SOLID ORAL FORMULATION OF UTIDELONE

Abstract

An oral pharmaceutical formulation using 4, 8-dihydroxy-5, 5, 7, 9, 13-pentamethyl-16-[1-methyl-2-(2-methyl-thiazole-4-yl)-ethenyl]]-oxacyclohexadec-13-ene-2,6-dione (utidelone) as an active ingredient, suitable for oral administration. The pharmaceutical formulation is a solid formulation such as tablets and capsules, and the pharmaceutical dosage form has good stability, in vitro dissolution behavior, and bioavailability.

Claims

1. A solid oral formulation comprising Untielone, or a pharmaceutically acceptable salt, solvate or ester thereof as an active ingredient and a pharmaceutically acceptable excipient.

2. The solid oral formulation. according to claim 1, wherein the pharmaceutically acceptable excipient comprises a hydrophilic pharmaceutical excipient, a sustained-release pharmaceutical excipient, and optionally a surfactant

3. The solid oral formulation according to claim 1, wherein the ratio of the active ingredient to the pharmaceutically acceptable excipient is in the range of 1:1 to 1:30.

4. The solid oral formulation according to claim 3, wherein the ratio of the active ingredient to the pharmaceutically acceptable excipient is in the range of 1:5 to 1:20.

5. The solid oral formulation according to claim 2, wherein the hydrophilic pharmaceutical excipient is selected from at least one of povidone, hypromellose, mannitol, lactose, sucrose, poloxamer and polyvinyl alcohol; the sustained-release pharmaceutical excipient is selected from at least one of povidone, hypromellose, polyethylene glycol, ethyl cellulose, polyvinyl acetal diethylamine acetate, hypromellose acetate succinate, acetate methacrylate copolymer, cellulose acetate, methyl cellulose, polyacrylic resin, polyvinyl phthalate, cellulose phthalate, and hypromellose phthalate; the surfactant is selected from at least one of polysorbate, polyoxyl castor oil, sodium lauryl sulfate, cholate, fatty acid glyceride, sorbitan, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, and poloxamer.

6. The solid oral formulation according to claim 5. wherein the hydrophilic pharmaceutical excipient is selected from at least one of low viscosity hyprom.ellose, povidone and poloxamer; the sustained-release pharmaceutical excipient is selected from at least one of high viscosity hypromellose, high viscosity polyethylene glycol, ethyl cellulose and cellulose acetate; the surfactant is selected from at least one of polyoxyl castor oil, polysorhate and poloxamer.

7. The solid oral formulation according to claim 1, which is a micropellet capsule or a tablet.

8. The solid oral formulation according to claim 7, wherein the micropellet capsule or tablet comprises 2%-10% (w/w) of the active ingredient based on the weight of the micropel let or the weight of the tablet.

9. (canceled)

10. The solid oral formulation according to claim 8, wherein the micropellet capsule or tablet further comprises 30%-70% (w/w) of pharmaceutical excipients and. 20%˜60% (w/w) pill core based on the weight of the micropellet or tablet.

11. The solid oral formulation according to claim 1, which is a micropellet capsule comprising Utidelone as an active ingredient, and polyoxyethylene (40) hydrogenated castor oil, low-viscosity hypromellose and high viscosity hypromellose as pharmaceutical excipients.

12. (canceled)

13. The solid oral formulation according to claim 1, wherein the active ingredient Utidelone is present in an amorphous or molecular form.

14. A method of treatin.g a cancer in a subject comprising administering a. therapeutically effective amount of the solid oral formulation according to claim 1 to the subject, wherein the cancer is selected from breast cancer, lung cancer, digestive tract tumors, lymphoid tumors, prostate cancer, brain cancer, gynecological tumors, liver cancer, head and neck tumors, ovarian cancer, colon cancer and stomach cancer.

Description

DESCRIPTION OF DRAWINGS

[0048] FIG. 1: Dissolution profile of the oral formulation of Example 1;

[0049] FIG. 2: Dissolution profile of the oral formulation of Example 2;

[0050] FIG. 3: Dissolution profile of the oral formulation of Example 3;

[0051] FIG. 4: Dissolution profile of the oral formulation of Example 4;

[0052] FIG. 5A: Dissolution profile of the oral formulation of Example 5-A;

[0053] FIG. 5B: Dissolution profile of the oral formulation of Example 5-B;

[0054] FIG. 6: Area under the plasma concentration-time curve of Utidelone injection;

[0055] FIG. 7: Area under the plasma concentration-time curve of Utidelone capsules of Example 1;

[0056] FIG. 8: Area under the plasma concentration-time curve of Utidelone injection;

[0057] FIG. 9: Area under the plasma concentration-time curve of Utidelone capsules of Example 5-A;

[0058] FIG. 10: X-ray diffraction pattern of a crystal form of Utidelone;

[0059] FIG. 11: X-ray diffraction pattern of the amorphous form of Utidelone;

[0060] FIG. 12: X-ray diffraction pattern of the pharmaceutical excipients (inactive ingredients) used in the Utidelone capsules prepared in Example 5-A;

[0061] FIG. 13A: X-ray diffraction pattern of the contents contained in the Utidelone capsules (stored at room temperature) prepared in Example 5-A;

[0062] FIG. 13B: HPLC chromatogram of the contents contained in the Utidelone capsules (stored at room temperature) prepared in Example 5-A.

EMBODIMENTS

[0063] The present application is further described below in conjunction with examples, but the present application is not limited to the following examples. For those skilled in the art, appropriate improvements and modifications may be carried out without departing from the principles of the present application. These improvements and modifications are also regarded as those within the protection scope of the present application.

[0064] Material:

[0065] Utidelone used in the formulations of the following examples was manufactured by Chengdu Huahao Zhongtian Pharmaceutical Co., Ltd., and the implementation standards of all excipients are the national approval or the 2020 edition of the Chinese Pharmacopoeia. Among them, polyoxyethylene (40) hydrogenated castor oil was made by BASF China Co., Ltd., hypromellose E50 was made by Rohm and Haas, hypromellose K100 was made by Rohm and Haas, pill cores (sucrose) were made by Shanghai Colorcon Coating, and Vacant Hypromellose Capsules were manufactured by Suzhou Capsule Co., Ltd. However, the excipients used in the oral solid formulations of the following examples are not limited by the manufacturer.

EXAMPLE 1: Utidelone Oral Solid Formulations

[0066]

TABLE-US-00001 Amount Amount material (Formulation 1) (Formulation 2) Utidelone  15 g  15 g Povidone K30  155 g  110 g Polyoxyethylene  30 g  30 g (40) Hydrogenated Castor Oil Hypromellose E5 0  45 g Sugar Spheres  100 g  100 g anhydrous ethanol 2800 g 2800 g purified water 1200 g 1200 g

[0067] Take the indicated amount of Utidelone, polyoxyethylene (40) hydrogenated castor oil, and povidone K30 in a beaker to be dissolved with the amount of anhydrous ethanol, and then add the amount of purified water and mix well or slowly add hypromellose E5 aqueous solution and stir for about approx. 1 hour to mix well. The hypromellose E5 aqueous solution was obtained by adding the indicated amount of hypromellose E5 to the amount of purified water while stirring to dissolve. In the multifunctional granulation and coating machine, the indicated amount of pill core was added, and coated with the above obtained solution containing drug. After coated, fully dried and discharged, and the obtained pellets were filled into capsules. Each capsule was filled with 10-30 mg of Utidelone.

Dissolution Test:

[0068] The test sample was capsules containing 20 mg of Utidelone. According to “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1, capsules were added to a rotating basket at a rotation speed of 100 rpm, in the dissolution medium of 900 ml phosphate buffer with pH 6.8. The release was determined by high performance liquid chromatography, with a C18 chromatographic column, acetonitrile: water=(65:35) as the mobile phase, at 30° C. of column temperature, detected at a wavelength of 250 nm. The dissolution profile is shown in FIG. 1.

[0069] Using the hydrophilic carrier material as a solid dispersant, after the carrier and Utidelone were prepared into a solid dispersion, although the solubility of the drug was significantly improved, the dissolved drug was prone to recrystallization in the body, thereby reducing the bioavailability of the drug. The bioavailability in the beagle of this example was 29%.

EXAMPLE 2: Utidelone oral solid formulations

[0070]

TABLE-US-00002 Material Amount Utidelone  15 g Polyoxyethylene (40)  30 g Hydrogenated Castor Oil Hypromellose E5  155 g Sugar Spheres  100 g Ethyl cellulose  11 g polyethylene glycol 400   1.5 g anhydrous ethanol 2800 g purified water 1200 g

[0071] Take the indicated amount of Utidelone and polyoxyethylene (40) hydrogenated castor oil in a beaker to be dissolved with the amount of anhydrous ethanol and then slowly add hypromellose E5 aqueous solution and stir for about approx. 1 hour to mix well. The hypromellose E5 aqueous solution was obtained by adding the indicated amount of hypromellose E5 to the amount of purified water while stirring till dissolved. In the multifunctional granulation and coating machine, the indicated amount of pill core was added, and coated with the above solution obtained. After coated, fully dried and discharged to render pellets containing the drug.

[0072] Take 11 g of ethyl cellulose and 1.5 g of polyethylene glycol 400 into a beaker to dissolve with 175 ml of absolute ethanol, and then add water to dilute to 250 ml to obtain a controlled release coating solution. The drug-containing pellets were coated with the controlled-release coating solution in fluidized bed, and the coating weight increased by about 4%. After coated, age at 40° C. for more than 2 hours to obtain Utidelone sustained-release pellets which were then filled in capsules.

[0073] Dissolution Test:

[0074] The test sample was capsules containing 20 mg of Utidelone. According to “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1, capsules were put into a rotating basket at a rotation speed of 100 rpm, in the dissolution medium of 900m1 phosphate buffer with pH 6.8. The release was determined by high performance liquid chromatography, with a C18 chromatographic column, acetonitrile: water =(65:35) as the mobile phase, at 30° C. of column temperature, detected at a wavelength of 250 nm. The dissolution profile is shown in FIG. 2.

EXAMPLE 3

[0075] Utidelone Oral Solid Formulations

TABLE-US-00003 Material Amount Utidelone  15 g Polyoxyethylene (40) Hydrogenated  30 g Castor Oil Hypromellose E50  80 g Hypromellose K100  25 g Sugar Spheres  100 g anhydrous ethanol 3000 g purified water 1400 g

[0076] Take the indicated amount of Utidelone and polyoxyethylene (40) hydrogenated castor oil in a beaker to be dissolved with the amount of anhydrous ethanol and then slowly add hypromellose aqueous solution and stir for about approx. 1 hour to mix well. The hypromellose aqueous solution was obtained by adding the indicated amount of hypromellose E50 and hypromellose K100 to the amount of purified water while stirring till dissolved. In the multifunctional granulation and coating machine, the indicated amount of pill core was added, and coated with the above solution obtained. After coated, fully dried and discharged to render pellets containing the drug.

[0077] Dissolution Test:

[0078] The test sample was capsules containing 20 mg of Utidelone. According to “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1, capsules were put into a rotating basket at a rotation speed of 100 rpm, in the dissolution medium of 900m1 phosphate buffer with pH 6.8. The release was determined by high performance liquid chromatography, with a C18 chromatographic column, acetonitrile: water =(65:35) as the mobile phase, at 30° C. of column temperature, detected at a wavelength of 250 nm. The dissolution profile is shown in FIG. 3.

EXAMPLE 4

[0079] Utidelone Oral Solid Formulations

TABLE-US-00004 Material Amount Utidelone  15 g Polyoxyethylene (40) Hydrogenated  30 g Castor Oil Hypromellose E50  95 g Ethyl cellulose  10 g Sugar Spheres  100 g anhydrous ethanol 2800 g purified water 1200 g

[0080] Take the indicated amount of Utidelone and polyoxyethylene (40) hydrogenated castor oil and ethyl cellulose in a beaker to be dissolved with the amount of anhydrous ethanol and then slowly add hypromellose aqueous solution and stir for about approx. 1 hour to mix well. The hypromellose aqueous solution was obtained by adding the indicated amount of hypromellose E50 to the amount of purified water while stirring till dissolved. In the multifunctional granulation and coating machine, the indicated amount of pill core was added, and coated with the above solution obtained. After coated, fully dried and discharged to render pellets containing the drug, which were then filled into capsules.

[0081] Dissolution Test:

[0082] The test sample was capsules containing 20 mg of Utidelone. According to “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1, capsules were put into a rotating basket at a rotation speed of 100 rpm, in the dissolution medium of 900m1 phosphate buffer with pH 6.8. The release was determined by high performance liquid chromatography, with a C18 chromatographic column, acetonitrile: water=(65:35) as the mobile phase, at 30° C. of column temperature, detected at a wavelength of 250 nm. The dissolution profile is shown in FIG. 4.

EXAMPLE 5-A

[0083] Utidelone Oral Solid Formulations

TABLE-US-00005 Material Amount Utidelone  15 g Polyoxyethylene (40) Hydrogenated  30 g Castor Oil Hypromellose E50  60 g Hypromellose K100  45 g Sugar Spheres  100 g anhydrous ethanol * 3000 g purified water * 1400 g Vacant Hypromellose Capsules as needed * Solvent used in the process and finally removed.

[0084] Take the indicated amount of Utidelone and polyoxyethylene (40) hydrogenated castor oil and ethyl cellulose in a beaker to be dissolved with the amount of anhydrous ethanol and then slowly add hypromellose aqueous solution and stir for about approx. 1 hour to mix well. The hypromellose aqueous solution was obtained by adding the indicated amount of hypromellose E50 and K100 to the amount of purified water while stirring till dissolved. In the multifunctional granulation and coating machine, the indicated amount of pill core was added, and coated with the above solution obtained. After coated, fully dried and discharged to render pellets containing the drug, which were then filled into capsules.

Dissolution Test:

[0085] The test sample was capsules containing 20 mg of Utidelone. According to “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1, capsules were put into a rotating basket at a rotation speed of 100 rpm, in the dissolution medium of 900m1 phosphate buffer with pH 6.8. The release was determined by high performance liquid chromatography, with a C18 chromatographic column, acetonitrile: water=(65:35) as the mobile phase, at 30° C. of column temperature, detected at a wavelength of 250 nm. The dissolution profile is shown in FIG. 5A. The in vitro dissolution characteristics of the prepared samples meet the expected goals. They were dissolved about 57% at 30 minutes and about 99% at 60 minutes, and there was no burst or incomplete release occurred.

EXAMPLE 5-B

[0086] The preparation method and dissolution testing method of the micropellet capsule in this example are the same as those in Example 5-A.

TABLE-US-00006 Material Amount Utidelone  15 g Polyoxyethylene (40) Hydrogenated  30 g Castor Oil Hypromellose E50  80 g Hypromellose K100  30 g Sugar Spheres  100 g anhydrous ethanol * 2500 g purified water * 2000 g Vacant Hypromellose Capsules as needed

[0087] The dissolution profiles are shown in FIG. 5B, showing good release uniformity for capsules prepared in multiple batches (as shown in FIG. 5B).

EXAMPLE 6

[0088] Utidelone Oral Solid Formulations

TABLE-US-00007 Material Amount Utidelone  15 g Polyoxyethylene (40) Hydrogenated  30 g Castor Oil Hypromellose E50  60 g Hypromellose K100  45 g Sugar Spheres  75 g Povidone K30  50 g lactose  125 g talcum powder   5 g anhydrous ethanol 3000 g purified water 1400 g

[0089] Take the indicated amount of Utidelone and polyoxyethylene (40) hydrogenated castor oil in a beaker to be dissolved with the amount of anhydrous ethanol and then slowly add hypromellose aqueous solution and stir for about approx. 1 hour to mix well. The hypromellose aqueous solution was obtained by adding the indicated amount of hypromellose E50 and K100 to the amount of purified water while stirring till dissolved. In the multifunctional granulation and coating machine, the indicated amount of pill core was added, and coated with the above solution obtained. After coated, fully dried and discharged to render pellets containing the drug. Mix the pellets with povidone K30, lactose and talc powder evenly, and press into tablets to obtain Utidelone tablets.

EXAMPLE 7

[0090] Utidelone Oral Solid Formulations

TABLE-US-00008 Material Amount Utidelone  15 g Polyoxyethylene (40) Hydrogenated  10 g Castor Oil Povidone K30 120 g lactose 100 g Hypromellose K100M 150 g talcum powder  5 g anhydrous ethanol 600 g

[0091] Take the indicated amount of Utidelone, polyoxyethylene (40) hydrogenated castor oil and povidone K30 in a beaker to be dissolved with the amount of anhydrous ethanol and mix evenly to obtain a solution containing Utidelone. The solution was spray-dried with a multifunctional granulation coating machine to obtain a solid dispersion of Utidelone. After dry granulation of the solid dispersion, lactose, hypromellose KlOOM and talc powder, tablet pressing was performed to obtain the Utidelone tablets.

EXAMPLE 8

[0092] Utidelone Oral Solid Formulations

TABLE-US-00009 Material Amount Utidelone  15 g polyethylene glycol 6000  155 g Tween 80  30 g Sugar Spheres  100 g anhydrous ethanol 1500 g purified water  500 g

[0093] Take the indicated amount of Utidelone, polyoxyethylene (40) hydrogenated castor oil, Tween 80, and polyethylene glycol 6000 in a beaker to dissolve with the amount of absolute ethanol, then add purified water, and mix well. In the multifunctional granulation and coating machine, the indicated amount of pill cores was added, and coated with the above solution obtained. After coated, fully dried and discharged to render pellets containing the drug, which were then filled into capsules.

EXAMPLE 9

[0094] Utidelone Oral Solid Formulations

TABLE-US-00010 Material Amount Utidelone  15 g Poloxamer 407  65 g polyethylene glycol 8000  85 g Sugar Spheres  100 g anhydrous ethanol 1500 g purified water  500 g

[0095] Take the indicated amount of Utidelone, Poloxamer 407, and polyethylene glycol 8000 in a beaker to dissolve with the amount of absolute ethanol, then add purified water, and mix well. In the multifunctional granulation and coating machine, the indicated amount of pill cores was added, and coated with the above solution obtained. After coated, fully dried and discharged to render pellets containing the drug, which were then filled into capsules.

EXAMPLE 10

[0096] Utidelone Oral Solid Formulations

TABLE-US-00011 Material Amount Utidelone  15 g polyethylene glycol 6000  155 g Polyoxyethylene (40) Hydrogenated  30 g Castor Oil Povidone K90  15 g lactose  100 g silica  155 g anhydrous ethanol 1000 g

[0097] Take the indicated amount of Utidelone, polyoxyethylene (40) hydrogenated castor oil and polyethylene glycol 6000 in a beaker to be dissolved with the amount of anhydrous ethanol and mix evenly to obtain a solution containing Utidelone. The solution was spray-dried with a multifunctional granulation coating machine to obtain a solid dispersion of Utidelone. After dry granulation of the solid dispersion, lactose, silica and povidone K90, tablet pressing was performed to obtain the Utidelone tablets.

EXAMPLE 11

[0098] Utidelone Oral Solid Formulations

TABLE-US-00012 Material Amount Utidelone  15 g polyethylene glycol 4000  150 g Poloxamer 407  30 g Glyceryl Behenate  30 g Polyvinylpyrrolidone   5 g sucrose  100 g Micro powder silica  100 g Anhydrous ethanol 1500 g

[0099] Take the indicated amount of Utidelone, Poloxamer 407 and polyethylene glycol 4000 in a beaker to be dissolved with the amount of anhydrous ethanol and mix evenly to obtain a solution containing Utidelone. The solution was spray-dried with a multifunctional granulation coating machine to obtain a solid dispersion of Utidelone. After dry granulation of the solid dispersion, lactose, silica, glyceryl behenate, and polyvinylpyrrolidone, tablet pressing was performed to obtain Utidelone tablets.

EXAMPLE 12

[0100] Utidelone Oral Solid Formulations

TABLE-US-00013 Material Amount Utidelone  15 g Polysorbate 80  30 g lactose  110 g Cellulose acetate  45 g pill core  100 g anhydrous ethanol 3000 g purified water 1400 g

[0101] Take the indicated amount of Utidelone, polysorbate 80, and cellulose acetate in a beaker to dissolve with the amount of absolute ethanol, then add slowly lactose aqueous water obtained by dissolving lactose into the amount of purified water while stirring, and mix well by stirring for about 1 hour. In the multifunctional granulation and coating machine, the indicated amount of pill cores was added, and coated with the above solution obtained. After coated, fully dried and discharged to render pellets containing the drug, which were then filled into capsules.

EXAMPLE 13

Bioavailability Test

[0102] 1. Bioavailability of Utidelone Capsules prepared in Example 1

[0103] Experiment Method:

[0104] Four Beagle dogs were divided into two groups, one group was administered orally Utidelone micropellets 1mg/kg in the first test; in the other group, each dog was administered by intravenous infusion 1mg/kg of Utidelone injection in the first test. Intravenous blood was collected at 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h before administration and after administration. After the samples were centrifuged to separate the plasma, the concentration of Utidelone in the plasma was determined by LC-MS/MS. The test results are shown in FIG. 6.

[0105] The pharmacokinetic data of Utidelone Injection and Utidelone Capsules (Example 1) are shown in the following table.

TABLE-US-00014 TABLE 1 PK/PD data of Utidelone injection PK First Time Second Time parameters Unit 101# 102# 111# 112# Mean K.sub.el h.sup.−1 0.15 0.06 0.11 0.14 0.12 t.sub.1/2 h 4.48 11.46 6.21 5.01 6.79 Tmax h 1.5 1.5 1.5 1.5 1.500 Cmax ng .Math. mL.sup.−1 2320 1590 2900 3090 2475 AUC.sub.0-t ng .Math. h .Math. 7964.9 6526.3 10780.5 10327.3 8899.7 mL.sup.−1 AUC.sub.0-inf ng .Math. h .Math. 8352.6 7435.9 12195.5 11031.8 9753.9 mL.sup.−1 AUMC.sub.0-t ng .Math. h.sup.2 .Math. 37593.0 37436.3 68136.5 54171.7 49334.4 mL.sup.−1 AUMC.sub.0-inf ng .Math. h.sup.2 .Math. 49405.1 74313.1 114769.0 76174.5 78665.4 mL.sup.−1 MRT.sub.IV h 5.91 9.99 9.41 6.91 8.06 CL mL .Math. kg.sup.−1 .Math. 119.7 134.5 82.0 90.6 106.7 h.sup.−1 Vd.sub.ss mL .Math. kg.sup.−1 773.7 2224.2 734.3 655.6 1097.0

TABLE-US-00015 TABLE 2 PK/PD data of Utidelone capsules (Example 1) PK Second Time First Time Mean parameters Unit 101# 102# 111# 112# Mean K.sub.el h.sup.−1 0.15 0.20 0.19 0.12 0.16 t.sub.1/2 h 4.48 3.53 3.69 5.84 4.39 Tmax h 1 0.5 0.5 2 1.000 Cmax ng .Math. mL.sup.−1 439.0 577.0 998.0 456.0 618 AUC.sub.0-t ng .Math. h .Math. mL.sup.−1 1985.3 2511.7 3463.7 2806.9 2691.9 AUC.sub.0-inf ng .Math. h .Math. mL.sup.−1 2134.7 2575.9 3587.6 3126.9 2856.3 AUMC.sub.0-t ng .Math. h.sup.2 .Math. mL.sup.−1 9707.6 10242.5 13860.4 18067.8 12969.6 AUMC.sub.0-inf ng .Math. h.sup.2 .Math. mL.sup.−1 14261.0 12111.9 17493.1 28442.4 18077.1 MRT.sub.PO h 4.89 4.08 4.00 6.44 4.85 F % 21.9 26.4 36.8 32.1 29.3

[0106] The average relative bioavailability of the oral formulation of Example 1 can reach about

[0107] Using the same test method, the average relative bioavailability of the oral formulations prepared in Examples 2, 3, and 4 was found to be between 30-50%.

[0108] 2. The Bioavailability Test of the Oral Formulations Prepared in Examples 5 and 6

[0109] Experimental Method:

[0110] Six Beagle dogs were divided into two groups, with 3 dogs in each group. In the first group, each dog was orally administered with 1.5 mg/kg of Utidelone capsules of Example 5-A. Each dog in the other group received an intravenous infusion of 1 mg/kg of Utidelone as reference. Intravenous blood was collected at 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h before administration and after administration. After the samples were centrifuged to separate the plasma, the concentration of Utidelone in the plasma was determined by LC-MS/MS. The results of the injection test are shown in FIG. 8, and the experimental results of the capsules are shown in FIG. 9.

[0111] The pharmacokinetic data of Utidelone injection and Utidelone capsules (Example 5-A) are shown in Table 3 below.

TABLE-US-00016 TABLE 3 Mean values of pharmacokinetic parameters after a single intravenous administration of Utidelone injection and oral administration of Utidelone capsules in beagle dogs Mean values intravenous oral Parameters administration administration SD Kel (h.sup.−1) 0.12 ± 0.04 0.16 ± 0.13 T.sub.1/2 (h) 6.18 ± 2.57 8.70 ± 6.70 T.sub.max (h)  1.5 ± 0.00 0.75 ± 0.43 C.sub.max (ng/mL) 1273 ± 351  2410 ± 1331 AUC.sub.0-t 3686 ± 733  4166 ± 2164 AUC.sub.0-∞ 3789 ± 653  4459 ± 2298 AUMC.sub.0-t 15252 ± 373  12665 ± 5968  AUMC.sub.0-inf 19017 ± 3458  24715 ± 16308 MRT (h) 4.47 ± 1.87 4.89 ± 5.88 CL (mL .Math. h) 2694 ± 474  — Vd.sub.ss (mL) 25031 ± 14804 —

[0112] The relative bioavailability of Utidelone capsules after a single oral administration ranged from 53.1% to 103.8%, with an average relative bioavailability of 78.5%.

[0113] With the test method of Example 5-A, it was measured that the average relative bioavailability of the Utidelone tablets prepared in Example 6 reached more than 55%.

EXAMPLE 14

Stability

[0114] Utidelone capsules (Examples 1 and 5) were stored under the accelerated test conditions of 40° C. and 75% RH, and the related substance detection results after 1 month of storage showed that the degradation impurities in the product were within the range specified by ICH Q3. It shows that the oral formulation of Utidelone of the present invention has good stability.

[0115] Utidelone capsules (Examples 1 and 5) were stored under the accelerated test conditions of 40° C. and 75% RH. The X-ray diffraction analysis of the preparations after 1 month of storage showed that the Utidelone in the capsules exists in an amorphous or molecular form.

EXAMPLE 15

Preparation of Amorphous Utidelone

[0116] Method 1:

[0117] Dissolve 1 g of Utidelone in 5 ml of dichloromethane or chloroform or any two or three mixed solvents of dichloromethane, chloroform and ethyl acetate, and dried under reduced pressure of −0.05Mpa at 30° C.˜80° C. to obtain the target product.

[0118] Method 2:

[0119] Dissolve 1 g of Utidelone in 5 ml of dichloromethane or chloroform or any two or three mixed solvents of dichloromethane, chloroform and ethyl acetate, and spray-dry it with a fluidized bed with feed and inlet air temperature of >30° C. to obtain the target product.

[0120] Method 3:

[0121] Dissolve 1 g of Utidelone in 10 ml of methanol or ethanol, and evaporate to dryness under reduced pressure with a rotary evaporator to obtain the target product.

[0122] The X-ray diffraction pattern of amorphous Utidelone is shown in FIG. 11 .

[0123] Utidelone in the capsules obtained in the examples of the present application exists in an amorphous or molecular form.