FULVESTRANT PHARMACEUTICAL COMPOSITION, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF

Abstract

A fulvestrant pharmaceutical composition, a preparation method therefor, and an application thereof are provided. The fulvestrant pharmaceutical composition contains fulvestrant solid particles. The particle size of the fulvestrant solid particles satisfies that Dv(10) is selected from 0.400 micrometers to 6.000 micrometers, Dv(50) is selected from 0.700 micrometers to 6.000 micrometers, and Dv(90) is selected from 1.000 micrometers to 6.000 micrometers, provided that Dv(10) is not 0.400 micrometers, Dv(50) is not 0.700 micrometers, and Dv(90) is not 1.000 micrometers. The fulvestrant pharmaceutical composition has a long-acting sustained release.

Claims

1. A fulvestrant pharmaceutical composition comprising fulvestrant solid particles, wherein the fulvestrant solid particles have a particle size of Dv(10) selected from 0.400-6.000 μm, Dv(50) selected from 0.700-6.000 μm and Dv(90) selected from 1.000-6.000 μm, provided that Dv(10) is not 0.400 μm, Dv(50) is not 0.700 μm, and Dv(90) is not 1.000 μm.

2. The fulvestrant pharmaceutical composition according to claim 1, wherein the fulvestrant solid particles have a particle size of Dv(10) of 0.500-6.000 μm; preferably, the fulvestrant solid particles have a particle size of Dv(10) of 0.600-2.000 μm; preferably, the fulvestrant solid particles have a particle size of Dv(10) of 0.900-1.800 μm; preferably, the fulvestrant solid particles have a particle size of Dv(50) of 0.800-6.000 μm; preferably, the fulvestrant solid particles have a particle size of Dv(50) of 0.900-4.000 μm; preferably, the fulvestrant solid particles have a particle size of Dv(50) of 1.000-3.000 μm; preferably, the fulvestrant solid particles have a particle size of Dv(75) of 1.000-4.000 μm; preferably, the fulvestrant solid particles have a particle size of Dv(90) of 1.000-5.000 μm; preferably, the fulvestrant solid particles have a particle size of Dv(90) of 1.500-4.500 μm; and preferably, the fulvestrant solid particles have a particle size of Dv(25) of 1.000-3.000 μm.

3. The fulvestrant pharmaceutical composition according to claim 1, further comprising a vehicle, wherein preferably, the vehicle is an oily vehicle and/or a non-oily vehicle; and preferably, the oily vehicle comprises, but is not limited to castor oil, triglyceride, cottonseed oil and sesame oil; and/or, the non-oily vehicle comprises, but is not limited to water.

4. The fulvestrant pharmaceutical composition according to claim 1, further comprising one or more selected from the following: a suspending agent, a wetting agent, a osmotic pressure regulator, a solvent, a stabilizer, a buffer, a pH adjusting agent, a surfactant, a polymer, an electrolyte, a non-electrolyte, and a co-solvent, wherein preferably, the polymer is a cross-linked polymer and/or a non-cross-linked polymer; preferably, the suspending agent comprises, but is not limited to sodium carboxymethylcellulose, polyethylene glycol and povidone; preferably, the wetting agent comprises, but is not limited to one or more of poloxamer and tween; preferably, the osmotic pressure regulator comprises, but is not limited to one or more of sodium chloride, mannitol and sucrose; preferably, the solvent comprises, but is not limited to one or more of water for injection and oil for injection; preferably, the stabilizer comprises, but is not limited to one or more of an antioxidant, a metal ion chelating agent, polyethylene oxide, polyethylene oxide derivatives, polysorbate, poloxamer, polyethoxylated vegetable oil, polyethoxylated castor oil, sorbitan palmitate, lecithin, polyvinyl alcohol, human serum albumin, polyvinylpyrrolidone, povidone, polyethylene glycol, sodium chloride, calcium chloride, dextrose, glycerol, mannitol, and a cross-linked polymer; preferably, the buffer comprises, but is not limited to buffers from phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid, sodium hydroxide, sodium citrate, citric acid, tris(hydroxymethyl)aminomethane or a mixture thereof; and/or, the pH adjusting agent comprises, but is not limited to one or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide; and/or, the co-solvent comprises, but is not limited to one or more of ethanol and propylene glycol.

5. The fulvestrant pharmaceutical composition according to claim 4, wherein the antioxidant comprises, but is not limited to one or more of citric acid, vitamin C and vitamin E; and/or, the metal ion chelating agent comprises, but is not limited to ethylenediaminetetraacetic acid; and/or, the poloxamer comprises, but is not limited to one or more of poloxamer 188, poloxamer 124 and poloxamer 407; and/or, the polysorbate comprises, but is not limited to one or more of polysorbate 80 and polysorbate 20; and/or, the povidone comprises, but is not limited to one or more of povidone K12, povidone K17, PLASDONETM C-12 povidone, PLASDONETM C-17 povidone, and PLASDONETM C-30 povidone; and/or, the polyethylene glycol comprises, but is not limited to polyethylene glycol 3350; and/or, the cross-linked polymer comprises, but is not limited to sodium carboxymethylcellulose; and/or, the phosphate comprises, but is not limited to sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, anhydrous sodium dihydrogen phosphate, disodium hydrogen phosphate monohydrate, disodium hydrogen phosphate dihydrate, and anhydrous disodium hydrogen phosphate.

6. The fulvestrant pharmaceutical composition according to claim 1, wherein the fulvestrant pharmaceutical composition is selected from any one of the following formulas: formula I: 18.09% fulvestrant solid particles, 1.67% wetting agent and 80.24% water; formula II: 19.59% fulvestrant solid particles, 1.74% wetting agent and 78.67% water; formula III: 24.56% fulvestrant solid particles, 1.62% wetting agent, 1.00% suspending agent, 2.82% osmotic pressure regulator, 0.42% buffer and 0-1% pH adjusting agent; formula IV: 25.00% fulvestrant solid particles, 1.62% wetting agent, 1.00% suspending agent, 2.89% osmotic pressure regulator, 0.43% buffer and 0-1% pH adjusting agent; and formula V: 25.00% fulvestrant solid particles, 1.62% wetting agent, 0.20% suspending agent, 2.29% osmotic pressure regulator, 0.51% buffer and 70.38% water.

7. The fulvestrant pharmaceutical composition according to claim 1, wherein the fulvestrant pharmaceutical composition is selected from any one of the following formulas: formula A: 18.09% fulvestrant solid particles, 1.67% tween 80 and 80.24% sterile water for injection; formula B: 19.59% fulvestrant solid particles, 1.74% tween 80 and 78.67% sterile water for injection; formula C: 24.66% fulvestrant solid particles, 1.62% tween 20, 1.00% sodium carboxymethylcellulose, 2.82% mannitol, 0.42% anhydrous sodium dihydrogen phosphate, sodium hydroxide and sterile water for injection; formula D: 25.00% fulvestrant solid particles, 1.62% tween 20, 1.00% sodium carboxymethylcellulose, 2.89% mannitol, 0.43% anhydrous sodium dihydrogen phosphate, sodium hydroxide and sterile water for injection, wherein preferably, the fulvestrant pharmaceutical composition has a pH of 7.4; and formula E: 25.00% fulvestrant solid particles, 1.62% tween 20, 0.20% sodium carboxymethylcellulose, 2.29% mannitol, 0.09% anhydrous sodium dihydrogen phosphate, 0.42% anhydrous disodium hydrogen phosphate and 70.38% sterile water for injection.

8. Use of the fulvestrant pharmaceutical composition according to claim 1 in the manufacture of a fulvestrant pharmaceutical formulation, wherein preferably, the fulvestrant pharmaceutical formulation comprises, but is not limited to a tablet, a granule, a capsule, a pellet, an oral liquid and an injection; preferably, the tablet comprises, but is not limited to one or more of a sustained-release tablet, an osmotic pump tablet and an orally disintegrating tablet; and preferably, the injection can be a liquid injection, a powder for injection or a tablet for injection; for example, the liquid injection can be a suspension, such as an aqueous suspension or an oily suspension; for example, the powder for injection is a freeze-dried powder injection.

9. The use according to claim 8, wherein the injection is a long-acting injection, wherein preferably, the long-acting injection is an aqueous suspension, an oily suspension or a powder for suspension.

10. A fulvestrant pharmaceutical formulation comprising the fulvestrant pharmaceutical composition according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0067] FIG. 1 shows a particle size morphology of the fulvestrant solid particles before grinding in Example 1, on a 100 μm scale;

[0068] FIG. 2 shows a particle size morphology of the fulvestrant solid particles after grinding for 5 min in Example 1, on a 10 μm scale;

[0069] FIG. 3 shows a particle size morphology of the fulvestrant solid particles after grinding for 7 min in Example 1, on a 10 μm scale;

[0070] FIG. 4 shows a particle size morphology of the fulvestrant solid particles before grinding in Example 2, on a 100 μm scale;

[0071] FIG. 5 shows a particle size morphology of the fulvestrant solid particles after grinding for 30 min in Example 2, on a 10 μm scale;

[0072] FIG, 6 shows a particle size morphology of the fulvestrant solid particles after grinding for 1 h in Example 2, on a 10 μm scale;

[0073] FIG. 7 shows a particle size morphology of the fulvestrant solid particles after grinding for 2 h in Example 2, on a 10 μm scale;

[0074] FIG. 8 shows a particle size morphology of the fulvestrant solid particles after grinding for 4 h in Example 2, on a 10 μm scale;

[0075] FIG. 9 shows an XRPD pattern of the fulvestrant solid particles before grinding in Example 3, wherein instrument model is Bruker D8 Advance X-ray diffractometer, and test condition is Target: Cu 40 kv 40 mA;

[0076] FIG. 10 shows XRPI) patterns of the fulvestrant solid particles in the suspensions after grinding in Example 3 after being placed at 60° C. for 20 days, at 40° C. for 20 days, at 40° C. for 30 days. at 25° C. for 30 days, at 4° C. for 30 days and at −20° C. for 30 days, respectively; wherein,

[0077] 1 represents the XRPD pattern of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 60° C. for 20 days;

[0078] 2 represents the XRPD pattern of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 40° C. for 30 days;

[0079] 3 represents the XRPD pattern of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 40° C. for 20 days;

[0080] 4 represents the XRPD pattern of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 25° C. for 30 days;

[0081] 5 represents the XRPD pattern of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 4° C. for 30 days; and

[0082] 6 represents the XRPD pattern of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at −20° C. for 30 days.

[0083] FIG. 11 shows a polarized light photomicrograph of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 60° C. for 20 days, on a 10 μm scale;

[0084] FIG. 12 shows a polarized light photomicrograph of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 40° C. for 20 days, on a 10 μm scale;

[0085] FIG. 13 shows a polarized light photomicrograph of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 40° C. for 30 days, on a 10 μm scale;

[0086] FIG. 14 shows a polarized light photomicrograph of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 25° C. for 30 days, on a 10 μm scale:

[0087] FIG. 15 shows a polarized light photomicrograph of the fulvestrant solid particles in the suspension after grinding in Example 3 after being placed at 4° C. for 30 days, on a 10 μm scale;

[0088] FIG. 16 shows a polarized light photomicrograph of the fulvestrant solid particles in the suspension after grinding in Example 4, on a 10 μm scale;

[0089] FIG. 17 shows a polarized light photomicrograph of the fulvestrant solid particles in the suspension after grinding in Example 5, on a 10 μm scale;

[0090] FIG. 18 shows a polarized light photomicrograph of the fulvestrant solid particles in the suspension after grinding in Example 6, on a 10 μm scale;

[0091] FIG. 19 shows particle size distribution of the fulvestrant solid particles in the suspension after grinding in Example 7;

[0092] FIG. 20 shows a particle size morphology of the fulvestrant solid particles in the suspension after grinding in Example 7, on a 10 μm scale;

[0093] FIG. 21 shows particle size distribution of the fulvestrant solid particles in the suspension after grinding in Example 8;

[0094] FIG. 22 shows a particle size morphology of the fu vestra.nt solid particles in the suspension after grinding in Example 8, on a 10 μm scale;

[0095] FIG. 23 shows particle size distribution of the fulvestrant solid particles in the suspension after grinding in Example 9;

[0096] FIG. 24 shows a particle size morphology of the fulvestrant solid particles in the suspension after grinding in Example 9, on a 10 μm scale;

[0097] FIG. 25 shows pharmacokinetic profiles of fulvestrant in formulation No. 1 of Example 11 (i.e., marketed comparative fulvestrant formulation); wherein

[0098] represents the pharmacokinetic profile in animal 1;

[0099] represents the pharmacokinetic profile in animal 2;

[0100] represents the pharmacokinetic profile in animal 3;

[0101] represents the pharmacokinetic profile in animal 4;

[0102] represents the pharmacokinetic profile in animal 5; and

[0103] represents the pharmacokinetic profile in animal 6;

[0104] FIG. 26 shows pharmacokinetic profiles of fulvestrant in formulation No. 2 of Example 11; wherein

[0105] represents the pharmacokinetic profile in animal 1;

[0106] represents the pharmacokinetic profile in animal 2;

[0107] represents the pharmacokinetic profile in animal 3;

[0108] represents the pharmacokinetic profile in animal 4;

[0109] represents the pharmacokinetic profile in animal 5; and

[0110] represents the pharmacokinetic profile in animal 6;

[0111] FIG. 27 shows pharmacokinetic profiles of fulvestrant in formulation No. 3 of Example 11; wherein

[0112] represents the pharmacokinetic profile in animal 1;

[0113] represents the pharmacokinetic profile in animal 2;

[0114] represents the pharmacokinetic profile in animal 3;

[0115] represents the pharmacokinetic profile in animal 4;

[0116] represents the pharmacokinetic profile in animal 5; and

[0117] represents the pharmacokinetic profile in animal 6;

[0118] FIG. 28 shows pharmacokinetic profiles of fulvestrant in formulation No. 4 of Example 11; wherein

[0119] represents the pharmacokinetic profile in animal 1;

[0120] represents the pharmacokinetic profile in animal 2;

[0121] represents the pharmacokinetic profile in animal 3;

[0122] represents the pharmacokinetic profile in animal 4;

[0123] represents the pharmacokinetic profile in animal 5; and

[0124] represents the pharmacokinetic profile in animal 6; and

[0125] FIG. 29 shows mean pharmacokinetic profiles of fulvestrant in formulation No. 1 i.e. the marketed comparative fulvestrant formulation) and formulation Nos. 2, 3 and 4; wherein

[0126] represents the mean pharmacokinetic profile of fulvestrant in formulation No. 1;

[0127] represents the mean pharmacokinetic profile of fulvestrant in formulation No. 2;

[0128] represents the mean pharmacokinetic profile of fulvestrant in formulation No. 3; and

[0129] represents the mean pharmacokinetic profile of fulvestrant in formulation No. 4.

DETAILED DESCRIPTION

[0130] The technical scheme of the present disclosure will be further illustrated in detail with reference to the following specific examples. It should be understood that the following examples are merely exemplary illustration and explanation of the present disclosure, and should not be construed as limiting the protection scope of the present disclosure. All techniques implemented based on the above contents of the present disclosure are encompassed within the protection scope of the present disclosure.

[0131] Unless otherwise stated, the starting materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

[0132] Unless otherwise specified, the particle sizes described in the following examples are all particle sizes Dv weighted by volume.

EXAMPLE 1

[0133]

TABLE-US-00001 TABLE 1 Formula of the suspension injection of Example 1 Component Ratio (%, W/W) Feeding amount (g) Fulvestrant 18.09 1.94 Tween 80 1.67 0.18 Sterile water for injection 80.24 8.60

[0134] According to the formula as shown in Table 1, 0.18 g of tween 80 was weighed, and 1.94 g of fulvestrant solid particles were added, followed by the addition of 8.60 g of sterile water for injection, and the mixture was stirred and mixed well to obtain a premixed solution.

[0135] The premixed solution and 118.5 g of 1 mm zirconium beads were added into a grinding jar (the volume ratio of the premixed solution to the zirconium beads is 1:3) for grinding to obtain the fulvestrant pharmaceutical composition as a suspension injection.

[0136] The grinding was performed in a ball mill, and the parameters of the planetary ball mill were set as follows: fixed parameters: the diameter of the revolution plate: about 191 mm, the diameter of the rotation cup: about 71 mm, the height of the rotation cup: about 70 mm, the capacity of the rotation cup: 100 mL, the revolution speed of the revolution plate: 10 r/min, and the rotation speed: 720 r/min.

[0137] After the determination using a laser particle analyzer (the parameters were set as follows: the dispersion medium: water, the refractive index of the dispersion medium: 1.333, the absorbance of the sample material: 0.01, and the refractive index of the sample material: 1.521), the particle size distribution of the fulvestrant solid particles in the suspension is shown in Table 2. The particle size morphology of the fulvestrant solid particles in the suspension before grinding is shown in FIG. 1, the particle size morphology of the fulvestrant solid particles after grinding for 5 min is shown in FIG. 2, and the particle size morphology of the fulvestrant solid particles after grinding for 7 min is shown in FIG. 3.

TABLE-US-00002 TABLE 2 Particle size distribution of fulvestrant in the suspension of Example 1 No. D10 (μm) D25 (μm) D50 (μm) D75 (μm) D90 (μm) Example 1 1.794 2.284 2.939 3.68 4.279

EXAMPLE 2

[0138]

TABLE-US-00003 TABLE 3 Formula of the suspension injection of Example 2 Component Ratio (%, W/W) Feeding amount (g) Fulvestrant 19.59 0.98 Tween 80 1.74 0.09 Sterile water for injection 78.67 3.94

[0139] According to the formula as shown in Table 3. 0.09 g of tween 80 was weighed, and 0.98 g of fulvestrant solid particles were added, followed by the addition of 3.94 g of sterile water for injection, and the mixture was stirred and mixed well to obtain a premixed solution.

[0140] The premixed solution and 60.00 g of 1 mm zirconium beads were added into a grinding jar (the volume ratio of the premixed solution to the zirconium beads is 1:3) for grinding for 7 h to obtain the fulvestrant pharmaceutical composition as a suspension injection. The grinding was performed in a ball mill, and the parameters of the planetary ball mill were set as follows: fixed parameters: the diameter of the revolution plate: about 191 mm, the diameter of the rotation cup: about 71 mm, the height of the rotation cup: about 70 mm, the capacity of the rotation cup: 100 mL, the revolution speed of the revolution plate: 10 r/min, and the rotation speed: 720 r/min.

[0141] After the determination using a laser particle analyzer (the parameters were set as follows: the dispersion medium: water, the refractive index of the dispersion medium: 1.333, the absorbance of the sample material: 0.01, and the refractive index of the sample material: 1.521), the particle size distribution of the fulvestrant solid particles in the suspension after grinding for different periods of time is shown in Table 4. The particle size morphology of the fulvestrant solid particles in the suspension before grinding is shown in FIG. 4, the particle size morphology of the fulvestrant solid particles after grinding for 30 min is shown in HG. 5, the particle size morphology of the fulvestrant solid particles after grinding for 1 h is shown in FIG. 6, the particle size morphology of the fulvestrant solid particles after grinding for 2 h is shown in FIG. 7, and the particle size morphology of the fulvestrant solid particles after grinding for 4 h is shown in FIG. 8.

TABLE-US-00004 TABLE 4 Particle size distribution of fulvestrant in the suspension of Example 2 Grinding time D10 (μm) D25 (μm) D50 (μm) D75 (μm) D90 (μm) 1 hr 1.215 1.764 2.468 3.238 4.012 4 hrs 1.010 1.376 1.887 2.463 3.027

EXAMPLE 3

[0142]

TABLE-US-00005 TABLE 5 Formula of the suspension injection of Example 3 Component Ratio (%, W/W) Feeding amount (g) Fulvestrant 24.66  7.51 Tween 20 1.62 0.492 Sodium carboxymethylcellulose 1.00 0.30 Mannitol 2.82 22.00 Anhydrous sodium 0.42 dihydrogen phosphate Sodium hydroxide q.s. to pH 7.4 Sterile water for injection q.s. to 100

[0143] According to the formula as shown in Table 5, 0.492 g of tween 20 was weighed, and 7.51 g of fulvestrant solid particles were added, followed by the addition of 4% mannitol-pH 7,4 anhydrous sodium dihydrogen phosphate solution to make up to 30 g (the percentage here refers to the percentage of the mass of mannitol to the total volume of mannitol-pH 7.4 anhydrous sodium dihydrogen phosphate solution), and the mixture was stirred and mixed well to obtain a premixed solution.

[0144] The premixed solution and 97.6 g of 0.3 mm zirconium beads were added into a grinding jar (the volume ratio of the premixed solution to the zirconium beads is 1:1) for grinding for 3 h to obtain the fulvestrant pharmaceutical composition as a suspension injection. The grinding was performed in a ball mill, and the parameters of the planetary ball mill were set as follows: fixed parameters: the diameter of the revolution plate: about 191 mm, the diameter of the rotation cup: about 71 mm, the height of the rotation cup: about 70 mm, the capacity of the rotation cup: 100 mL, the revolution speed of the revolution plate: 10 r/min, and the rotation speed: 720 r/min.

[0145] After the determination using a laser particle analyzer (the parameters were set as follows: the dispersion medium: water, the refractive index of the dispersion medium: 1.333, the absorbance of the sample material: 0.01, and the refractive index of the sample material: 1.521), the particle size distribution of the fulvestrant solid particles in the suspension after grinding for different periods of time is shown in Table 6. After grinding, 0.30 g of CMC-Na (sodium carboxymethylcellulose) was added and the mixture was fully stirred and mixed well. The sample was taken out and filtered to remove the grinding beads. The filtrate was subpackaged into vials and capped, placed in aluminum foil packages and stored at 4° C. away from the light.

TABLE-US-00006 TABLE 6 Particle size distribution of fulvestrant in the suspension of Example 3 Grinding time D10 (μm) D25 (μm) D50 (μm) D75 (μm) D90 (μm )  0 min 5.837 11.177 20.476 39.125 83.029 10 min 1.315 1.75 2.327 2.99 3.639  1 hr 1.054 1.457 2.051 2.664 3.254  4 hrs 0.903 1.27 1.983 2.823 3.644

[0146] Stability test on the fulvestrant suspensions prepared in Examples 1-3 The fulvestrant suspensions prepared in Examples 1 and 2 were stored in a refrigerator at 4° C. for 14 days or 10 days, and tested for related substances. The results are shown in Table 7.

[0147] The fulvestrant suspension prepared in Example 3 was placed at −20° C., 4° C., 25° C., 40° C. or 60° C., and tested for related substances, the morphology, particle size distribution and crystalline form changes of the fulvestrant solid particles. The results are shown in Tables 8 and 9. The XPRD test patterns are shown in FIGS. 9 and 10. The particle size morphology of the fulvestrant solid particles is shown in FIGS. 11-15. The test for the related substances was performed according to the EP10.0 method.

TABLE-US-00007 TABLE 8 Related substances in the fulvestrant suspension prepared in Example 3 after being placed at different temperatures Placement Peak area (%, RRT) Main RRT RRT RRT RRT Total conditions peak 0.93 1.21 1.28 1.48 impurities 4° C., 30 days 99.73 0.06 0.05 0.02 0.03 0.27 −20° C., 30 99.73 0.06 0.05 0.02 0.04 0.28 days 25° C., 30 days 99.73 0.06 0.05 0.02 0.04 0.29 40° C., 20 days 99.70 0.06 0.05 0.02 0.04 0.30 40° C., 30 days 99.73 0.06 0.05 0.02 0.01 0.26 60° C., 20 days 99.65 0.07 0.05 0.03 0.03 0.36

TABLE-US-00008 TABLE 9 Particle size distribution in the fulvestrant suspension prepared in Example 3 after being placed at different temperatures Placement conditions D10 (μm) 1025 (μm) D50 (μm) D75 (μm) D90 (μm) 60° C., 20 days 0.904 1.082 1.28 1.525 1.737 40° C., 30 days 1.738 2.373 3.215 4.116 5.048 25° C., 30 days 2.206 2.769 3.473 4.229 5.073  4° C., 30 days 1.347 1.973 2.777 3.601 4.325  4° C., 40 days 0.909 1.325 1.822 2.385 2.934

[0148] The test results of the related substances showed that the related substances in the suspension were slightly increased after grinding; after being placed under different conditions, the related substances in the suspension were not significantly increased. The maximum content of single impurities was 0.07% and the maximum content of total impurities was 0.36% under all conditions, so that the quality standards were met.

TABLE-US-00009 TABLE 7 Related substances in the fulvestrant suspension prepared in Examples 1 and 2 after being placed at 4 °C Peak area (%), placed at 4° C. Main RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT Total No. peak 0.25 0.36 0.39 0.43 0.51 0.88 1.15 1.19 1.39 1.49 1.63 1.88 2.49 2.85 2.92 impurities Fulvestrant 99.84 / / / / 0.01 0.05 / 0.04 / / / / / / 0.03 0.05 solid particle starting material Fulvestrant 99.78 / / / 0.02 0.01 0.05 / 0.03 / 0.02 0.03 / / / 0.02 0.13 suspension prepared in Example 1 14 days Fulvestrant 99.59 0.01 / / 0.16 / 0.05 / 0.03 / 0.03 0.03 / / / 0.02 0.3 suspension prepared in Example 2 10 days

[0149] It can be seen from the particle size morphology (PLM) of FIGS. 11-15 that the morphology of fulvestrant solid particles in the samples remained unchanged under all conditions, and no significant increase in the particle size was found except for the aggregation of a small amount particles in some of the samples. Laser particle size analysis showed that the particle size of the fulvestrant solid particles in the suspensions did not exceed 5 μm under all conditions, was slightly increased at 25° C. and 40° C. (possibly related to the aggregation of the sample particles, but single particles remained unchanged), and was slightly reduced at 60° C.

[0150] The XRPD results of FIGS. 9 and 10 showed that the crystalline forms of the fulvestrant solid particles in the suspensions under different conditions were consistent with the initial fulvestrant solid particles, suggesting that there is no change in the crystalline form of the fulvestrant solid particles.

EXAMPLE 4

[0151]

TABLE-US-00010 TABLE 10 Formula of the suspension injection of Example 4 Component Ratio (%, W/W) Feeding amount (g) Fulvestrant 25.00  5.00 Tween 20 1.62 0.333 Sodium carboxymethylcellulose 1.00 0.20 Mannitol 2.89 14.467 Anhydrous sodium dihydrogen 0.43 phosphate Sodium hydroxide q.s. to pH 7.4 Sterile water for injection q.s. to 100

[0152] According to the formula as shown in Table 10, 0.333 g of tween 20 was weighed, and 5.00 g of fulvestrant solid particles were added, followed by the addition of 4% mannitol-pH 7.4 anhydrous sodium dihydrogen phosphate solution to make up to 19.80 g (the percentage here refers to the percentage of the mass of mannitol to the total volume of mannitol-pH 7.4 anhydrous sodium dihydrogen phosphate solution), and the mixture was stirred and mixed well to obtain a premixed solution.

[0153] The premixed solution and 97.5 g of 0.3 mm zirconium beads were added into a grinding jar (the volume ratio of the premixed solution to the zirconium beads is 2:3) for grinding for 27 h to obtain the fulvestrant pharmaceutical composition as a suspension injection. The grinding was performed in a ball mill, and the parameters of the planetary ball mill were set as follows: fixed parameters: the diameter of the revolution plate: about 191 mm, the diameter of the rotation cup: about 71 mm, the height of the rotation cup: about 70 mm, the capacity of the rotation cup: 100 mL, the revolution speed of the revolution plate: 10 r/min, and the rotation speed: 720 r/min.

[0154] After the determination using a laser particle analyzer (the parameters were set as follows: the dispersion medium: water, the refractive index of the dispersion medium: 1.333, the absorbance of the sample material: 0.01, and the refractive index of the sample material: 1.521), the particle size distribution of the fulvestrant solid particles in the suspension after grinding for different periods of time is shown in Table 11. The particle size morphology of the fulvestrant solid particles in the suspension after grinding is shown in FIG. 16.

TABLE-US-00011 TABLE 11 Particle size distribution of fulvestrant in the suspension of Example 4 Grinding time D10 (μm) D25 (μm) D50 (μm) D75 (μm) D90 (μm)  2 min 1.799 2.362 3.29 4.341 5.353  5 min 1.737 2.236 2.967 3.781 4.524 10 min 1.597 2.058 2.699 3.397 4.116 30 min 1.452 1.889 2.477 3.137 3.806   1 hr 1.351 1.772 2.355 3.025 3.682 1.5 hrs 1.211 1.629 2.153 2.73 3.3   3 hrs 0.854 1.075 1.346 1.639 1.967   6 hrs 0.914 1.094 1.304 1.551 1.795   9 hrs 0.871 0.985 1.145 1.301 1.503  12 hrs 0.894 1.026 1.171 1.328 1.534  27 hrs 0.91 1.056 1.202 1.397 1.587

EXAMPLE 5

[0155]

TABLE-US-00012 TABLE 12 Formula of the suspension injection of Example 5 Component Ratio (%, W/W) Feeding amount (g) Fulvestrant 25 5.00 Tween 20 1.62 0.324 Sodium carboxymethylcellulose 1.00 0.20 Mannitol 2.89 14.476 Anhydrous sodium dihydrogen 0.43 phosphate Sodium hydroxide q.s. to pH 7.4 Sterile water for injection q.s. to 100

[0156] According to the formula as shown in Table 12, 0.324 g of tween 20 was weighed, and 5.00 g of fulvestrant solid particles were added, followed by the addition of 4% mannitol-pH 7.4 anhydrous sodium dihydrogen phosphate solution to make up to 19.80 g (the percentage here refers to the percentage of the mass of mannitol to the total volume of mannitol-pH 7.4 anhydrous sodium dihydrogen phosphate solution), and the mixture was stirred and mixed well to obtain a. premixed solution.

[0157] The premixed solution and 111.6 g of 0.6 mm zirconium beads were added into a grinding jar (the volume ratio of the premixed solution to the zirconium beads is 2:3) for grinding for 27 h to obtain the fulvestrant pharmaceutical composition as a suspension injection. The grinding was performed in a ball mill, and the parameters of the planetary ball mill were set as follows: fixed parameters: the diameter of the revolution plate: about 191 mm, the diameter of the rotation cup: about 71 mm, the height of the rotation cup: about 70 mm, the capacity of the rotation cup: 100 mL, the revolution speed of the revolution plate: 10 r/min, and the rotation speed: 720 r/min.

[0158] After the determination using a laser particle analyzer (the parameters were set as follows: the dispersion medium: water, the refractive index of the dispersion medium: 1.333, the absorbance of the sample material: 0.01, and the refractive index of the sample material: 1.521), the particle size distribution of the fulvestrant solid particles in the suspension after grinding for different periods of time is shown in Table 13, The particle size morphology of the fulvestrant solid particles in the suspension after grinding is shown in FIG. 17.

TABLE-US-00013 TABLE 13 Particle size distribution of fulvestrant in the suspension of Example 5 Grinding time D10 (μm) D25 (μm) D50 (μm) D75 (μm) D90 (μm)  3 hrs 0.882 1.075 1.307 1.581 1.881  6 hrs 0.841 0.98 1.207 1.509 1.841  9 hrs 0.886 1.074 1.29 1.551 1.816 12 hrs 0.915 1.093 1.307 1.561 1.825 27 hrs 0.92 1.075 1.241 1.469 1.644

EXAMPLE 6

[0159]

TABLE-US-00014 TABLE 14 Formula of the suspension injection of Example 6 Component Ratio (%, W/W) Feeding amount (g) Fulvestrant 25 5.00 Tween 20 1.62 0.328 Sodium carboxymethylcellulose 1.00 0.20 Mannitol 2.89 14.472 Anhydrous sodium 0.43 dihydrogen phosphate Sodium hydroxide q.s. to pH 7.4 Sterile water for injection q.s. to 100

[0160] According to the formula as shown in Table 14, 0.328 g of tween 20 was weighed, and 5.0 g of fulvestrant solid particles were added, followed by the addition of 4% mannitol-pH 7.4 anhydrous sodium dihydrogen phosphate solution to make up to 19.80 g (the percentage here refers to the percentage of the mass of mannitol to the total volume of mannitol-pH 7.4 anhydrous sodium dihydrogen phosphate solution), and the mixture was stirred and mixed well to obtain a premixed solution.

[0161] The premixed solution and 112.0 g of 1.0 mm zirconium beads were added into a grinding jar (the volume ratio of the premixed solution to the zirconium beads is 2:3) for grinding for 27 h to obtain the fulvestrant pharmaceutical composition as a suspension injection. The grinding was performed in a ball mill, and the parameters of the planetary ball mill were set as follows: fixed parameters: the diameter of the revolution plate: about 191 mm, the diameter of the rotation cup: about 71 mm, the height of the rotation cup: about 70 mm, the capacity of the rotation cup: 100 mL, the revolution speed of the revolution plate: 10 r/min, and the rotation speed: 720 r/min.

[0162] After the determination using a laser particle analyzer (the parameters were set as follows: the dispersion medium: water, the refractive index of the dispersion medium: 1.333, the absorbance of the sample material: 0.01, and the refractive index of the sample material: 1.521), an appropriate amount of the suspension was weighed, and tested for the fulvestrant content and related substances according to the EP10.0 method. The particle size distribution of the fulvestrant solid particles in the suspensions after grinding for different periods of time is shown in Table 15. The particle size morphology of the fulvestrant solid particles in the suspension after grinding is shown in FIG. 18.

TABLE-US-00015 TABLE 15 Particle size distribution of fulvestrant in the suspension of Example 6 Grinding time D10 (μm) D25 (μm) D50 (μm) D75 (μm) D90 (μm)  3 hrs 0.838 1.041 1.388 1.87 2.376  6 hrs 0.852 1.059 1.416 1.904 2.406  9 hrs 0.906 1.087 1.327 1.629 1.969 12 hrs 0.976 1.168 1.43 1.708 2.007 27 hrs 1.058 1.235 1.493 1.795 2.058

EXAMPLE 7

[0163]

TABLE-US-00016 TABLE 16 Formula of the suspension injection of Example 7 Component Ratio (%, w/w) Fulvestrant 25.00 Tween 20 1.62 Sodium 0.20 carboxymethylcellulose Mannitol 2.29 Anhydrous sodium 0.09 dihydrogen phosphate Anhydrous disodium 0.42 hydrogen phosphate Sterile water for injection q.s. 100 (70.38)

[0164] According to the formula as shown in Table 16, the raw and auxiliary materials were weighed and mixed well, followed by the addition of 1.5-fold volume of 0.6 mm zirconium beads, and the mixture was placed in a grinding jar for grinding for 3 h to obtain the fulvestrant pharmaceutical composition, which was recorded as batch 1. The grinding was performed in a ball mill, and the parameters of the planetary ball mill were set as follows: fixed parameters: the diameter of the revolution plate: about 191 mm, the diameter of the rotation cup: about 71 mm, the height of the rotation cup: about 70 mm, the capacity of the rotation cup: 100 mL, the revolution speed of the revolution plate: 10 r/min, and the rotation speed: 720 r/min.

[0165] After the determination using a laser particle analyzer (the parameters were set as follows: the dispersion medium: water, the refractive index of the dispersion medium: 1.333, the absorbance of the sample material: 0.01, and the refractive index of the sample material: 1.521), an appropriate amount of the suspension was weighed, and tested for the fulvestrant content and related substances according to the EP10.0 method. The content and particle size distribution of the fulvestrant solid particles in the suspension after grinding are shown in Table 17. The particle size distribution of the fulvestrant solid particles in the suspension after grinding is shown in FIG. 19 and the morphology of the fulvestrant solid particles in the suspension after grinding is shown in FIG. 20. The related substances are shown in Table 19.

EXAMPLE 8

[0166]

TABLE-US-00017 TABLE 18 Formula of the suspension injection of Example 8 Component Ratio (%, w/w) Fulvestrant 25.00 Tween 20 1.62 Sodium 0.20 carboxymethylcellulose Mannitol 2.29 Anhydrous sodium 0.09 dihydrogen phosphate Anhydrous disodium 0.42 hydrogen phosphate Sterile water for injection q.s. 100 (70.38)

[0167] According to the formula as shown in Table 18, the raw and auxiliary materials were weighed and mixed well, followed by the addition of 3-fold volume of 1 mm zirconium beads, and the mixture was placed in a grinding jar for grinding for 5 min to obtain the fulvestrant pharmaceutical composition, which was recorded as batch 2. The grinding was performed in a ball mill, and the parameters of the planetary ball mill were set as follows: fixed parameters: the diameter of the revolution plate: about 191 mm, the diameter of the rotation cup: about 71 mm, the height of the rotation cup: about 70 mm, the capacity of the rotation cup: 100 mL, the revolution speed of the revolution plate: 10 r/min, and the rotation speed: 720 r/min.

[0168] After the determination using a laser particle analyzer (the parameters were set as follows: the dispersion medium: water, the refractive index of the dispersion medium: 1.333, the absorbance of the sample material: 0.01, and the refractive index of the sample material: 1.521), an appropriate amount of the suspension was weighed, and tested for the fulvestrant content and related substances according to the EP10.0 method. The content and particle size distribution of the fulvestrant solid particles in the suspension after grinding are shown in Table 17. The particle size distribution of the fulvestrant solid particles in the suspension after grinding is shown in FIG. 21 and the morphology of the fulvestrant solid particles in the suspension after grinding is shown in FIG. 22. The related substances are shown in Table 19.

EXAMPLE 9

[0169]

TABLE-US-00018 TABLE 20 Formula of the suspension injection of Example 9 Component Ratio (%, w/w) Fulvestrant 25 Tween 20 1.62 Sodium 0.2 carboxymethylcellulose Mannitol 2.29 Anhydrous sodium 0.09 dihydrogen phosphate Anhydrous disodium 0.42 hydrogen phosphate Sterile water for injection q.s. 100 (70.38)

[0170] According to the formula as shown in Table 20, the raw and auxiliary materials were weighed and mixed well to obtain the fulvestrant pharmaceutical suspension, which was recorded as batch 3. The API was obtained by jet milling.

[0171] After the determination using a laser particle analyzer (the parameters were set as follows: the dispersion medium: water, the refractive index of the dispersion medium: 1.333, the absorbance of the sample material: 0.01, and the refractive index of the sample material: 1.521), an appropriate amount of the suspension was weighed, and tested for the fulvestrant content and related substances according to the EP10.0 method. The content and particle size distribution of the fulvestrant solid particles in the suspension are shown in Table 17. The particle size distribution of the fulvestrant solid particles in the suspension after grinding is shown in FIG. 23 and the morphology of the fulvestrant solid particles in the suspension after grinding is shown in FIG. 24. The related substances are shown in Table 19.

TABLE-US-00019 TABLE 17 API concentration, particle size and particle size distribution in the fulvestrant suspensions of Examples 7-9 Concentration Particle size (μm) Batch (mg/mL) Dv(10) Dv(25) Dv(50) Dv(75) Dv(90) 1 341.9 0.806 0.922 1.127 1.459 1.955 2 263.8 1.373 1.840 2.610 3.781 5.191 3 270.1 1.856 2.675 4.215 6.570 9.982

EXAMPLE 10

[0172] The formulations obtained in Examples 7, 8 and 9 (recorded as formulation Nos. 2, 3 and 4, respectively) and the marketed comparative formulation fulvestrant injection FASLODEX (5 mL: 250 mg, VETTER Pharma-fertigung GmbH & Co KG, Germany, lot No. RD693, expiration date: August, 2023, recorded as formulation No. 1) were used. The formulation Nos. 2, 3 and No. 1 were placed for the stability under long-term conditions (25 ±2° C., 60% +5% RH) and accelerated conditions (40±2° C., 75%±5% RH) as shown in Table 21, and tested for related substances of fulvestrant according to the EP10.0 method. The results are shown in Table 19, Meanwhile, the particle size and particle size distribution of the formulation Nos. 2 and 3 were also determined. The results are shown in Tables 22 and 23.

[0173] The stability results showed that the levels of the degradation impurities 6-keto fulvestrant and fulvestrant sulphone, the unknown single impurities and the total impurities in the self-made fulvestrant suspension were all lower than those of the comparative formulation fulvestrant injection FASLODEX under the same conditions, suggesting that the stability of the self-made fulvestrant suspension is superior to that of the marketed comparative formulation.

TABLE-US-00020 TABLE 21 Placement for the stability of the formulation Nos. 2 and 3 formulations and the comparative formulation Long-term conditions (25 ± 2° C., 60% ± 5% Accelerated conditions Sample RH) (40 ± 2° C., 75% ± 5% RH) Marketed comparative 1 month, 3 months 10 days, 30 days formulation Formulation Nos. 2 and 3 1 month, 3 months 1 month, 2 months, 3 months

TABLE-US-00021 TABLE 22 Particle size and particle size distribution in the fulvestrant suspension of Example 7 (formulation No. 2) Placement Particle size (μm) conditions Time Dv(10) Dv(25) Dv(50) Dv(75) Dv(90) 25 ± 2° C., Day 0 0.806 0.922 1.127 1.459 1.955 60% + 5% RH 1 month 0.852 1.094 1.518 2.087 2.647 3 months 0.747 0.930 1.252 1.777 2.334 40 ± 2° C., 1 month 0.797 0.916 1.119 1.457 1.962 75% ± 5% RH 2 months 0.759 0.923 1.168 1.493 1.857 3 months 0.852 1.038 1.262 1.540 1.822

TABLE-US-00022 TABLE 23 Particle size and particle size distribution in the fulvestrant suspension of Example 8 (formulation No. 3) Placement Particle size (μm) conditions Time Dv(10) Dv(25) Dv(50) Dv(75) Dv(90) 25 ± 2° C., Day 0 1.373 1.840 2.610 3.781 5.191 60% + 5% RH 1 month 1.624 2.132 2.877 3.788 4.727 3 months 1.328 1.645 2.215 3.221 3.662 40 ± 2° C., 1 month 1.642 2.195 3.152 4.357 5.541 75% ± 5% RH 2 months 1.484 1.995 2.682 3.442 4.194

TABLE-US-00023 TABLE 19 Related substances for the stability of Example 7 (formulation No. 2) and Example 8 (formulation No. 3) and the comparative formulation Single impurities (%) Fulvestrant Total Sample Placement 6-keto 6,7- Fulvestrant Fulvestrant bromo Fulvestrant Fulvestrant Other (%) name conditions Time fulvestrant* fulvestrant β-isomer sulphone* analogue extended sterol dimer maximum impurities Example 7 Long-term Day 0 ND ND ND ND ND ND ND 0.06 0.06 Fulvestrant  1 ND ND ND 0.02 ND ND ND 0.06 0.06 Suspension month  3 ND ND ND 0.04 ND ND ND 0.07 0.12 months Accelerated  1 ND ND ND 0.03 ND ND ND 0.06 0.06 month  2 ND ND ND 0.04 ND ND ND 0.07 0.12 months  3 0.01 ND ND 0.05 ND ND ND 0.07 0.17 months Example 8 Long-term Day 0 ND ND ND ND ND ND ND 0.06 0.06 Fulvestrant  1 ND ND ND 0.02 ND ND ND 0.06 0.06 Suspension month  3 ND ND ND 0.04 ND ND ND 0.06 0.11 months Accelerated  1 ND ND ND 0.03 ND ND ND 0.06 0.06 month  2 ND ND ND 0.05 ND ND ND 0.08 0.18 months  3 0.01 ND ND 0.06 ND ND ND 0.08 0.19 months FASLODEX Long-term Day 0 0.02 ND ND 0.16 ND ND ND 0.07 0.37 (LOT:  1 0.02 ND ND 0.17 ND ND ND 0.09 0.46 RD693) month  3 0.02 ND ND 0.19 ND ND ND 0.09 0.52 months Accelerated 10 0.02 ND ND 0.22 ND 0.04 ND 0.09 0.57 days  1 0.02 ND ND 0.16 ND ND ND 0.09 0.45 month Note: ND means not detected; *denotes the degradation product of fulvestrant; 6-keto fulvestrant, 6,7-fulvestrant, fulvestrant β-isomer, fulvestrant sulphone, fulvestrant bromine analogue, fulvestrant extended, and fulvestrant sterol dimer.

EXAMPLE 11

[0174] The formulations obtained in Examples 7, 8 and 9 (formulation Nos. 2, 3 and 4, respectively) were diluted to 50 mg/mL with a diluent. The diluent comprises the following components: 1.62% tween 20, 0.2% sodium carboxymethylcellulose, 2.29% mannitol, 0.09% anhydrous sodium dihydrogen phosphate, and 0.42% anhydrous disodium hydrogen phosphate. The diluted fulvestrant suspension and the marketed comparative formulation fulvestrant injection FASLODEX (i.e., the formulation No. 1, 50 mg/mL, VETTER, Pharma-fertigung GmbH & Co KG, Germany, lot No. RD693, expiration date: August, 2023) were intramuscularly injected at a fulvestrant dose of 15 mg/kg (0.3 mL/kg) into the lateral thigh of SPF-grade Wistar rats weighing 217-235 g and aged 6-9 weeks (Zhejiang Vital River Laboratory Animal Technology Co., Ltd., certificate No. 110011200105465684, license No. SYXK (Su) 2018-0034), 6 animals per group. Clinical observations were made after the administration, with 2 observations on the first day of administration (D1): before the administration and in the afternoon of the day after the administration, and 1 observation everyday thereafter for a total of 45 days. Clinical observations involve skin, hair, eyes, ears, nose, oral cavity, chest, abdomen, urogenital area, limbs and other sites, and comprise breath, movement, urination, defecation and behavioral changes as well as muscle irritation responses at the site of administration. In addition, blood samples were collected before the administration (0 h, D-1), and 1 h, 3 h, 7 h, 24 h, D4 (72 h), D7 (144 h), D11 (240 h), D15(336 h), D20 (456 h), D25 (576 h), D30 (696 h), D35 (816 h), D40 (936 h) and D45 (1056 h) after the D1 administration, bioanalysis was performed and pharmacokinetic parameters Tmax, Cmax, AUX (0-t), AUC (0-∞), T1/2, MRT, CL, Vz and the like of each group were calculated using a non-compartmental model of WinNolin version 8.1. On D45 after the administration, animals were dissected and the site of administration was histopathologically examined for inflammatory responses and drug residues.

[0175] No abnormalities were observed in clinical observations, body weight, irritation observation at the site of administration, and gross anatomy of the site of administration in all animal subjects in each dose group, no inflammation or drug residues were observed at the site of administration, and no abnormalities related to the administration of the test sample were observed in histopathological examination.

[0176] Pharmacokinetic parameters for 15 mg/kg fulvestrant formulation Nos. 1, 2, 3 and 4 (formulation No. 1 represents the marketed comparative fulvestrant formulation; formulation No. 2 represents the fulvestrant formulation prepared in Example 7, formulation No. 3 represents the fulvestrant formulation prepared in Example 8, and formulation No. 4 represents the fulvestrant formulation prepared in Example 9) intramuscularly injected into Wistar rats at a single dose are shown in Table 24. The pharmacokinetic profiles for 15 mg/kg fulvestrant formulation Nos. 1, 2, 3 and 4 intramuscularly injected into Wistar rats at a single dose are shown in FIGS. 25, 26, 27 and 28, respectively, and the mean pharmacokinetic profiles of the formulation Nos. 1, 2, 3 and 4 are shown in FIG, 29.

[0177] After 15 mg/kg formulation No. 1 (the marketed comparative fulvestrant formulation) was intramuscularly injected into Wistar rats at a single dose, the Cmax of fulvestrant in plasma was 13.5±4.32 ng/mL, the area under the drug concentration-time curve AUCINF_obs was 6350±949 h*ng/mL, AUClast was 5000±932 h*ng/mL, the drug's terminal elimination half-life T1/2_Z was 413±88.0 h, the clearance rate Cl ohs was 2410±433 mL/h/kg, the mean residence time MRTINF_obs was 641±136 h, and the distribution volume Vz_obs was 1,450,000±421,000 mL/kg.

[0178] After 15 mg/kg formulation No. 2 (the fulvestrant formulation prepared in Example 7) was intramuscularly injected into Wistar rats at a single dose, the Cmax of fulvestrant in plasma was 10.0±3.16 ng/mL, the area under the drug concentration-time curve AUCINIF_obs was 6990±2010 h*ng/mL, AUClast was 3490±745 h*ng/mL, the drug's terminal elimination half-life T1/2_Z was 776±300 h, the clearance rate Cl_obs was 2340±814 mL/h/kg, the mean residence time MRTINF_obs was 1310±443 h, and the distribution volume Vz_obs was 2,470,000±881,000 mL/kg.

[0179] After 15 mg/kg formulation No. 3 (the fulvestrant formulation prepared in Example 8) was intramuscularly-injected into Wistar rats at a single dose, the Cmax of fulvestrant in plasma was 8.10±2.89 ng/mL, the area under the drug concentration-time curve AUCINF_obs was 71,800±125.000 h*ng/mL, AUClast was 3970±701 h*ng/mL, the drug's terminal elimination half-life T1/2_Z was 12,300±23,900 h, the clearance rate Cl_obs was 655±398 mL/h/kg, the mean residence time MRTINF_obs was 18.000±34,500 h, and the distribution volume Vz_obs was 2,950,000±721,000 mL/kg.

[0180] After 15 mg/kg formulation No. 4 (the fulvestrant formulation prepared in Example 9) was intramuscularly injected into Wistar rats at a single dose, the Cmax of fulvestrant in plasma was 9.23±2.78 ng/mL, the area under the drug concentration-time curve AUCINF obs was 35,000±61,100 h*ng/mL, AUClast was 3280±518 h*ng/mL, the drug's terminal elimination half-life T1/2_Z was 5300±9230 h, the clearance rate Cl_obs was 1550±1150 mL/h/kg, the mean residence time MRTINF ohs was 7820±13,300 h, and the distribution volume Vz_obs was 3,170,000±571,000 mL/kg.

[0181] The results showed that after 15 mg/kg formulation was intramuscularly injected into Wistar rats at a single dose, the Cmax was ranked in descending order as the formulation No. 1>the formulation No. 2>the formulation No. 4>the formulation No. 3; the AUClast was ranked in descending order as the formulation No. 1>the formulation No. 3>the formulation No. 2>the formulation No. 4; the mean residence time MRTINF_obs was ranked in descending order as the formulation No. 3>the formulation No. 4>the formulation No. 2>the formulation No. 1; the distribution volume Vz_obs was ranked in descending order as the formulation No. 4>the formulation No. 3>the formulation No. 2>the formulation No. 1. It can be seen from the above comparison of the parameters that the formulation Nos. 2, 3 and 4 have longer MRTin vivo and larger distribution volume as compared to the formulation No. 1, suggesting that the in vivo sustained-release effect of the formulations of Examples 7-9 is significant.

TABLE-US-00024 TABLE 24 Pharmacokinetic parameters for 15 mg/kg fulvestrant suspensions of Examples 7-9 (formulation Nos. 2-4) and marketed comparative formulation intramuscularly injected into Wistar rats at a single dose Formulation No. 1 Formulation No. 2 CV CV Variables Unit N Mean SD (%) N Mean SD (%) AUClast h*ng/mL 6 5000 932 18.7 6 3490 745 21.3 Cmax ng/mL 6 13.5 4.32 32.1 6 10.0 3.16 31.5 MRT_obs h 6 641 136 21.3 6 1310 443 33.9 MRTlast h 6 357 29.5 8.25 6 440 42.3 9.62 *Tmax h 6 7.00 15.5 24.0 6 1.00 2.00 7.00 Vz_F_obs mL/kg 6 1,450,000 421,000 29.1 6 2,470,000 881,000 35.6 Formulation No. 3 Formulation No. 4 CV CV Variables Unit N Mean SD (%) N Mean SD (%) AUClast h*ng/mL 6 3970 701 17.6 6 3280 518 15.8 Cmax ng/mL 6 8.10 2.89 35.7 6 9.23 2.78 30.1 MRT_obs h 6 18,000 34,500 192 6 7820 13,300 170 MRTlast h 6 518 13.6 2.63 6 505 36.7 7.26 *Tmax h 6 1.00 3.00 3.00 6 1.00 1.00 1.00 Vz_F_obs mL/kg 6 2,950,000 721,000 24.5 6 3,170,000 571,000 18.0

[0182] Examples of the present disclosure have been described above. However, the present disclosure is not limited to the above examples. Any modification, equivalent, improvement and the like made without departing from the spirit and principle of the present disclosure shall fall within the protection scope of the present disclosure.