79.9 69.5 Comparative Example 8 97.2 90.5 84.2 78.7

[0116] Note: “-” means not detected.

[0117] Table 3 Dissolution rate (%) of tablets in environment 2 (temperature 10±2°C, relative humidity 50±5%)

[0118] example 0 6 months 12 months 24 months Example 1 98.3 97.2 96.5 95.8 Example 2 97.4 96.4 95.1 94.9 Example 3 97.1 96.6 95.5 95.1 Example 4 97.5 96.9 96.2 95.7 Comparative Example 1 95.3 80.4 60.3 - Comparative Example 2 97.2 94.2 91.6 85.1 Comparative Example 3 97.0 93.7 88.9 83.2 Comparative Example 4 97.6 93.8 89.7 78.4 Comparative Example 5 97.5 93.1 88.5 73.9 Comparative Example 6 97.6 94.3 86.7 79.3 Comparative Example 7 95.1 90.4 81.5 71.8 Comparative Example 8 97.2 95.6 91.4 80.5

[0119] Note: “-” means not detected.

[0120] Table 4 Dissolution rate (%) performance of tablets in environment 3 (temperature 25±2°C, relative humidity 70±5%)

[0121] example 0 6 months 12 months 24 months Example 1 98.3 97.5 97.1 96.3 Example 2 97.4 96.4 95.9 95.1 Example 3 97.1 96.7 96.1 95.5 Example 4 97.5 96.8 96.4 95.9 Comparative Example 1 95.3 60.5 50.3 - Comparative Example 2 97.2 90.6 85.8 78.3 Comparative Example 3 97.0 91.5 87.6 77.4 Comparative Example 4 97.6 82.5 78.7 65.9 Comparative Example 5 97.5 95.6 88.5 71.7 Comparative Example 6 97.6 94.3 81.8 70.4 Comparative Example 7 95.1 87.7 74.9 65.4 Comparative Example 8 97.2 94.2 89.1 78.3

[0122] Note: “-” means not detected.

[0123] Table 5 Dissolution rate (%) of tablets in environment 4 (temperature 25±2°C, relative humidity 60±5%, simulated sunlight (125W high pressure mercury lamp))

[0124] example 0 6 months 12 months 24 months Example 1 98.3 90.6 88.2 82.8 Example 2 97.4 89.3 86.3 81.5 Example 3 97.1 88.8 86.6 80.8 Example 4 97.5 88.1 85.7 81.3 Comparative Example 1 95.3 60.0 - - Comparative Example 2 97.2 85.3 68.1 46.9 Comparative Example 3 97.0 84.2 60.5 49.2 Comparative Example 4 97.6 80.5 69.2 58.4 Comparative Example 5 97.5 88.2 80.4 70.2 Comparative Example 6 97.6 86.9 79.1 68.6 Comparative Example 7 95.1 80.7 61.9 49.2 Comparative Example 8 97.2 90.5 82.8 74.3

[0125] Note: “-” means not detected.

[0126] Although the present invention has been disclosed as above in the form of a preferred embodiment, it is not intended to limit the present invention. Anyone familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the definition of the claims.

Claims

1. A method for preparing apremilast tablets with good stability and high solubility, characterized in that: The steps include: (1) mixing and grinding apremilast and fumed silica to obtain a mixed powder; (2) mixing panthenol, choline chloride, and citric acid in a molar ratio of 0.5-1:0.5-1:2, and mixing at 60-80° C. for 1-3 hours to obtain a low eutectic solvent; dissolving the low eutectic solvent in water to obtain a low eutectic solvent solution; (3) dispersing the mixed powder in a deep eutectic solvent solution to obtain a suspension; (4) mixing the suspension, the hydrophilic filler, and the disintegrant, and granulating to obtain granules; (5) mixing the granules, the hydrophobic filler, the disintegrant, and the lubricant, and tableting to obtain apremilast tablets; Wherein, the disintegrant in step (4) is hydroxypropyl cellulose; In step (5), the hydrophobic filler is a mixture of microcrystalline cellulose and calcium hydrogen phosphate, and the mass ratio of the two is 1:

1.

2. The method according to claim 1, characterized in that In step (1), the mass ratio of apremilast to fumed silica is 1-3:

1.

3. The method according to claim 1, characterized in that In step (4), the dosage ratio of the suspension, the hydrophilic filler and the disintegrant is 20-25 mg: 5-15 mg: 5-15 mg.

4. The method according to claim 1, characterized in that: In step (5), the mass ratio of the particles, the hydrophobic filler, the disintegrant and the lubricant is 75-85:8-12:4-6:4-6.

5. The method according to claim 1, characterized in that In step (2), the mass ratio of the low eutectic solvent to water is 1:1-3.

6. The method according to claim 1, characterized in that In step (3), the mass ratio of the mixed powder to the low eutectic solvent solution is 10-20:10-20.

7. The method according to claim 1, characterized in that In step (4), the hydrophilic filler is starch, and the starch is corn starch or potato starch.

8. Apremilast tablets prepared by the method according to any one of claims 1 to 7.

9. A method for improving the stability and dissolution performance of apremilast tablets, characterized in that: The steps include: (1) mixing and grinding apremilast and fumed silica to obtain a mixed powder; (2) mixing panthenol, choline chloride, and citric acid in a molar ratio of 0.5-1:0.5-1:2, and mixing at 60-80° C. for 1-3 hours to obtain a low eutectic solvent; dissolving the low eutectic solvent in water to obtain a low eutectic solvent solution; (3) dispersing the mixed powder in a deep eutectic solvent solution to obtain a suspension; (4) mixing the suspension, the hydrophilic filler, and the disintegrant, and granulating to obtain granules; (5) mixing the granules, the hydrophobic filler, the disintegrant, and the lubricant, and tableting to obtain apremilast tablets; Wherein, the disintegrant in step (4) is hydroxypropyl cellulose; In step (5), the hydrophobic filler is a mixture of microcrystalline cellulose and calcium hydrogen phosphate, and the mass ratio of the two is 1:1.

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