SORAFENIB PHARMACEUTICAL COMPOSITION WITH HIGH BIOAVAILABILITY AND USE THEREOF

Abstract

A sorafenib pharmaceutical composition with high bioavailability and use thereof, and specifically a low-dose sorafenib oral solid preparation, comprising: a) a sorafenib solid dispersion; b) a crystallization inhibitor; and c) additional pharmaceutically acceptable adjuvant. The low-dose sorafenib oral solid preparation has high bioavailability and reduces the dosage of sorafenib such that the same therapeutic effect as that of Nexavar tablets can be achieved when a patient takes orally 35% to 70% of the administered dose of Nexavar tablets; it has higher stability, better safety, and less incidence of side effects; it has lower C.sub.max and AUC.sub.0-t variation, a higher dissolution, and a low crystal precipitation rate with the increase of pH in the gastrointestinal tract; it is easy to be taken by patients due to the small volume of the tablet; it has a fast disintegration speed and a good dissolution effect; and it is easy to realize industrialization.

Claims

1. A sorafenib pharmaceutical composition with high bioavailability, comprising: a) sorafenib, or a salt, hydrate, solvate, or a hydrate or solvate of the salt thereof; and b) a carrier comprising VA64 and HPMCAS; the mass ratio of the component a) to VA64 and HPMCAS in component b) is 1:(0.5˜3):(0.1˜1).

2. (canceled)

3. The sorafenib pharmaceutical composition according to claim 1, wherein the mass ratio of the component a) to VA64 and HPMCAS in component b) is 1:1:(0.1˜0.5), preferably 1:1:0.25.

4. The sorafenib pharmaceutical composition according to claim 1, wherein the sorafenib pharmaceutical composition is a solid dispersion, the solid dispersion is prepared according to a spray drying method, and the solvent of the spray drying method is a mixed solvent of methanol and dichloromethane.

5. The sorafenib pharmaceutical composition according to claim 4, wherein the volume ratio of methanol and dichloromethane is 1:(1˜4), preferably 1:3.

6. A low-dose sorafenib oral solid preparation, comprising: a) a sorafenib solid dispersion; b) a crystallization inhibitor; and c) additional pharmaceutically acceptable adjuvant; the crystallization inhibitor is selected from polyvinylpyrrolidone; or the crystallization inhibitor is one or more selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium glycocholate, sodium taurocholate, sodium glycodeoxycholate, sodium glycochenodeoxycholate, sodium glycoursodeoxycholate, sodium taurodeoxycholate and sodium tauroursodeoxycholate, as well as sodium dodecyl sulfonate.

7. The low-dose sorafenib oral solid preparation according to claim 6, wherein the sorafenib solid dispersion comprises: a) sorafenib, or a salt, hydrate, solvate, or a hydrate or solvate of the salt thereof; and b) a carrier comprising VA64.

8. The low-dose sorafenib oral solid preparation according to claim 6, wherein the sorafenib solid dispersion comprises: a) sorafenib, or a salt, hydrate, solvate, or a hydrate or solvate of the salt thereof; and b) a carrier comprising VA64 and HPMCAS.

9. The sorafenib oral solid preparation according to claim 6, wherein the component a) has a unit dose of 70˜200 mg, preferably 70˜140 mg.

10. (canceled)

11. The sorafenib oral solid preparation according to claim 6, wherein the mass content of the crystallization inhibitor is 1%˜40%, preferably 1%˜20%.

12. The sorafenib oral solid preparation according to claim 6, wherein the adjuvant is one or more selected from a filler, disintegrant, binder, glidant, lubricant, and flavoring agent.

13. The sorafenib oral solid preparation according to claim 12, wherein the filler is one or more selected from mannitol, pregelatinized starch, lactose, calcium hydrogen phosphate, starch, microcrystalline cellulose, pregelatinized starch, partially pregelatinized starch, magnesium sulfate, and calcium sulfate; the disintegrant is one or more selected from corn starch, partially pregelatinized starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone; the binder is one or more selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, starch slurry, and sodium carboxymethyl cellulose; the glidant is one or more selected from talc and silica; and the lubricant is one or more selected from magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, hydrogenated vegetable oil, polyethylene glycol, sodium dodecyl sulfate, talc, and silica.

14. The sorafenib oral solid preparation according to claim 12, wherein the glidant is silica.

15. The sorafenib oral solid preparation according to claim 13, wherein the mass content of the silica is 2%˜20%, preferably 5%˜15%, and more preferably 10%.

16. The sorafenib oral solid preparation according to claim 6, wherein the dosage form of the oral solid preparation is tablet, granule, dry suspension, capsule or film.

17. Use of the sorafenib pharmaceutical composition with high bioavailability according to claim 1 in the manufacture of a medicament for preventing, treating or alleviating liver cancer, renal cell carcinoma and thyroid cancer.

18. Use of the sorafenib oral solid preparation according to claim 6 in the manufacture of a medicament for preventing, treating or alleviating liver cancer, renal cell carcinoma and thyroid cancer.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0084] FIG. 1 shows the dissolution profile of tablets prepared with different ratios of VA64 solid dispersion in a pH 6.8 phosphate buffer solution (0.1% SDS); and

[0085] FIG. 2 shows the dissolution profile of tablets prepared with a composite carrier solid dispersion in a pH 6.8 phosphate buffer solution (0.1% SDS).

DETAILED DESCRIPTION

[0086] In order to further illustrate the present disclosure, the sorafenib pharmaceutical composition with high bioavailability provided by the present disclosure and use thereof will be described in detail below in combination with examples.

Example 1 Solubility of Sorafenib in Different Organic Solvents

[0087] An appropriate amount of sorafenib raw material was added to 25 ml of organic solvent and shaken in a shaker at room temperature for different times. Samples were taken to detect the amount of dissolved drug, and the results are shown in Table 1 below:

TABLE-US-00001 TABLE 1 Solubility of sorafenib in different organic solvents Ratio Solubility (mg/mL)-37° C. Organic solvent (v/v) 30 min 24 h Methanol- .sup. 1:0.5 8.34 19.17 dichloromethane 1:1 14.28 24.22 1:2 20.90 36.17 1:3 36.36 36.44 1:4 31.31 36.32 Acetone-ethanol 1:2 18.51 18.48 1:3 Less API dissolved by visual N/A 1:5 inspection than 1:2 ratio Dichloromethane- 1:1 Less API dissolved by visual N/A acetone 2:1 inspection than 3:1 ratio 3:1 3.60 4.04 Isopropanol N/A 2.91 2.81

[0088] Related substances were detected by HPLC method, and the results are shown in Table 2 below:

TABLE-US-00002 TABLE 2 Stability of sorafenib in different organic solvents Related substances (%) Organic Standing RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT solvent Ratio time 0.03 0.05 0.07 0.08 0.30 0.35 0.40 0.55 0.92 1.00 API \ \ 0.011 0.008 0.029 \ 0.006 0.028 0.054 99.864 Methanol- 1:2 30 min \ \ 0.013 0.011 0.030 \ 0.008 0.031 0.037 99.870 dichloromethane 24 h \ \ 0.012 0.013 0.035 \ 0.009 0.028 0.049 99.853 1:3 30 min \ \ 0.013 0.015 0.029 \ 0.006 0.026 0.050 99.861 24 h \ \ 0.011 0.012 0.035 \ 0.009 0.025 0.037 99.872 1:4 30 min \ \ 0.011 0.013 0.028 \ 0.007 0.024 0.034 99.884 24 h \ \ 0.012 0.013 0.028 \ 0.008 0.032 0.045 99.862 Acetone-ethanol 1:2 30 min \ 4.314 0.005 0.011 0.029 \ 0.008 0.025 0.047 95.562 24 h \ 3.946 0.055 0.010 0.033 \ 0.007 0.020 0.035 95.893 Dichloromethane- 3:1 30 min \ 12.979 \ 2.491 0.020 0.282 \ \ 0.039 84.196 acetone 24 h \ 14.191 0.652 \ \ \ \ \ \ 85.157 Isopropanol N/A 30 min 0.161 \ \ \ \ \ \ \ \ 99.839 24 h \ \ 0.635 \ \ \ \ \ \ 99.365

[0089] From the above results, it can be seen that sorafenib has a relatively large solubility in methanol-dichloromethane (1:3), and there is no significant change in related substances in terms of API when placed in this organic solvent for 30 min and 24 h. Therefore, methanol-dichloromethane is preferably used as the organic solvent for preparing a solid dispersion of sorafenib by a spray drying method.

Example 2 Solubility and Stability of a Solid Dispersion (SD)

[0090] 1. Preparation of SD

[0091] Sorafenib (SLFN)/Sorafenib tosylate (TSSLFN) was added to a methanol-dichloromethane (1:3) mixed solvent, stirred and dissolved at 30-33° C. The main drug: the mixed solvent was 1:100. A carrier was then added and dissolved, and the carrier was used in an amount of the main drug: the carrier of 1:3.

[0092] Spray drying: the inlet air temperature was 120° C., the outlet air temperature was set to 60° C., and nitrogen was used as a carrier gas. The results are shown in Table 3.

TABLE-US-00003 TABLE 3 DSC test results of solid dispersions prepared with different carriers and different ratios of carrier to main drug Endothermic peak of crystalline Main drug Carrier Ratio drugs in DSC curve SLFN No — Endothermic peak at 208~220° C. SLFN PVP K30 1:3 No SLFN PVP K30 1:1 No SLFN HPC LF 1:3 No SLFN HPMC E5 1:3 No SLFN HPMC K100 1:3 No SLFN HPMC AS 126G 1:3 No SLFN HPMC AS 716G 1:3 No SLFN VA64 1:3 No SLFN VA64 1:1 No TSSLFN No — Endothermic peak at 180-200° C. and/or 215~235° C. TSSLFN HPMC E5 1:3 No TSSLFN HPMC AS 716G 1:3 No TSSLFN VA64 1:3 No

[0093] According to the above results, the samples prepared with different carriers all formed solid dispersions.

[0094] 2. Solubility Test

[0095] An appropriate amount of solid dispersion (SD) was added to a pH 1.0 hydrochloric acid solution and a pH 6.8 phosphate buffer solution, while keeping the SD in excess, and shaken at 37° C. in a shaker at 300 rpm. Samples were taken at different times to detect the content of sorafenib. The solid dispersions with VA64 and PVPK30 as carriers were investigated for the solubility in simulated intestinal fluid and simulated gastric fluid, and the results are as follows:

TABLE-US-00004 TABLE 4 Solubility test results of sorafenib solid dispersion Dissolution Solubility (μg/mL) Main drug Carrier medium 0.5 h 1 h 2 h 3 h 4 h SLFN / pH 1.0 <0.09 \ <0.09 \ <0.09 TSSLFN / hydrochloric 3.7 \ 4.1 \ 4.1 SLFN PVP K30 acid solution 11.2  \ 9.1 \ 3.3 SLFN HPC LF (Main drug: 7.8 \ 3.9 \ 3.1 SLFN HPMC E5 Carrier 1:3) 16.7  \ 7.4 \ 3.4 SLFN HPMC K100 12.5  \ 7.8 \ 3.6 SLFN HPMC AS 126G 7.1 \ 6.5 \ 4.2 SLFN HPMC AS 716G 7.5 \ 6.3 \ 3.9 SLFN VA64 6.7 \ 5.9 \ 4.8 TSSLFN HPMC E5 15.8  \ 8.3 \ 5.2 TSSLFN HPMC AS 716G 8.2 \ 8.4 \ 5.6 TSSLFN VA64 6.9 \ 6.1 \ 5.3 SLFN / pH 6.8 <0.09 \ <0.09 \ <0.09 TSSLFN / (Main drug: <0.09 \ <0.09 \ <0.09 SLFN PVP K30 phosphate <0.09 \ <0.09 \ <0.09 SLFN HPC LF buffer <0.09 \ <0.09 \ <0.09 SLFN HPMC E5 solution <0.09 \ <0.09 \ <0.09 SLFN HPMC K100 Carrier 1:3) <0.09 \ <0.09 \ <0.09 SLFN HPMC AS 126G <0.09 \ <0.09 \ <0.09 SLFN HPMC AS 716G  0.42 \  0.39 \  0.15 SLFN VA64 <0.09 \ <0.09 \ <0.09 TSSLFN HPMC E5 <0.09 \ <0.09 \ <0.09 TSSLFN HPMC AS 716G  0.41 \  0.38 \  0.11 TSSLFN VA64 <0.09 \ <0.09 \ <0.09 SLFN VA64 (1:1) FaSSGF  6.69 \  7.24 \ \ FaSSIF \ 349.85 \ 12.38 \ SLFN PVPK30 (1:1) FaSSGF  7.05 \  7.90 \ \ FaSSIF \ 131.36 \  3.60 \

[0096] It can be seen from the above results that although the initial solubility (0.5 h, 2 h, 4 h) of the solid dispersion in pH 1.0 hydrochloric acid medium increased, the solubility gradually decreased with the extension of time, and the crystalline drug of sorafenib appeared on the test tube wall, which was not much different from sorafenib tosylate at 24 h. In a pH 6.8 phosphate medium, except for the solid dispersion with HPMC AS 716G as a carrier, the solubility of solid dispersions prepared by using other polymer materials as a carrier was lower than the limit of quantification.

[0097] There was no significant difference in the measured solubility of solid dispersions prepared with polymer VA64 and PVPK30 as a carrier in simulated gastric fluid (FaSSGF) for 30 min and 2 hours, which was about 7 μg/mL; the solubility of the VA64 carrier solid dispersion measured 1 hour after transferring to the simulated intestinal fluid (FaSSIF) was 350 μg/mL and rapidly decreased to 12.38 μg/mL after 2 hours; while the solubility of the solid dispersion with PVP K30 as a carrier measured 1 hour after transferring to the simulated intestinal fluid was 131 μg/mL and rapidly decreased to 3.6 μg/mL after 2 hours.

[0098] 3. Determination of Stability

[0099] The SD prepared above was sealed in an aluminum foil bag, placed in a high temperature of 60° C. for investigation for 10 days and 30 days, and related substances were detected by HPLC method. The results are shown in Table 5 below.

TABLE-US-00005 TABLE 5 Test results of influencing factors of sorafenib solid dispersion prepared with different carriers at a high temperature of 60° C. Related substances (%) Maximum Investigation Main drug/ single Total time carrier impurity CTF-aniline impurity 0 day SLFN 0.03 Not detected 0.09 10 days 0.04 Not detected 0.10 30 days 0.05 Not detected 0.10 0 day SLFN/PVP K30 0.09 Not detected 0.20 10 days 0.11 Not detected 0.23 30 days 0.12 0.01 0.32 0 day SLFN/HPMC E5 0.04 Not detected 0.13 10 days 0.04 Not detected 0.13 30 days 0.06 0.02 0.23 0 day SLFN/HPMC AS 0.04 Not detected 0.10 10 days 716G 0.12 0.05 0.36 30 days 0.27 0.10 0.75 0 day SLFN/VA64 0.04 Not detected 0.11 10 days 0.04 Not detected 0.12 30 days 0.03 Not detected 0.13 0 day TSSLFN/VA64 0.03 Not detected 0.10 10 days 0.04 Not detected 0.12 30 days 0.04 Not detected 0.16 0 day TSSLFN/HPMC 0.04 Not detected 0.11 10 days AS 716G 0.12 0.06 0.41 30 days 0.29 0.11 0.83

[0100] From the above results, it can be seen that the SD prepared with VA64 as a carrier had the best chemical stability, while the solid dispersion with HPMCAS as a carrier had poor chemical stability; when a solid dispersion was prepared by using sorafenib free base and sorafenib tosylate as the main drug respectively and using the same ratio of the polymer carrier, the solid dispersion of sorafenib tosylate had slightly poor chemical stability after being placed at a high temperature of 60° C. for 30 days.

Example 3 Screening of Carrier Ratio

[0101] 1. Screening of VA64 Carrier Ratio

[0102] Sorafenib solid dispersions with different carrier ratios (mass ratios) were prepared according to the above spray drying method, and DSC test was performed to confirm whether the solid dispersion was completely formed. The results are shown in Table 6.

TABLE-US-00006 TABLE 6 DSC test results of solid dispersions prepared with different ratios of VA64 to the main drug Endothermic peak of crystalline Main drug Carrier Ratio drugs in DSC curve SLFN VA64 1:0.5 Disappeared SLFN VA64 1:1.sup.  Disappeared SLFN VA64 1:1.5 Disappeared SLFN VA64 1:2.sup.  Disappeared

[0103] The sorafenib solid dispersions with above different carrier ratios were prepared into tablets according to the formula shown in Table 7:

TABLE-US-00007 TABLE 7 Sorafenib solid dispersible tablet formula Composition of the formula Amount (mg/tablet) SD amount (based on SLFN) 100 Silicified microcrystalline cellulose (SMCC) 218.50 Sodium dodecyl sulfate (SDS) 4.50 Croscarmellose sodium (CCNa) 22.50 Magnesium stearate (MS) 4.50

[0104] Raw and adjuvant materials in the amount shown in the formula were weighed. All raw and adjuvant materials except for MS were passed through a 50-mesh sieve 6 times, mixed, and granulated by a dry method. The weight of the granules was weighed, and the amount of MS added externally was calculated and weighed. They were mixed for 5 min and subjected to tableting. The dissolution profile was determined and shown in FIG. 1.

[0105] Dissolution method: paddle method, pH 6.8 phosphate buffer solution+0.1% SDS, 900 mL, 100 rpm, 37° C.

[0106] Sampling and sample treatment method: 10 mL of sample was taken and filtered with a PES filter membrane (diameter 25 mm, pore size 0.45 μm). 7 mL of filtrate was discarded, 2˜3 mL of subsequent filtrate was taken, and 10 mL of medium was added to the dissolution cup. 1 ml of the filtered sample was transferred with a pipette into a 10 ml volumetric flask, and diluted by 10 times by adding a mobile phase to the scale mark.

TABLE-US-00008 TABLE 8 Dissolution profile of sorafenib solid dispersion tablet (n = 3) Disinte- gration Cumulative dissolution (%) time 5 15 30 45 Batch No. min min min min min 1 h 1.5 h 2 h 4 h AUC.sub.0-4h Nexavar 4 14.6 16.4 14.6 13.1 12.4 11.1 10.2 9.9 2687.5 (half tablet, 100 mg) SLFN-VA 38 25.3 36.2 31.7 20.8 14.2 10.3 9.2 9.1 3260.5 64 (1:0.5) SLFN-VA 55 47.5 58.4 48.97 31.97 22.5 15.56 13.45 10.6 4847.4 64 (1:1) SLFN-VA 85 34.2 40.1 33.5 24.8 21.7 13.8 12.6 10.2 4042.0 64 (1:1.5) SLFN-VA 130 23.6 35.9 32.4 23.7 22.3 14.1 12.7 10.1 3924.3 64 (1:2) Note: The disintegration time here was the time for the tablet to disintegrate/dissolve completely in the dissolution cup. The same below.

[0107] It can be seen based on the above results that the disintegration time of the tablet was significantly prolonged as the amount of VA64 increased. Due to the prolonged disintegration time caused by high VA64 amount, the dissolution did not increase linearly with the increase of VA64 ratio, but first increased and then decreased, and the optimal amount was 1:1. Although the cumulative dissolution of different solid dispersion tablets within 15 min of dissolution was significantly higher than that of the original Nexavar, it decreased rapidly in 15 min˜60 min. That is to say, sorafenib drug crystallized and precipitated out immediately after dissolution, and the cumulative dissolution at 60 min˜120 min was not significantly different from that of Nexavar tablet.

[0108] 2. Screening of Composite Carriers

[0109] Solid dispersions were prepared according to the ratio in Table 9.

TABLE-US-00009 TABLE 9 DSC test results of solid dispersions prepared with different composite carriers and main drugs Endothermic peak of SD formula crystalline drugs in No. Main drug Carrier Ratio DSC curve 1 SLFN VA64 HPMCAS 126G 1:0.5:1 Disappeared 2 SLFN VA64 HPMCAS 126G 1:0.5:0.5 Disappeared 3 SLFN VA64 HPMCAS 126G 1:1:0.5 Disappeared 4 SLFN VA64 HPMCAS 126G 1:1:0.25 Disappeared 5 SLFN VA64 HPMCAS 126G 1:1:0.125 Disappeared 6 SLFN VA64 HPMCAS 126G 1:2:0.2 Disappeared 7 SLFN VA64 HPMCAS 716G 1:1:0.25 Disappeared 8 SLFN VA64 HPMC E5 1:1:0.25 Disappeared 9 SLFN VA64 TPGS1000 1:1:0.25 Disappeared 10 SLFN VA64 Tween 80 1:1:0.1 Disappeared 11 SLFN HPMC E5 HPMCAS 126G 1:1:0.25 Disappeared

[0110] The solid dispersions prepared with the above different carrier ratios were tableted according to the formula shown in Table 10.

TABLE-US-00010 TABLE 10 Sorafenib solid dispersible tablet formula Composition of the formula Amount (mg/tablet) SD amount (based on SLFN) 100 Silicified microcrystalline cellulose (SMCC) 218.50 Sodium dodecyl sulfate (SDS) 4.50 Croscarmellose sodium (CCNa) 22.50 Magnesium stearate (MS) 4.50

[0111] Raw and adjuvant materials in the amount shown in the formula were weighed. All raw and adjuvant materials except for MS were passed through a 50-mesh sieve 6 times, mixed, and granulated by a dry method. The weight of the granules was weighed, and the amount of MS added externally was calculated and weighed. They were mixed for 5 min and subjected to tableting. The dissolution profile was determined and shown in FIG. 2.

[0112] Dissolution method: paddle method, pH 6.8 phosphate buffer solution+0.1% SDS, 900 mL, 100 rpm, 37° C.

[0113] Sampling and sample treatment method: 10 mL of sample was taken and filtered with a PES filter membrane (diameter 25 mm, pore size 0.45 μm). 7 mL of filtrate was discarded, 2˜3 mL of subsequent filtrate was taken, and 10 mL of medium was added to the dissolution cup. 1 ml of the filtered sample was transferred with a pipette into a 10 ml volumetric flask, and diluted by 10 times by adding a mobile phase to the scale mark.

TABLE-US-00011 TABLE 11 Dissolution profile of tablets prepared with a composite carrier SD (n = 3) Disinte- SD gration Cumulative dissolution (%) formula time 5 15 30 45 60 90 120 240 No. min min min min min min min min min AUC.sub.0-4h Nexavar 4 14.6 16.4 14.6 13.1 12.4 11.1 10.2 9.9 2687.5 (half tablet, 100 mg) 1 28 33.7 31.2 25.4 22.1 20.9 20.6 18.7 18.4 4906.5 2 26 35.9 31.5 25.2 21.3 16.1 15.3 13.7 12.8 3930.0 3 43 42.1 38.1 29.6 26.4 20.9 17.8 16.7 14.2 4677.0 4 35 57.8 43.4 22.6 18.8 16.5 15.6 14.7 13.1 4168.8 5 28 31.2 23.6 17.9 16.9 15.4 13.2 12.3 11.5 3363.3 6 145 28.3 25.4 14.7 18.4 17.1 16.3 14.8 14.3 3787.8 7 33 55.9 45.2 23.7 17.9 16.2 14.3 14.1 13.3 4096.0 8 54 33.7 25.4 18.9 11.2 10.1 9.6 9.1 8.7 2692.8 9 49 34.2 37.3 20.1 13.5 11.7 10.4 9.8 9.3 2966.0 10 41 39.3 36.1 20.1 13.4 10.6 9.6 9.1 9 2877.5 11 58 34.8 24.9 14.8 13.2 12.5 10.7 9.4 8.2 2715.8

[0114] The above tablets were sealed in an aluminum foil bag and placed in 60° C. for investigation for 10 days, and related substances were detected by HPLC method. The results are shown in Table 12 below.

TABLE-US-00012 TABLE 12 Test results of related substances in tablets prepared from solid dispersions of different composite carriers at a high temperature of 60° C. Related substances %) Maximum SD formula Investigation single Total No. time impurity CTF-aniline impurity 1 0 day 0.04 Not detected 0.10 10 days 0.11 0.10 0.34 2 0 day 0.04 Not detected 0.13 10 days 0.11 0.06 0.31 3 0 day 0.04 Not detected 0.10 10 days 0.04 0.03 0.27 4 0 day 0.04 Not detected 0.12 10 days 0.05 0.01 0.20 5 0 day 0.04 Not detected 0.10 10 days 0.05 0.01 0.20 6 0 day 0.04 Not detected 0.10 10 days 0.04 0.01 0.22 7 0 day 0.04 Not detected 0.11 10 days 0.05 0.02 0.28 8 0 day 0.04 Not detected 0.10 10 days 0.05 Not detected 0.18 9 0 day 0.04 Not detected 0.10 10 days 0.05 0.01 0.21 10 0 day 0.04 Not detected 0.12 10 days 0.05 0.02 0.24 11 0 day 0.05 Not detected 0.12 10 days 0.08 0.05 0.34

[0115] It can be seen from the above data that as for the carrier VA64+HPMCAS, with the increase of the amount of HPMCAS, the dissolution decreased slowly in the later stage, but the stability became poor. Considering the dissolution results and chemical stability results comprehensively, the optimal ratio was 1:1:0.25. The effect was not obvious for other composite carriers.

Example 4 Screening of Crystallization Inhibitor

[0116] An appropriate amount of sorafenib or sorafenib tosylate was weighed, respectively, dissolved by adding dimethyl sulfoxide and diluted to prepare a high-concentration stock solution containing about 15 mg of sorafenib per 1 ml.

[0117] Taking a pH 6.8 phosphate buffer solution containing 0.1% sodium dodecyl sulfate (SDS) as a base medium (pH 6.8 phosphate+0.1% SDS), an appropriate amount of a polymer carrier polyvinylpyrrolidone (PVP) such as PVP K25, PVP K30, PVP K90, a vinylpyrrolidone-vinyl acetate copolymer, such as PVP VA64, hydroxypropyl methylcellulose acetate succinate (HPMCAS), such as HPMCAS HG (or 126 G), HPMCAS MG (912 G), HPMCAS LG (or 716 G), hydroxypropyl methylcellulose, such as HPMC K100LV, polyethylene glycol, such as PEG 1000, PEG 3350, PEG 4000, PEG 6000, and PEG 8000, sodium glycocholate (SGC), sodium taurocholate (STC), sodium deoxycholate (SDC), sodium glycodeoxycholate (SGDC), sodium glycochenodeoxycholate (SGCDC), sodium glycoursodeoxycholate (SGUDC), sodium taurodeoxycholate (STDC) and sodium tauroursodeoxycholate (STUDC), as well as sodium dodecyl sulfonate (SDS), etc. were weighed respectively, and dissolved respectively with pH 6.8 phosphate+0.1% SDS to prepare a polymer carrier medium containing about 0.5% of the above polymer carrier or a medium containing 0.3% cholate per 1 ml, for later use.

[0118] 50 ml of the above polymer carrier medium was measured out respectively, placed in a 100 ml stoppered test tube, and shaken in a shaker at 37° C. for 1 hour. 0.4 ml of sorafenib stock solution was then added to each stoppered test tube, which was transferred to a constant temperature shaking shaker at 37° C. after ultrasonically dispersed uniformly at 37° C. Samples were taken at 0.5 h, 1 h, 2 h, 3 h, 4 h and 6 h, and the concentration of sorafenib in each polymer carrier medium was detected by HPLC method. The results are shown in the Table below.

TABLE-US-00013 TABLE 13 Screening of polymer carriers, cholates and surfactant type crystallization inhibitors Sorafenib content detection (μg/ml) Sampling time 0.5 h 1 h 2 h 3 h 4 h 6 h Base medium 76.48 76.99 61.16 19.39 8.34 5.30 0.5% HPMCAS H (126G) 75.84 75.66 75.96 76.08 76.41 76.46 0.5% HPMCAS M 76.43 76.18 76.65 76.11 76.83 76.88 0.5% HPMCAS L (716G) 76.36 76.20 77.25 79.22 76.97 76.98 0.5% PVP K25 77.53 79.71 78.19 78.25 79.41 78.66 0.5% PVP K30 75.71 76.02 76.22 76.20 76.78 77.33 0.5% PVP K90 74.40 75.53 75.12 74.76 75.79 77.04 0.5% PVP-VA64 76.69 76.34 76.65 76.79 76.97 77.51 0.5% PEG 1000 75.66 70.78 20.46 10.69 9.06 8.43 0.5% PEG 3350 23.97 15.34 12.52 11.74 11.57 11.70 0.5% PEG 4000 49.17 26.27 14.35 12.76 11.87 11.69 0.5% PEG 8000 74.01 70.07 58.32 39.73 28.13 19.01 0.5% HPMC K100 LV 14.22 11.86 11.43 10.77 10.25 8.27 0.3% SGDC 15.78 6.28 4.11 4.01 4.04 3.87 0.3% SGCDC 61.59 47.08 10.41 5.38 4.28 3.68 0.3% STC 77.62 74.69 44.23 21.29 13.70 8.69 0.3% STDC 47.72 25.90 11.19 7.82 6.58 5.90 0.3% STCDC 14.43 6.22 4.69 4.79 4.81 5.79 0.4% SDS 76.31 69.80 47.08 34.46 29.92 24.24 0.3% SDC 14.98 8.88 5.37 4.56 4.04 4.94 0.2% VA-64 + 0.3% SDC 77.73 77.86 77.77 78.04 77.96 77.84 0.2% VA-64 + 0.4% SDS 77.87 77.84 77.43 77.40 77.31 77.10 0.3% SGC 14.32 5.88 4.32 3.98 3.77 3.57 0.2% VA-64 + 0.3% SGC 77.82 77.85 77.84 77.92 77.96 77.83 0.2% VA-64 + 0.3% SGCDC 78.01 77.98 77.95 77.89 77.88 77.86 0.2% VA-64 + 0.3% STDC 77.56 77.67 77.88 77.89 77.83 77.38

[0119] According to the above screening results, polyvinylpyrrolidone series and hydroxypropyl methylcellulose acetate succinate (HPMCAS) series polymer carriers had a significant crystallization inhibition effect, and the crystallization inhibition effect did not decrease with the extension of time. PEG 1000 and PEG 8000 had a good crystallization inhibition effect within 1 hour, but the crystallization became serious with the extension of time. HPMC K100 LV, PEG 3350 and PEG4000 basically had no crystallization inhibition effect.

[0120] Cholate is a physiological surfactant secreted by human bile into the intestinal tract. When the preparation made of the pharmaceutical composition containing PVP-VA64 is taken orally, it enters the intestinal tract, and is mixed with cholate with the peristalsis of the gastrointestinal tract, which will not lead to rapid crystallization and precipitation of drugs.

Example 5 Screening of Formula of Crystallization Inhibitors

[0121] 1. Screening of a crystallization Inhibitor in SLFN-VA64 (1:1) SD Tablet Formula

[0122] (1) A polymer carrier crystallization inhibitor/cosolvent was screened according to Table 13 below, and was compared with the PVP series crystallization inhibitor.

TABLE-US-00014 TABLE 14 Screening formula of crystallization inhibitors Composition of formula Amount (mg/tablet) Material SLFN-SD (based on the total 200.00 added amount of SLFN and VA64) internally SMCC 126.00 Crystallization inhibitor/ 75.00 cosolvent CCNa 45.00 MS 3.00 Material SMCC 88.00 added SiO.sub.2 60.00 externally MS 3.00

[0123] Among them, the mass ratio of SLFN to VA64 was 1:1.

[0124] Crystallization inhibitor/cosolvent: HPMC E5, HPMC K4M, polyoxyethylene hydrogenated castor oil RH40, xanthan gum, TPGS 1000, SOLUPLUS, PVP K25, PVP K30, and HPMCAS 126G.

[0125] Preparation process: raw and adjuvant materials in the amount shown in the formula were weighed. Raw and adjuvant materials added internally were passed together through a 50-mesh sieve 6 times, mixed, and granulated by a dry method. The weight of the granules was weighed, and the amount of material added externally was calculated and weighed. They were mixed for 5 min and subjected to tableting, and cumulative dissolution was tested.

[0126] The dissolution method was the same as before.

TABLE-US-00015 TABLE 15 Cumulative dissolution of different crystallization inhibitor/cosolvent formulas (n = 3) Disinte- gration Cumulative dissolution (%) time 5 15 30 45 60 90 120 240 SD No. min min min min min min min min min AUC.sub.0-4h Nexavar 4 14.6 16.4 14.6 13.1 12.4 11.1 10.2 9.9 2687.5 (half tablet, 100 mg) PVP K25 2 90.3 70.5 49.6 40.2 35.4 31.3 28.1 27.6 8002.5 PVP K30 2 88.9 68.9 46.3 37.3 32.7 28.1 25.4 24.3 7554.3 HPMC E5 8 49.2 50.1 33.6 25.8 21.3 17.9 14.2 12.9 4617.8 HPMC K4M 39 33.7 40.1 41.5 30.1 24.6 20.4 18.2 14.6 5245.0 RH40 68 29.5 33.4 35.4 28.6 27.1 20.5 14.6 11.9 4647.5 Xanthan gum 24 39.4 40.8 30.4 28.7 25.3 20.6 18.5 16.9 5202.8 TPGS1000 55 29.3 44.2 40.1 33.4 20.6 18.7 14.3 13.2 4733.0 SOLUPLUS 13 38.9 49.8 50.1 30.3 18.9 16.4 14.2 12.8 4872.8 HPMCAS126G 15 79.3 54.6 31.1 24.5 21.5 18.6 17.4 15.7 5166.0

[0127] It can be seen from the above results that the crystallization inhibitors PVPK 30 and PVP K25 were obviously superior to other cosolvents/crystallization inhibitors.

[0128] The above tablets were sealed in aluminum foil bags, and were investigated for influencing factors at a high temperature of 60° C. Related substances were detected by HPLC, and the physical stability was detected by DSC. The results are shown in Table 15 below:

TABLE-US-00016 TABLE 16 Stability results of solid dispersion tablets added with different crystallization inhibitors at a high temperature of 60° C. Related substances (%) Maximum Endothermic peak of Crystallization single Total crystalline drugs in inhibitor Time impurity CTF-aniline impurity DSC curve PVP K30 0 day 0.04 Not detected 0.10 No 10 days 0.04 Not detected 0.13 No PVP K25 0 day 0.04 Not detected 0.10 No 10 days 0.04 Not detected 0.12 No HPMC E5 0 day 0.04 Not detected 0.10 No 10 days 0.05 0.01 0.18 No HPMC K4M 0 day 0.04 Not detected 0.10 No 10 days 0.04 0.01 0.17 No RH40 0 day 0.04 Not detected 0.11 No 10 days 0.05 0.03 0.26 Yes Xanthan gum 0 day 0.04 Not detected 0.10 No 10 days 0.04 0.01 0.26 No TPGS1000 0 day 0.04 Not detected 0.09 No 10 days 0.05 Not detected 0.19 Yes SOLUPLUS 0 day 0.04 Not detected 0.10 No 10 days 0.04 Not detected 0.14 No HPMCAS 126G 0 day 0.04 Not detected 0.09 No 10 days 0.04 0.03 0.25 No

[0129] From the above data, it can be seen that the low-melting cosolvent underwent crystal transformation of the main drug during placement, resulting in a poor physical stability.

[0130] (2) Screening of Cholate Crystallization Inhibitors

TABLE-US-00017 TABLE 17 Screening formulas of crystallization inhibitors Composition of formula Amount (mg/tablet) Material SLFN-SD (based on the total 200.00 added amount of SLFN and VA64) internally SMCC 126.00 CCNa 45.00 MS 3.00 Material SMCC 88.00 added Crystallization inhibitor 75.00 externally SiO.sub.2 60.00 MS 3.00

[0131] Among them, the mass ratio of SLFN to VA64 was 1:1.

[0132] Crystallization inhibitor/cosolvent: SGC, SDC.

[0133] Preparation process: raw and adjuvant materials in the amount shown in the formula were weighed. Raw and adjuvant materials added internally were passed together through a 50-mesh sieve 6 times, mixed, and granulated by a dry method. The weight of the granules was weighed, and the amount of material added externally was calculated and weighed. They were mixed for 5 min and subjected to tableting, and cumulative dissolution was tested.

[0134] The dissolution method was the same as before. Comparison was made with the formula of PVPK25 as the crystallization inhibitor.

TABLE-US-00018 TABLE 18 Dissolution results of SLFN-VA64 solid dispersion-cholate crystallization inhibitor (n = 3) Disinte- gration Cumulative dissolution (%) time 5 15 30 45 60 90 120 240 SD No. min min min min min min min min min AUC.sub.0-4h Nexavar 4 14.6 16.4 14.6 13.1 12.4 11.1 10.2 9.9 2687.5 (half tablet, 100 mg) PVP K25 2 90.3 70.5 49.6 40.2 35.4 31.3 28.1 27.6 8002.5 SGC 4 51.6 69.6 80.3 60.8 35.1 17.1 13.3 12.1 6399.9 SDC 5 45.0 66.2 82.9 85.0 65.0 17.7 9.6 9.1 6942.5

[0135] According to the above results, in the case of the formula with VA-64 as a carrier and the external addition of cholates, the dissolution of sorafenib solid dispersion tablets within 60 min was greatly improved, but decreased to the same level as Nexavar after 60 min, and the time to maintain the crystal inhibition effect was not as long as that of the PVP series.

[0136] 2. Screening of Crystallization Inhibitors in Tablets Prepared from Solid Dispersions with SLFN-VA64-HPMCAS (1:1:0.25) as a Carrier

[0137] The crystallization inhibitors/cosolvents were screened according to Table 19 below.

TABLE-US-00019 TABLE 19 Screening of crystallization inhibitors - carrier SLFN-VA64-HPMCAS (1:1:0.25) Composition of formula Amount (mg/tablet) Material SLFN-SD (based on the total 225 added amount of SLFN-VA64-HPMCAS) internally MCC101 69.3 CaSO4 34.7 Crystallization inhibitor 80 CCNa 45 MS 3 Material MCC102 80 added SiO2 60 externally MS 3

[0138] Preparation process: raw and adjuvant materials in the amount shown in the formula were weighed. Raw and adjuvant materials added internally were passed together through a 50-mesh sieve 6 times, mixed, and granulated by a dry method. The weight of the granules was weighed, and the amount of material added externally was calculated and weighed. They were mixed for 5 min and subjected to tableting, and the dissolution profile was determined.

[0139] The dissolution method was the same as before.

TABLE-US-00020 TABLE 20 Dissolution profiles of different crystallization inhibitor formulas (n = 3) Disinte- Different gration Cumulative dissolution (%) inhibitors time 5 15 30 45 60 90 120 240 crystallization min min min min min min min min min AUC0-4h Nexavar 4 14.6 16.4 14.6 13.1 12.4 11.1 10.2 9.9 2687.5 (half tablet, 100 mg) PVP K30 3 75.7 89.5 71.2 55.4 47.6 41.0 37.8 33.3 10582.3 PVP K25 2 78.2 92.6 75.4 57.6 50.1 43.8 39.5 35.1 11248.1 HPMC K4M 28 22.9 56.4 43.9 30.8 23.4 19.3 17.1 15.7 5233.5 Xanthan gum 21 39.4 43.8 36.7 29.5 21.5 18.1 17.2 16.2 5071.5 SOLUPLUS 11 59.4 42.6 40.2 27.1 21.3 19.2 16.8 15.4 5208.8

[0140] From the above results, it can be seen that the crystallization inhibition effects of PVP K25 and PVPK30 were superior to that of the other three crystallization inhibitors.

Example 6 Screening of Preparation Formula

[0141] 5.1. Effects of Silica on Disintegration and Dissolution of Preparations

[0142] Tablets were prepared according to the formula shown in Table 21. The preparation method was the same as before.

TABLE-US-00021 TABLE 21 Investigation formula of the amount of silica Amount of raw and adjuvant materials/tablet (mg) Composition of formula Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Material SLFN-SD 200.00 200.00 200.00 200.00 200.00 added (Based on the internally total amount of SLFN and VA64) SMCC 126.00 126.00 126.00 126.00 126.00 PVP K30 75.00 75.00 75.00 75.00 75.00 CCNa 45.00 45.00 45.00 45.00 45.00 MS 3.00 3.00 3.00 3.00 3.00 Material SMCC 88.00 88.00 88.00 88.00 88.00 added SiO.sub.2 / 6 12 30 90 externally MS 3.00 3.00 3.00 3.00 3.00

[0143] Among them, the mass ratio of SLFN to VA64 was 1:1.

[0144] The dissolution results are shown in Table 22.

TABLE-US-00022 TABLE 22 Effects of different SiO.sub.2 on dissolution (n = 3) Disinte- gration Cumulative dissolution (%) time 5 15 30 45 60 90 120 240 SD No. min min min min min min min min min AUC.sub.0-4h Nexavar 4 14.6 16.4 14.6 13.1 12.4 11.1 10.2 9.9 2687.5 (half tablet, 100 mg) Formula 1 35 33.4 40.7 35.8 25.2 23.1 21.2 18.3 17.4 5209.8 Formula 2 28 38.2 43.6 36.7 26.4 22.8 20.7 18.9 17.3 5315.8 Formula 3 16 51.1 52.4 37.8 29.5 26.1 23.4 21.5 19.8 6028.0 Formula 4 13 67.4 54.2 40.1 31.5 27.6 23.7 22.6 20.2 6390.3 Formula 5 2 88.4 71.2 50.6 36.8 31.4 27.8 24.3 23.7 7494.5

[0145] From the above results, it can be seen that with the increase of the amount of silica, the disintegration became faster and the dissolution improved.

[0146] 5.2. Investigation of Fillers

[0147] Tablets were prepared according to the formula shown in Table 23. The preparation method was the same as before.

TABLE-US-00023 TABLE 23 Investigation formula of the amount of fillers Amount of raw and adjuvant materials in each formula/tablet (mg) Composition of formula Formula 6 Formula 7 Formula 8 Formula 9 Formula 10 Material SLFN-SD 225 225 225 225 225 added (based on the internally total amount of SLFN-VA64- HPMCAS) MCC101 69.3 69.3 69.3 69.3 79.3 Mannitol 34.7 / / / / Pregelatinized / 34.7 / / / starch Lactose / / 34.7 / / Calcium / / / 34.7 / hydrogen phosphate Starch / / / / 24.7 PVPK30 80 80 80 80 80 CCNa 45 45 45 45 45 MS 3 3 3 3 3 Material MCC102 80 80 80 80 80 added SiO.sub.2 60 60 60 60 60 externally MS 3 3 3 3 3

[0148] Among them, the mass ratio of SLFN-VA64-HPMCAS was 1:1:0.25.

[0149] The dissolution results are shown in Table 24 below:

TABLE-US-00024 TABLE 24 Effects of different fillers on dissolution (n = 3) Disinte- gration Cumulative dissolution (%) time 5 15 30 45 60 90 120 240 SD No. min min min min min min min min min AUC.sub.0-4h Nexavar 4 14.6 16.4 14.6 13.1 12.4 11.1 10.2 9.9 2687.5 (half tablet, 100 mg) Formula 6 6 72.1 85.4 63.2 51.9 40.3 37.2 34.5 24.6 9254.5 Formula 7 8 70.6 81.3 55.9 47.2 41.3 32.8 29.6 25.4 8559.0 Formula 8 7 65.7 80.4 51.3 49.2 37.8 30.5 27.4 22.9 7981.5 Formula 9 5 75.7 81.9 62.3 54.3 36.5 30.4 26.8 20.7 8178.8 Formula 10 8 77.6 80.1 51.4 46.1 34.6 28.7 25.8 23.7 7827.0

[0150] The above results show that different fillers had a slight influence on the dissolution results, but the dissolution was higher compared to the original preparation.

[0151] 5.3 Investigation of Disintegrants

[0152] Tablets were prepared according to the formula shown in Table 25. The preparation method was the same as before.

TABLE-US-00025 TABLE 25 Investigation formula of the amount of disintegrants Amount of raw and adjuvant materials in each formula/tablet (mg) Composition of formula Formula 11 Formula 12 Formula 13 Material SLFN-SD (based on the total 225 225 225 added amount of SLFN-VA64-HPMCAS) internally MCC101 69.3 69.3 69.3 CaSO4 34.7 34.7 34.7 PVP K30 80 80 80 PVPP 45 / / CMS-Na / 45 / L-HPC / / 90 MS 3 3 3 Material MCC102 80 80 80 added SiO.sub.2 60 60 60 externally MS 3 3 3

[0153] Among them, the mass ratio of SLFN-VA64-HPMCAS was 1:1:0.25.

[0154] The dissolution results are shown in Table 26 below:

TABLE-US-00026 TABLE 26 Effects of different disintegrants on dissolution (n = 3) Disinte- gration Cumulative dissolution (%) time 5 15 30 45 60 90 120 240 Formula No. min min min min min min min min min AUC.sub.0-4h Nexavar 4 14.6 16.4 14.6 13.1 12.4 11.1 10.2 9.9 2687.5 (half tablet, 100 mg) Formula 11 2 85.4 72.3 65.7 58.7 43.6 40.5 35.7 30.6 10070.3 Formula 12 9 80.1 71.2 55.7 43.6 38.1 30.5 25.8 22.6 7927.3 Formula 13 6 84.3 73.5 64.8 55.1 42 30.4 23.2 21.2 8153.3

[0155] It can be seen from the above results that although there were differences between different disintegrants, the dissolution was all good.

[0156] 5.4 Preparation of Samples with Different Specifications

TABLE-US-00027 TABLE 27 Formulas of samples with different specifications (100 tablets/batch) 70 mg 80 mg 120 mg 140 mg 150 mg specification specification specification specification specification Amount Amount Amount Amount Amount Composition of formula (mg/tablet) (mg/tablet) (mg/tablet) (mg/tablet) (mg/tablet) Material SD carrier SLFN-VA64- SLFN-VA64- SLFN-VA64- SLFN-VA64- SLFN-VA64- added and ratio HPMCAS HPMCAS HPMCAS HPMCAS HPMCAS internally (1:1:0.25) (1:1:0.25) (1:1:0.25) (1:1:0.25) (1:1:0.25) SLFN-SD 157.5 180.0 270.0 315.0 337.5 MCC 69.3 83.2 83.2 93.2 104.0 PH101 CaSO4 34.7 41.6 41.6 51.6 52.1 PVPK30 80 / 96 / 120 PVPK25 / 90 / 110 / CCNa 45 54 54 64 67.5 MS 3 3.6 3.6 4.2 4.5 Material MCC 80 96 96 110 120 added PH102 externally SiO.sub.2 60 72 72 85 90 MS 3 3.6 3.6 4.2 4.5

[0157] Preparation process: raw and adjuvant materials in the amount shown in the formula were weighed. Raw and adjuvant materials added internally were passed together through a 50-mesh sieve 6 times, mixed, and granulated by a dry method. The weight of the granules was weighed, and the amount of material added externally was calculated and weighed. They were mixed for 5 min and subjected to tableting.

[0158] The dissolution results are shown in Table 28 below:

TABLE-US-00028 TABLE 28 Dissolution results of samples with different specifications (n = 3) Disinte- gration Cumulative dissolution (%) time 5 15 30 45 60 90 120 240 Formula No. min min min min min min min min min AUC.sub.0-4h Nexavar 4 14.6 16.4 14.6 13.1 12.4 11.1 10.2 9.9 2687.5 (half tablet, 100 mg) 70 mg 3 99.8 99.9 98.2 90.4 75.8 66.4 59.9 52.1 16129.5 80 mg 3 99.7 99.6 96.1 90.8 77.3 71.5 61.4 55 16559.3 120 mg 11 80.3 71.6 63.7 55.8 40.8 35.9 33.6 30.3 9563.5 140 mg 11 73.1 65.2 60.8 50.4 37.7 33.4 32.8 27.6 8964.5 150 mg 13 66.4 55.1 50.8 44.9 35.7 31.6 29.7 25.4 8092.8

[0159] It can be seen that as the specification increased, the dissolution percentage decreased slightly, but it was much higher than that of the reference preparation Nexavar.

Example 7 Comparison of Animal Experiments

[0160] 6.1 Preparation of Animal Experimental Samples

TABLE-US-00029 TABLE 29 Formulas of animal experimental samples (1000 tablets/batch) 20200509-1 20200509-2 20200509-3 Composition of formula Amount (mg/tablet) Amount (mg/tablet) Amount (mg/tablet) Material SD carrier and SLFN-VA64 SLFN-VA64 SLFN-VA64-HPMCAS added ratio (1:1) (1:1) (1:1:0.25)  internally SLFN-SD 200.00  200.00  225 SMCC 126.00  126.00  / MCC PH101 / / 69.3 CaSO4 / / 34.7 PVPK30 75.00 / 80 HPMCE5 / 75.00 1 CCNa 45.00 45.00 45 MS  3.00  3.00 3 Material SMCC 88.00 88.00 / added MCC PH102 / / 80 externally SiO.sub.2 60.00 60.00 60 MS  3.00  3.00 3

[0161] Preparation process: raw and adjuvant materials in the amount shown in the formula were weighed. Raw and adjuvant materials added internally were passed together through a 50-mesh sieve 6 times, mixed, and granulated by a dry method. The weight of the granules was weighed, and the amount of material added externally was calculated and weighed. They were mixed for 5 min and subjected to tableting.

[0162] The above samples (specification 100 mg) and a reference preparation Nexavar (specification 200 mg) were used for animal experiments.

[0163] Animals: adult male Beagle (8-11 kg), which can be non-naïve; they were divided into 4 groups with 2 in each group.

[0164] Administration route and administration frequency: single oral administration of 1 tablet by gavage, fasting for 16 hours or more before administration, and free feeding after 4 hours of administration; the cleaning period was 4 days. 4 cycles of cross administration.

[0165] Blood sampling time points: 0, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 48 h.

[0166] LC/MS/MS method was used to detect blood concentration, and Phoenix WinNonlin 7.0 was used to calculate pharmacokinetic parameters (AUC.sub.0-t, AUC.sub.0-∞, C.sub.max, T.sub.1/2, T.sub.max and arithmetic mean (±SD) and geometric mean of these parameters).

TABLE-US-00030 TABLE 30 Experimental results of Beagles Cmax (ng/ml) AUC0.fwdarw.t(ng/ml*h) No. Reference 20200509-1 20200509-2 20200509-3 Reference 20200509-1 20200509-2 20200509-3 dog-#1 2103.3 3151.4 820.5 2987.3 11744.5 18830.6 4774.1 16656.2 dog-#2 3727.9 1300.5 1289.7 2138.7 21184.8 9465.3 9038.7 12778.1 dog-#3 1147.9 1410.4 1402.5 3210.1 9054.1 8596.5 8623.8 18922.1 dog-#4 3038.3 3287.2 2587.5 2463.3 17725.1 19089.2 13543.5 12931.2 dog-#5 2352.6 2660.1 2634.5 2180.5 12350.7 14397.4 12508.6 11207.4 dog-#6 934.8 2304.7 1388.1 2003.3 7418.3 13382.7 9665.9 10532.2 dog-#7 1904.3 1986.3 676.8 2507.5 10367.9 10888.7 3728.7 17340.5 dog-#8 856.7 1355.0 1050.8 1049.3 6124.3 9679.5 6705.1 9331.9 Mean 2008.2 2182.0 1481.3 2317.5 11996.2 13041.2 8573.6 13712.5 CV 51.1 36.7 50.2 12.5 42.8 31.8 40.2 25.6 Geometric 1774.052 2051.327 1333.31 2215.58 11111.03 12494.55 7904.149 13326.41 mean R test/ / 1.16 0.75 1.25 / 1.12 0.71 1.20 reference

[0167] It can be seen from the above results that 20200509-1 and 20200519-3 were significantly higher than 20200509-2. The 100 mg dosage of the two was basically equivalent to 200 mg of the reference preparation. Comparing the CVs of the reference and the test sample, it can be seen that 20200509-1 and 20200509-3 were significantly better than the reference preparation.

[0168] The description of the above examples is only used to help understand the method of the present disclosure and core idea thereof. It should be noted that for those of ordinary skill in the art, several improvements and modifications can be made to the present disclosure without departing from the principles of the present disclosure, and these improvements and modifications also fall within the protection scope of the claims of the present disclosure.